Fluorodeoxyglucose Positron Emission Tomography Scans Research Articles

Only strongly enhanced residual FDG uptake in early response PET (Deauville 5 or qPET ≥ 2) is prognostic in pediatric Hodgkin lymphoma: Results of the GPOH‐HD2002 trial

In 2014, we published the qPET method to quantify fluorodeoxyglucose positron emission tomography (FDG-PET) responses. Analysis of the distribution of the quantified signals suggested that a clearly abnormal FDG-PET response corresponds to a visual Deauville score (vDS) of 5 and high qPET values ≥ 2. Evaluation in long-term outcome data is still pending. Therefore, we analyzed progression-free survival (PFS) by early FDG-PET response in a subset of the GPOH-HD2002 trial for pediatric Hodgkin lymphoma (PHL). Pairwise FDG-PET scans for initial staging and early response assessment after two cycles of chemotherapy were available in 93 PHL patients. vDS and qPET measurement were performed and related to PFS. Patients with a qPET value ≥ 2.0 or vDS of 5 had 5-year PFS rates of 44%, respectively 50%. Those with qPET values<2.0 or vDS 1 to 4 had 5-year PFS rates of 90%, respectively 80%. The positive predictive value of FDG-PET response assessment increased from 18% (9%; 33%) using a qPET threshold of 0.95 (vDS ≤ 3) to 30% (13%; 54%) for a qPET threshold of 1.3 (vDS ≤ 4) and to 56% (23%; 85%) when the qPET threshold was ≥ 2.0 (vDS 5). The negative predictive values remained stable at ≥92% (CI: 82%; 98%). Only strongly enhanced residual FDG uptake in early response PET (vDS 5 or qPET ≥ 2, respectively) seems to be markedly prognostic in PHL when treatment according to the GPOH-HD-2002 protocol is given.

Normal patterns of regional brain 18F-FDG uptake in normal aging.

Normal aging alters the brain function even in the absence of recognizable structural changes, which can be detected using modern in vivo functional imaging modalities such as fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) scan. It is highly important to recognize normal age-dependent changes in order to correctly diagnose pathologic states. The goal of the current study was to evaluate the age-related changes in regional brain 18F-FDG uptake in normal healthy population. This study was part of the cardiovascular molecular calcification assessed by 18F-sodium fluoride (NaF) (CAMONA) PET/computed tomography (CT) study. This study was approved by the Danish National Committee on Health Research Ethics registered at ClinicalTrials.gov (NCT01724749). Forty normal healthy subjects were prospectively recruited in group A (22-32 years) and B (56-75 years) and underwent 18F-FDG PET/CT. Static images were obtained 180 minutes following 18F-FDG injection. Supratentorial (including individual measurements for frontal, parieto-occipital and temporal lobes) and cerebellar 18F-FDG uptakes were measured by manual placement of region of interest (ROI) over these regions based on predefined criteria for each and standardized uptake value (SUVmean) values were calculated using OsiriX software. The mean ages of the patients in group A was 26.1±3.4 versus 61±4.4 for group B. There were 10 females in group A and 10 females in group B. Mean SUV of cerebellum was 6.80±1.21 for the young subjects compared to 6.08±0.7 among old subjects (independent t-test, P=0.028). Mean SUV of supratentorial brain was 9.14±1.83 for the young subjects compared to 6.92±072 among old subjects (P<0.001). Mean SUV of frontal (9.72±1.97 vs. 7.03±0.69), temporal (7.37±1.52 vs. 5.65±0.68) and parieto-occipital region (10.7±2.28 vs. 7.41±0.79) was higher among young patients (P<0.001). More interestingly, SUVmean of supratentorial brain was significantly higher among female healthy volunteers in both groups (P= 0.025 and 0.047 for group A and B, respectively). In conclusion, these findings confirm a significant age dependent reduction of supratentorial 18F-FDG uptake among healthy individuals. However, cerebellum 18F-FDG uptake reduction was not so redundant. Fluorine-18-FDG uptake of all cerebral lobes including frontal, parieto-occipital and temporal decreases with normal aging in a same fashion. Interestingly, among both young and old female subjects, higher uptake was seen in supratentorial brain.

ACTR-51. PHASE 2 STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS AND CLINICAL ACTIVITY OF PI3K/MTOR INHIBITOR GDC-0084 GIVEN TO GLIOBLASTOMA (GBM) PATIENTS WITH UNMETHYLATED O6-METHYLGUANINE-METHYLTRANSFERASE PROMOTER STATUS

BACKGROUND GDC-0084 is a potent, oral, selective small molecule inhibitor of class I phosphoinositide 3-kinase and mammalian target of rapamycin (PI3K/mTOR) efficacious in GBM models driven by activation of the PI3K pathway. GDC-0084 crosses the blood-brain barrier (BBB) and achieves a brain / plasma ratio of approximately 1.0 in three animal species. GDC-0084 was given as once daily oral dosing in a phase 1 study (Wen et al, J Clin Oncol 34, 2016(15) suppl.2012; {type:clinical-trial,attrs:{text:NCT01547546,term_id:NCT01547546}}NCT01547546) in 47 patients with recurrent high-grade gliomas. The adverse events were generally consistent with the established Class I PI3K/mTOR inhibitor class-effects. GDC-0084 was rapidly absorbed and demonstrated linear- and dose-proportional increases in exposure. The MTD was determined to be 45 mg once daily, with 7/8 patients receiving this dose having drug exposures consistent with anti-tumor activity in pre-clinical models. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scans suggested that GDC-0084 crossed the BBB, with a uniform distribution throughout the brain. The current phase 2 study will investigate the efficacy and safety of GDC 0084 in patients with newly diagnosed GBM, with unmethylated O6-methylguanine-methyltransferase (MGMT) promoter status.

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Can 11C-PiB-PET Relative Delivery R1 or 11C-PiB-PET Perfusion Replace 18F-FDG-PET in the Assessment of Brain Neurodegeneration?

Background:Pittsburgh Compound B (PiB) positron emission tomography (PET) is used to visualize in vivo amyloid plaques in the brain. Frequently the PiB examinations are complemented with a fluorodeoxyglucose (FDG) PET scan to further assess neurodegeneration.Objective:Our goal is to identify alternative correlates of FDG images by assessing which kinetic methods originate PiB derived relative delivery ratio (R1) images that can be correlated with the FDG images, and to compare them with PiB perfusion (pPiB) images obtained from the early-phase of PiB acquisition.Methods:We selected 52 patients with cognitive impairment who underwent a dynamic PiB and FDG acquisitions. To compute the R1 images, two simplified reference tissue models (SRTM and SRTM2) and two multi-linear reference tissue models (MRTM and MRTM2) were used. The pPiB images were obtained in two different time intervals.Results:All six types of images were of good quality and highly correlated with the FDG images (mean voxelwise within-subjects r > 0.92). The higher correlation was found for FDG-R1(MRTM). Regarding the voxelwise regional correlation, the higher mean all brain correlations was r = 0.825 for FDG-R1(MRTM) and statistically significant in the whole brain analysis.Conclusion:All R1 and pPiB images here tested have potential to assess the metabolic impact of neurodegeneration almost as reliably as the FDG images. However, this is not enough to validate these images for a single-subject analysis compared with the FDG image, and thus they cannot yet be used clinically to replace the FDG image before such evaluation.

The use of Deauville 5-point score could reduce the risk of false-positive fluorodeoxyglucose-positron emission tomography in the posttherapy evaluation of patients with primary bone lymphomas.

Primary bone lymphoma (PBL) is a rare disease. Little is reported about response evaluation procedures in these patients. Our aim was to evaluate response to therapy according to fluorodeoxyglucose-positron emission tomography (FDG-PET) results, and in particular to test the Deauville 5-point scale as compared to the visual evaluation of FDG-PET scans in PBL. In this single-center study, we diagnosed 31 consecutive patients with PBL, of which 24 were evaluated with end-of-treatment FDG-PET. Patients' ages ranged from 19 to 82 years. Six patients were treated with chemotherapy, 24 with chemotherapy and radiotherapy, and one patient with radiotherapy alone. Six patients were affected by a pathological fracture. Four patients died within the range of 3 to 36 months after diagnosis. The average follow-up of the remaining patients was 70 (24–173) months. Overall survival was 87% at 5 years. The only positive prognostic factor was complete remission after chemotherapy. According to visual criteria, end-of-treatment FDG-PET was evaluated in 24 patients and it was positive in 11 (46%) and negative in 13 patients. We organized a retrospective central-blinded revision of end-of-therapy FDG-PET scans using the 5-point Deauville Score (DS). We reviewed 17 out of 24 patients and obtained the following results: at the end of therapy, 12 patients with DS score 2, three patients with DS score 3, one patient with DS score 4, and none with DS score 5. Considering that all the 24 patients achieved complete remission after treatment, visual interpretation produced 11/24 false-positive results, and DS interpretation produced 1/17 false-positive results, thus significantly reducing the number of false positives. In PBL, the final evaluation at the end of therapy with FDG-PET should be evaluated using Deauville 5-point scale in order to significantly reduce the risk of false-positive scans.

TRIAL OF OXALOACETATE IN ALZHEIMER’S DISEASE (TOAD): INTERIM FDG PET ANALYSIS

Brain bioenergetic function is defective in AD, and may contribute to reduced glucose utilization on fluorodeoxyglucose positron emission tomography (FDG PET) scans. Preclinical studies found oxaloacetate (OAA) enhanced brain bioenergetics and glucose flux, but human pharmacokinetic (PK) and pharmacodynamic (PD) data are lacking. The “Trial of Oxaloacetate in Alzheimer's Disease” (TOAD) study was designed to evaluate the PK and PD effects of 500 mg and 1000 mg OAA doses on AD participants. We obtained FDG PET scans on AD participants prior to starting a one month 500 mg twice daily (n=14) or 1000 mg twice daily (n=7) treatment intervention. We also obtained post-intervention FDG PET scans. We quantified the FDG PET signal from 7 different regions of interest (ROIs), and compared regional pre and post-intervention values. In 6 of the 7 FDG PET ROIs, relative to the 500 mg twice daily group the 1000 mg twice daily group trended towards a favorable response (either increased FDG PET signal at 1 month, or less decline at 1 month). Participants in the 1000 mg twice daily group showed a significant 2.5% increase in their hippocampal signal (p<0.05, paired T-test, nominal). The mean change in the 1000 mg twice daily group (2.5% mean increase, 0.9% standard error) also exceeded the mean change of the 500 mg twice daily group (0.3% mean decline, 0.7% standard error) (p<0.05, unpaired T-test). This TOAD study interim analysis suggests OAA at 1000 mg twice daily may engage brain bioenergetic metabolism. Whether or not positive findings persist at the conclusion of this study remains to be seen.

Visual Rating and Computer-Assisted Analysis of FDG PET in the Prediction of Conversion to Alzheimer's Disease in Mild Cognitive Impairment.

Fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful to predict Alzheimer's disease (AD) conversion in patients with mild cognitive impairment (MCI). However, few studies have examined the extent to which FDG PET alone can predict AD conversion and compared the efficacy between visual and computer-assisted analysis directly. The current study aimed to evaluate the value of FDG PET in predicting the conversion to AD in patients with MCI and to compare the predictive values of visual reading and computer-assisted analysis. A total of 54 patients with MCI were evaluated with FDG PET and followed-up for 2years with final diagnostic evaluation. FDG PET images were evaluated by (1) traditional visual rating, (2) composite score of visual rating of the brain cortices, and (3) composite score of computer-assisted analysis. Receiver operating characteristics (ROC) curves were compared to analyze predictive values. Nineteen patients (35.2%) converted to AD from MCI. The area under the curve (AUC) of the ROC curve of the traditional visual rating, composite score of visual rating, and computer-assisted analysis were 0.67, 0.76, and 0.79, respectively. ROC curves of the composite scores of the visual rating and computer-assisted analysis were comparable (Z = 0.463, p = 0.643). Visual rating and computer-assisted analysis of FDG PET scans were analogously accurate in predicting AD conversion in patients with MCI. Therefore, FDG PET may be a useful tool for screening AD conversion in patients with MCI, when using composite score, regardless of the method of interpretation.

Fluorodeoxyglucose positron emission tomography imaging for diagnosing periprosthetic hip infection: the importance of diagnostic criteria.

Fluorodeoxyglucose positron emission tomography (FDG-PET) is a novel method of assessing suspected periprosthetic hip infection. However, a heterogeneity of sensitivity and specificity using different diagnostic criteria across clinical studies has been published. The objective of this study is to evaluate the various diagnostic criteria using FDG-PET in diagnosing periprosthetic hip infection. FDG-PET scans of patients suffering from painful hip prostheses between 2008 and 2015 were retrospectively reviewed. The PET images were considered positive for infection using five criteria: any increased uptake at the (1) bone-prosthesis-interface, (2) periprosthetic soft tissue (PST), or (3) both, (4) increased uptake in the bone-prosthesis-interface compared to the PST, and (5) increased uptake along the femoral bone-prosthesis-interface. The final diagnosis of infection was based on the pre-operative and intra-operative findings with clinical follow-up > 12months. A total of 33 hip prostheses were evaluated in this study, of which 16 were determined to be infected and 17 uninfected. Any periprosthetic FDG uptake was found in all symptomatic prostheses (sensitivity 100%; specificity 0%). When increased uptake in the bone-prosthesis-interface (sensitivity 100%; specificity 65%) or PST (sensitivity 94%; specificity 59%) was considered infected, specificity increased. A higher intensity of uptake at the bone-prosthesis-interface than PST demonstrated only moderate specificity (sensitivity 44%; specificity 71%). The most specific criterion for infection was an increased FDG uptake along the femoral bone-prosthesis-interface (sensitivity 81%; specificity 94%). Our results demonstrated that the accuracy of FDG-PET is highly dependent of the diagnostic criteria used for periprosthetic hip infection. Only an acceptable diagnostic accuracy (sensitivity 81%; specificity 94%) was found when increased FDG uptake along the femoral bone-prosthesis-interface was considered positive for infection.

Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non–Small-cell Lung Cancer

BackgroundEmerging data support aggressive local treatment of oligometastatic non–small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker. Materials and MethodsWe conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS). ResultsOn univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014). ConclusionThe metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy.

Positron emission tomography imaging of cerebral glucose metabolism and type 1 cannabinoid receptor availability during temporal lobe epileptogenesis in the amygdala kindling model in rhesus monkeys.

We investigated changes in the endocannabinoid system and glucose metabolism during temporal lobe epileptogenesis. Because it is rarely possible to study epileptogenesis in humans, we applied the electrical amygdala kindling model in nonhuman primates to image longitudinal changes in type 1 cannabinoid receptor (CB1R) binding and cerebral glucose metabolism. Two rhesus monkeys received [18 F]-MK-9470 and fluorodeoxyglucose-positron emission tomography ([18 F]-FDG -PET) scans in each of the 4 kindling stages to quantify relative changes over time of CB1R binding and cerebral glucose metabolism in vivo. We constructed z-score images relative to a control group (n = 8), and considered only those changes measured in both kindled animals by calculating the binary conjunction image per kindling stage. The seizure-onset zone exhibited an increased CB1R binding and a decreased glucose metabolism, which both aggravated gradually in extent and intensity throughout kindling. The ipsilateral thalamus and insula showed hypometabolism that coincided with an increase and a decrease in CB1R binding, respectively. These changes also became gradually more severe throughout kindling and overlapped with ictal perfusion changes during the final stage of amygdala kindling, with hyperperfusion in the ipsilateral thalamus and hypoperfusion in the ipsilateral insula. The observed changes in CB1R binding may reflect a combination of a protective mechanism of neurons against seizure activity that becomes stronger over time to combat more severe seizures, and on the other hand, a process of epileptogenesis that facilitates seizure activity and generalization, depending on the cell type involved in those specific regions. This study provides unique evidence that the CB1R is dynamically and progressively involved from the start of mesial temporal lobe epileptogenesis.

To Compare and Determine the Diagnostic Accuracy of [18F]-fluorodeoxyglucose Positron Emission Tomography Scan in Predicting Pathological Response in Operated Carcinoma Esophagus Patients after Initial Neoadjuvant Chemoradiation and Neoadjuvant Chemotherapy.

The objective of this study was to determine whether [18F]-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan could predict the pathological response in esophageal carcinoma after surgery in patients receiving neoadjuvant concurrent chemoradiation (NACCRT) and neoadjuvant chemotherapy (NACT). A randomized prospective study was carried out from March 2014 to October 2016; thirty patients of histopathologically proven, locally advanced, potentially operable carcinoma esophagus comprising both squamous carcinoma and adenocarcinoma were randomized into NACCRT and NACT arms equally. Both groups had pretreatment FDG-PET-computed tomography (CT) scan and repeat scan after 5–6 weeks of neoadjuvant therapy (NAT). The change in mean %Δmaximum standardized uptake value (%ΔSUVmax) was compared with tumor regression grade (TRG) in the postoperative histology. Patients with TRG 1–2 were deemed responders and 3–5 were nonresponders. Pathologic response was correlated with percentage change in [18F]-FDG uptake (%ΔSUVmax); receiver operating characteristics (ROC) analyses were done to assess sensitivity and specificity of FDG-PET to determine its diagnostic accuracy. The mean SUV in NACCRT group decreased from 15.47 ± 2.92 to 7.31 ± 4.07 (P < 0.001), while in NACT group, mean SUV decreased from 14.74 ± 3.95 to 8.60 ± 3.89 (P < 0.001). Comparison between NACCRT and NACT leads to mean SUV of 57.80 ± 22.40 and 45.92 ± 19.23, respectively (P = 0.13). In NACCRT and NACT, TRG had mean %ΔSUVmax values of 2.53 ± 1.25 and 2.93 ± 1.28 (P = 0.393). However, we found a statistically significant correlation between SUV% reduction and TRG (P = 0.002). ROC curve analysis for FDG-PET-CT suggested an area under the curve of 0.693 and sensitivity and specificity of 80% and 46.7%, respectively. NACCRT and NACT lead to a statistically significant reduction in mean %ΔSUVmax and with statistical significance correlation when compared with pathological response assessment. Hence, PET-CT can be used for differentiating responders and nonresponders to NAT.

R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma

AbstractThe benefit of radiotherapy (RT) after chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. We conducted a randomized trial in patients with nonbulky limited-stage DLBCL to evaluate the benefit of RT after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients were stratified according to the modified International Prognostic Index, including lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, age, and disease stage. The patients received 4 or 6 consecutive cycles of R-CHOP delivered once every 2 weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last R-CHOP cycle. All patients were evaluated by fluorodeoxyglucose-positron emission tomography scans performed at baseline, after 4 cycles of R-CHOP, and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. The trial randomly assigned 165 patients in the R-CHOP arm and 169 in the R-CHOP plus RT arm. In an intent-to-treat analysis with a median follow-up of 64 months, 5-year EFS was not statistically significantly different between the 2 arms, with 89% ± 2.9% in the R-CHOP arm vs 92% ± 2.4% in the R-CHOP plus RT arm (hazard ratio, 0.61; 95% confidence interval [CI], 0.3-1.2; P = .18). Overall survival was also not different at 92% (95% CI, 89.5%-94.5%) for patients assigned to R-CHOP alone and 96% (95% CI, 94.3%-97.7%) for those assigned to R-CHOP plus RT (P = not significant). R-CHOP alone is not inferior to R-CHOP followed by RT in patients with nonbulky limited-stage DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT00841945.

FDG PET Parkinson's disease-related pattern as a biomarker for clinical trials in early stage disease.

BackgroundThe development of therapeutic interventions for Parkinson disease (PD) is challenged by disease complexity and subjectivity of symptom evaluation. A Parkinson's Disease Related Pattern (PDRP) of glucose metabolism via fluorodeoxyglucose positron emission tomography (FDG-PET) has been reported to correlate with motor symptom scores and may aid the detection of disease-modifying therapeutic effects.ObjectivesWe sought to independently evaluate the potential utility of the PDRP as a biomarker for clinical trials of early-stage PD.MethodsTwo machine learning approaches (Scaled Subprofile Model (SSM) and NPAIRS with Canonical Variates Analysis) were performed on FDG-PET scans from 17 healthy controls (HC) and 23 PD patients. The approaches were compared regarding discrimination of HC from PD and relationship to motor symptoms.ResultsBoth classifiers discriminated HC from PD (p < 0.01, p < 0.03), and classifier scores for age- and gender- matched HC and PD correlated with Hoehn & Yahr stage (R2 = 0.24, p < 0.015) and UPDRS (R2 = 0.23, p < 0.018). Metabolic patterns were highly similar, with hypometabolism in parieto-occipital and prefrontal regions and hypermetabolism in cerebellum, pons, thalamus, paracentral gyrus, and lentiform nucleus relative to whole brain, consistent with the PDRP. An additional classifier was developed using only PD subjects, resulting in scores that correlated with UPDRS (R2 = 0.25, p < 0.02) and Hoehn & Yahr stage (R2 = 0.16, p < 0.06).ConclusionsTwo independent analyses performed in a cohort of mild PD patients replicated key features of the PDRP, confirming that FDG-PET and multivariate classification can provide an objective, sensitive biomarker of disease stage with the potential to detect treatment effects on PD progression.

Transplantation of Human Embryonic Stem Cell–Derived Cardiovascular Progenitors for Severe Ischemic Left Ventricular Dysfunction

BackgroundIn addition to scalability, human embryonic stem cells (hESCs) have the unique advantage of allowing their directed differentiation toward lineage-specific cells. ObjectivesThis study tested the feasibility of leveraging the properties of hESCs to generate clinical-grade cardiovascular progenitor cells and assessed their safety in patients with severe ischemic left ventricular dysfunction. MethodsSix patients (median age 66.5 years [interquartile range (IQR): 60.5 to 74.7 years]; median left ventricular ejection fraction 26% [IQR: 22% to 32%]) received a median dose of 8.2 million (IQR: 5 to 10 million) hESC-derived cardiovascular progenitors embedded in a fibrin patch that was epicardially delivered during a coronary artery bypass procedure. The primary endpoint was safety at 1 year and focused on: 1) cardiac or off-target tumor, assessed by imaging (computed tomography and fluorine-18 fluorodeoxyglucose positron emission tomography scans); 2) arrhythmias, detected by serial interrogations of the cardioverter-defibrillators implanted in all patients; and 3) alloimmunization, assessed by the presence of donor-specific antibodies. Patients were followed up for a median of 18 months. ResultsThe protocol generated a highly purified (median 97.5% [IQR: 95.5% to 98.7%]) population of cardiovascular progenitors. One patient died early post-operatively from treatment-unrelated comorbidities. All others had uneventful recoveries. No tumor was detected during follow-up, and none of the patients presented with arrhythmias. Three patients developed clinically silent alloimmunization. All patients were symptomatically improved with an increased systolic motion of the cell-treated segments. One patient died of heart failure after 22 months. ConclusionsThis trial demonstrates the technical feasibility of producing clinical-grade hESC-derived cardiovascular progenitors and supports their short- and medium-term safety, thereby setting the grounds for adequately powered efficacy studies. (Transplantation of Human Embryonic Stem Cell-derived Progenitors in Severe Heart Failure [ESCORT]; NCT02057900)

Recovery of language function and brain metabolism in a patient with crossed aphasia: 2-year follow-up of brain FDG PET images

ABSTRACTBackground: Crossed aphasia, a language disturbance in right-handed individuals secondary to a right hemisphere lesion, is rare, occurring in only l-2% of brain-lesioned patients. The precise neurological mechanisms of crossed aphasia are still unknown, and follow-up studies in the long term of language function are sparse.Aims: We describe a detailed follow-up evaluation of language function and resting brain glucose metabolism in a well-defined crossed aphasia patient after right middle cerebral artery (MCA) infarction.Methods & Procedures: A 49-year-old man was referred for the treatment of 3-week history of aphasia after right MCA infarction. He indicated a strong right-handed preference confirmed by the Edinburgh Handedness Questionnaire, and his family members are all right handed. There was no history of developmental delay or learning disability in childhood or previous neurological disease. Formal language evaluation was carried out in the subacute phase (3 weeks after onset) and the late phase (5 and 24 months after onset) with the Korean version of Western Aphasia Battery. He received 40-min sessions of conventional speech and language therapy by a qualified therapist of comparable experience, three times a week. The serial F-18 fluorodeoxyglucose positron emission tomography (FDG PET) scan was performed on 3 weeks and 24 months after onset, respectively. Subtraction PET imaging between baseline and follow-up evaluation was conducted with coregistration with the patient’s magnetic resonance imaging.Outcomes & Results: In the initial evaluation, his aphasia was categorized as Broca’s aphasia [aphasia quotients (AQs) 50.4, language quotients (LQs) 49.8]. Four months after the initial evaluation, the function of spontaneous speech, repetition, naming, and reading significantly improved, with a relatively moderate progress of comprehension (AQ 83.5, LQ 78.1). At 2-year follow-up, the function of spontaneous speech, repetition, naming, reading, and writing improved, but the comprehension revealed impairment with minimal improvement (AQ 88.9, LQ 86.8). The result revealed that the 20% increased area of F-18 FDG uptake in the subtraction PET image corresponded to the right basal ganglia, the right medial temporal lobe, both occipital lobes, and the left cerebellum.Conclusions: Our case showed long-term recovery of brain glucose metabolism and language function in a patient with mirror image crossed aphasia. The restoration of perilesional brain function and diaschisis possibly contributed to the recovery of the crossed aphasia.

Brain metabolic correlates of fatigue in Parkinson's disease: a PET study

ABSTRACTPurpose: The neural bases of fatigue in Parkinson's disease (PD) remain uncertain. We aimed to assess the brain metabolic correlates of fatigue in patients with PD.Patients and methods: Twenty-seven PD patients without clinically relevant depression (17-item Hamilton Depression Rating Scale (HAMD) score ≥ 14), apathy (Apathy Scale (AS) score ≥ 14) and excessive daytime somnolence (Epworth Sleepiness Scale (ESS) score ≥ 10) were evaluated with Fatigue Severity Scale (FSS). Each patient had an F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scan. Motor symptoms were measured with the Unified Parkinson's Disease Rating Scale motor part. Levodopa equivalent daily dose for each patient was also calculated. The PET images were analyzed using statistical parametric mapping software. We introduced the age, educational level, HAMD scores, AS scores and ESS scores as covariates.Results: High FSS scores were associated with brain hypermetabolism in areas including the right middle temporal gyrus (Brodmann area (BA) 37) and left middle occipital gyrus (BA 19). Increased FSS scores correlated with hypometabolism in regions such as the right precuneus (BA 23), left inferior frontal gyrus (BA 45) and left superior frontal gyrus (orbital part, BA 11).Conclusion: This study demonstrates that brain areas including frontal, temporal and parietal regions indicative of emotion, motivation and cognitive functions are involved in fatigue in PD patients.

Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R.

Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3-91·5] and overall survival was 95·4% (95% CI 91·8-99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P=0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1-3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P<0·001). Our data support the use of DA-EPOCH-R for the treatment of PMBCL in children and adults. Patients with a positive end-of-therapy FDG-PET scan have an inferior outcome.

Subjective-Objective Sleep Discrepancy Is Associated With Alterations in Regional Glucose Metabolism in Patients With Insomnia and Good Sleeper Controls.

Sleep discrepancies are common in primary insomnia (PI) and include reports of longer sleep onset latency (SOL) than measured by polysomnography (PSG) or "negative SOL discrepancy." We hypothesized that negative SOL discrepancy in PI would be associated with higher relative glucose metabolism during nonrapid eye movement (NREM) sleep in brain networks involved in conscious awareness, including the salience, left executive control, and default mode networks. PI (n = 32) and good sleeper controls (GS; n = 30) completed [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans during NREM sleep, and relative regional cerebral metabolic rate for glucose (rCMRglc) was measured. Sleep discrepancy was calculated by subtracting PSG-measured SOL on the PET night from corresponding self-report values the following morning. We tested for interactions between group (PI vs. GS) and SOL discrepancy for rCMRglc during NREM sleep using both a region of interest mask and exploratory whole-brain analyses. Significant group by SOL discrepancy interactions for rCMRglc were observed in several brain regions (pcorrected < .05 for all clusters). In the PI group, more negative SOL discrepancy (self-reported > PSG-measured SOL) was associated with significantly higher relative rCMRglc in the right anterior insula and middle/posterior cingulate during NREM sleep. In GS, more positive SOL discrepancy (self-reported < PSG-measured SOL) was associated with significantly higher relative rCMRglc in the right anterior insula, left anterior cingulate cortex, and middle/posterior cingulate cortex. Although preliminary, these findings suggest regions of the brain previously shown to be involved in conscious awareness, and the perception of PSG-defined states may also be involved in the phenomena of SOL discrepancy.

Effects of L-theanine on anxiety-like behavior, cerebrospinal fluid amino acid profile, and hippocampal activity in Wistar Kyoto rats.

The amino acid L-theanine (N-ethyl-L-glutamine) has historically been considered a relaxing agent. In the present study, we examined the effects of repeated L-theanine administration on behavior, levels of amino acids in the cerebrospinal fluid (CSF), and hippocampal activity in Wistar Kyoto (WKY) rats, an animal model of anxiety and depressive disorders. Behavioral tests were performed after 7-10days of L-theanine (0.4mgkg-1day-1) or saline administration, followed by CSF sampling for high-performance liquid chromatography (HPLC) analysis. An independent set of animals was subjected to [18F]fluorodeoxyglucose positron emission tomography (PET) scanning after the same dose of L-theanine or saline administration for 7days. In the elevated plus maze test, the time spent in the open arms was significantly longer in the L-theanine group than in the saline group (P=0.035). In addition, significantly lower CSF glutamate (P=0.039) and higher methionine (P=0.024) concentrations were observed in the L-theanine group than in the saline group. A significant increase in the standard uptake value ratio was observed in the hippocampus/cerebellum of the L-theanine group (P<0.001). These results suggest that L-theanine enhances hippocampal activity and exerts anxiolytic effects, which may be mediated by changes in glutamate and methionine levels in the brain. Further study is required to more fully elucidate the mechanisms underlying the effects of L-theanine.