FDG-PET/CT after two cycles of R-CHOP in DLBCL predicts complete remission but has limited value in identifying patients with poor outcome - final result of a UK National Cancer Research Institute prospective study.

The UK National Cancer Research Institute initiated a prospective study (UKCRN-ID 1760) to assess the prognostic value of early fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in diffuse large B-cell lymphoma (DLBCL). In total, 189 patients with DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) had baseline and post-cycle-2 PET (PET2) within a quality assurance framework. Treatment decisions were based on CT; PET2 was archived for central blinded reporting after treatment completion. The association of PET2 response with end-of-treatment CT, progression-free (PFS) and overall survival (OS) was explored. The end-of-treatment complete response rate on CT was 83·9%, 75·0%, 70·5%, 40·4% and 36·4% for Deauville score (DS) 1 (n = 34), 2 (n = 39), 3 (n = 46), 4 (n = 56) and 5 (n = 14) (P < 0·001); and 64·1% and 50·0% for the maximum standardised uptake value (∆SUVmax ) of ≥66% (n = 168) and <66% (n = 21), respectively (P = 0·25). After a median 5·4 years of follow-up, the 5-year PFS was 69·4%, 72·8%, 76·7%, 71·2% and 47·6% by DS 1-5 (P = 0·01); and 72·6% and 57·1% by ∆SUVmax of ≥66% and <66% (P = 0·03), respectively. The association with DS remained in multivariable analyses, and was consistent for OS. Early complete metabolic response (DS 1-3) at interim PET/CT after two cycles of R-CHOP in DLBCL was associated with a higher end-of-treatment complete and overall response rate; however, only DS-5 patients had inferior PFS and OS.

Mesial temporal resection following long-term ambulatory intracranial EEG monitoring with a direct brain-responsive neurostimulation system.

OBJECTIVE: To describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain-responsive neurostimulator (RNS) system. METHODS: We retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS System using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS System chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3-month follow-up after MTL resection compared to seizure frequency 3 months before MTL resection. RESULTS: We identified 157 patients treated with the RNS System with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty-five patients (16%) subsequently had an MTL resection informed by chronic ambulatory ICEEG (mean = 42 months ICEEG); follow-up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow-up was 100% (mean: 94%; range: 50%-100%). Nine patients (38%) had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure-free at last follow-up after MTL resection; eight of nine continued RNS System treatment. Fifteen patients (62%) had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS System treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%-100%) at last follow-up, with eight of fifteen seizure-free. For those with more than 1 year of follow-up (N = 21), 15 patients (71%) were seizure-free during the most recent year, including all eight patients with unilateral onsets and 7 of 13 patients (54%) with bilateral onsets. SIGNIFICANCE: Chronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.

PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study.

International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design. PET-CT was reported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2 scans. The RATHL and PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a κ (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice.

Does aspirin use make it harder to collect seizures during elective video-EEG telemetry?

Aspirin has shown promise as an anticonvulsant drug in animal models. Whether aspirin alters seizure frequency in humans remains unstudied. We retrospectively looked at adults with focal onset epilepsy who took aspirin daily while undergoing elective video-EEG monitoring and compared them with similar age- and sex-matched controls to see if seizure frequencies were different between those two populations. Significantly fewer seizures were seen on day two of monitoring for patients on aspirin therapies. Higher aspirin doses were correlated with fewer seizures collected during the monitoring stay. Further prospective study is needed to determine whether aspirin affects more robust seizure control.

Pregnancy outcomes in women with epilepsy and MTHFR mutations supplemented with methylated folate and methylcobalamin (methylated B12).

Antiseizure medications (ASM) may contribute to adverse fetal outcomes in pregnant women with epilepsy (WWE). Folate processing (Methylenetetrahydrofolate reductase, MTHFR) gene abnormalities are common in women with epilepsy and depression. L-methylfolate supplements may bypass MTHFR deficiencies, yet their use in WWE during gestation or on fetal development is not well studied. We examine pregnancy histories of three WWE who supplemented with either folate or L-methylfolate and methylcobalamin (methylated B12) during pregnancies. Their pregnancy outcomes improved with L-methylfolate and methylcobalamin supplementation. L-methylfolate and methylcobalamin supplementation merits further study in WWE who have MTHFR mutations, fertility, recurrent miscarriage and or depression histories.

Does glucose influence multidien cycles of interictal and/or ictal activities?

PURPOSE: There are multidien patterns of seizure occurrence. Predicting seizure risk may be easier with biomarker correlates to multidien patterns. We hypothesize multiday hyper or hypoglycemia contributes to seizure risk. METHODS: In a type I diabetic (T1D) with focal onset epilepsy with continuous glucose monitoring (CGM) and responsive neurostimulation (RNS) devices, we studied multiday interictal activities (IEA), seizures, and glucose. Hourly CGM data was matched to hourly RNS captures of interictal and ictal activities over 33 months. RNS detection settings were unchanged. Multidien cycles were analyzed, active blocks of IEA and ictal episodes defined, and tissue glucose averages studied. RESULTS: Average glucose was 161 mg/dl. A 40-day cycle of interictal and ictal activities occurred, though no similar glucose cycle was evident. Glucose elevations relative to patient average were associated with increases in IEA but not seizure. Frequent seizures were not associated with obvious elevations or decreases of glucose from baseline, most seizures occurred at +/- 10 mg/dl of average daily glucose (i.e. 150-170 mg/dl). CONCLUSION: Tissue glucose may influence IEA but may not influence multiday seizure activity or very frequent seizures. In an ambulatory T1D patient multiday hypo or hyperglycemic extremes do not appear to provoke seizure activities.

Synthesis and biological evaluation of [(18)F]tetrafluoroborate: a PET imaging agent for thyroid disease and reporter gene imaging of the sodium/iodide symporter.

PURPOSE: The human sodium/iodide symporter (hNIS) is a well-established target in thyroid disease and reporter gene imaging using gamma emitters (123)I-iodide, (131)I-iodide and (99m)Tc-pertechnetate. However, no PET imaging agent is routinely available. The aim of this study was to prepare and evaluate (18)F-labelled tetrafluoroborate ([(18)F]TFB) for PET imaging of hNIS. METHODS: [(18)F]TFB was prepared by isotopic exchange of BF (4) (-) with [(18)F]fluoride in hot hydrochloric acid and purified using an alumina column. Its identity, purity and stability in serum were determined by HPLC, thin-layer chromatography (TLC) and mass spectrometry. Its interaction with NIS was assessed in vitro using FRTL-5 rat thyroid cells, with and without stimulation by thyroid-stimulating hormone (TSH), in the presence and absence of perchlorate. Biodistribution and PET imaging studies were performed using BALB/c mice, with and without perchlorate inhibition. RESULTS: [(18)F]TFB was readily prepared with specific activity of 10 GBq/mg. It showed rapid accumulation in FRTL-5 cells that was stimulated by TSH and inhibited by perchlorate, and rapid specific accumulation in vivo in thyroid (SUV = 72 after 1 h) and stomach that was inhibited 95% by perchlorate. CONCLUSION: [(18)F]TFB is an easily prepared PET imaging agent for rodent NIS and should be evaluated for hNIS PET imaging in humans.

Concordance between four European centres of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma.

PURPOSE: To determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between 'core' laboratories operating in different countries. METHODS: Four centres reported scans from 50 patients with stage II-IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using 'normal' mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading). RESULTS: There was agreement that the response scan was 'positive' or 'negative' for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74-0.96) for conservative reading and 0.79 (95% CI 0.67-0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively. CONCLUSION: The criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting.

Tourette syndrome and epilepsy: a strange case of possible sudden unexpected death.

Mechanisms of sudden unexpected death in epilepsy (SUDEP) are incompletely understood in part because the overwhelming majority of patients are not undergoing video telemetry when they die. Described here is a patient with Tourette syndrome and epilepsy who displayed a dangerous compulsive tic resulting in carotid occlusions and seizures as captured on video telemetry monitoring. He was later found dead, raising the possibility of SUDEP. Possible mechanisms of SUDEP are discussed in light of video, EEG, ECG, epilepsy and tic behaviors.

Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory. RESULTS: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ2). CONCLUSIONS: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

[18F]FDG PET/CT in the diagnosis of malignant peripheral nerve sheath tumours in neurofibromatosis type-1.

PURPOSE: The detection of malignant peripheral nerve sheath tumours (MPNSTs) in patients with neurofibromatosis 1 (NF1) remains a clinical challenge. The purpose of this study was to evaluate the use of [(18)F]2-fluoro-2-deoxy-D-glucose PET/CT (FDG PET/CT with early and delayed imaging) in patients with symptomatic neurofibromas, to revalidate current cut-off values for identification of malignant change within neurofibromas and to examine the relationship between SUV and tumour grade. METHODS: Patients with symptomatic neurofibromas underwent FDG PET/CT imaging at 90 and 240 min. Semiquantitative analysis using maximum standardized uptake value (SUVmax) was performed and correlated with histology. RESULT: In 69 patients, 85 lesions were identified for analysis, including 10 atypical neurofibromas and 21 MPNSTs. Sensitivity of FDG PET/CT in diagnosing NF1-associated MPNST was 0.97 (95% CI 0.81-0.99) and the specificity was 0.87 (CI 0.74-0.95). There was a significant difference in SUVmax between early and delayed imaging and in SUVmax between tumours identified as benign and malignant on PET/CT. There was also a significant difference in SUVmax between tumour grades. CONCLUSION: FDG PET/CT is a highly sensitive and specific imaging modality for the diagnosis of MPNST in NF1 patients. We recommend performing early (90 min) and delayed imaging at 4 h for accurate lesion characterization and using a cut-off SUVmax of 3.5 on delayed imaging to achieve maximal sensitivity.

Observer variation in FDG PET-CT for staging of non-small-cell lung carcinoma.

PURPOSE: Error and variation in reporting remains one of the weakest features of clinical imaging despite enormous technological advances in nuclear medicine and radiology. The aim of this study was to evaluate agreement amongst experienced readers in staging non-small-cell lung cancer (NSCLC) with PET-CT. METHODS: A series of (18)F-FDG PET-CT scans from 100 consecutive patients were reviewed independently by three experienced readers, with two readers reviewing each scan series a second time. Individual mediastinal lymph node stations were assessed as benign/inflammatory, equivocal or malignant, and AJCC N and M stage were also assigned. Kappa (kappa) was used to compare ratings from two categories and weighted kappa (kappa(w)) for three or more categories, and kappa values were interpreted according to the Landis-Koch benchmarks. RESULTS: Both intra- and interobserver agreement for N and M staging were high. For M staging there was almost perfect intra- and interobserver agreement (kappa = 0.90-0.93). For N staging, agreement was either almost perfect or substantial (intraobserver kappa(w) = 0.79, 0.91; interobserver kappa(w) = 0.75-0.81). Importantly, there was almost perfect agreement for N0/1 vs N2/3 disease (kappa = 0.80-0.97). Agreement for inferior and superior mediastinal nodes (stations 1, 2, 3, 7, 8, 9) was either almost perfect or substantial (kappa(w) = 0.71-0.88), but lower for hilar nodes (10; kappa(w) = 0.56-0.71). Interreporter variability was greatest for aortopulmonary nodes (5, 6; kappa(w) = 0.48-0.55). CONCLUSION: Amongst experienced reporters in a single centre, there was a very high level of agreement for both mediastinal nodal stage and detection of distant metastases with PET-CT. This supports the use of PET-CT as a robust imaging modality for staging NSCLC.

Retrospective data-driven respiratory gating for PET/CT.

Respiratory motion can adversely affect both PET and CT acquisitions. Respiratory gating allows an acquisition to be divided into a series of motion-reduced bins according to the respiratory signal, which is typically hardware acquired. In order that the effects of motion can potentially be corrected for, we have developed a novel, automatic, data-driven gating method which retrospectively derives the respiratory signal from the acquired PET and CT data. PET data are acquired in listmode and analysed in sinogram space, and CT data are acquired in cine mode and analysed in image space. Spectral analysis is used to identify regions within the CT and PET data which are subject to respiratory motion, and the variation of counts within these regions is used to estimate the respiratory signal. Amplitude binning is then used to create motion-reduced PET and CT frames. The method was demonstrated with four patient datasets acquired on a 4-slice PET/CT system. To assess the accuracy of the data-derived respiratory signal, a hardware-based signal was acquired for comparison. Data-driven gating was successfully performed on PET and CT datasets for all four patients. Gated images demonstrated respiratory motion throughout the bin sequences for all PET and CT series, and image analysis and direct comparison of the traces derived from the data-driven method with the hardware-acquired traces indicated accurate recovery of the respiratory signal.

Are there mortality risks for patients with epilepsy who use cannabis treatments as monotherapy?

Mortality associated with cannabis used for treatment of epilepsy is not well documented. We discuss two fatalities in the setting of epilepsy and self-determined therapy with cannabis (SDTC). One patient had probable sudden unexpected death in epilepsy, the second death was due to seizure-associated drowning. Both directed SDTC over conventional anti-seizure medications. Where recreational cannabis is legal, decisions to use cannabis are often self-directed and independent of physician advice of cannabis risks, in part because physicians may not be aware of the risk of SDTC. Further study of morbidity and mortality of SDTC in patients with epilepsy is needed.

Down syndrome associated moyamoya may worsen epilepsy control and can benefit from surgical revascularization.

OBJECTIVES: To examine outcome of bilateral extracranial to intracranial (EC-IC) bypass surgeries for a Down syndrome patient with hard-to-treat epilepsy and moyamoya. MATERIALS AND METHODS: Superficial temporal arteries were anastamosed using an indirect bypass technique to middle cerebral arteries bilaterally to help limit perfusion deficits and seizure controls. RESULTS: Two superficial temporal to middle cerebral artery indirect bypass surgeries were performed within 3 months. Post-revascularization improvements included seizure control, gait, perfusion, wakefulness, language and quality of life. CONCLUSION: In patients with Down syndrome and moyamoya, improvements in seizure control and quality of life may occur with EC-IC bypass procedures.

Positron Emission Tomography Score Has Greater Prognostic Significance Than Pretreatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK RAPID Study.

PURPOSE: Accurate stratification of patients is an important goal in Hodgkin lymphoma (HL), but the role of pretreatment clinical risk stratification in the context of positron emission tomography (PET) -adapted treatment is unclear. We performed a subsidiary analysis of the RAPID trial to assess the prognostic value of pretreatment risk factors and PET score in determining outcomes. PATIENTS AND METHODS: Patients with stage IA to IIA HL and no mediastinal bulk underwent PET assessment after three cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine; 143 PET-positive patients (PET score, 3 to 5) received a fourth doxorubicin, bleomycin, vinblastine, and dacarbazine cycle and involved-field radiotherapy, and 419 patients in complete metabolic remission were randomly assigned to receive involved-field radiotherapy (n = 208) or no additional treatment (n = 211). Cox regression was used to investigate the association between PET score and pretreatment risk factors with HL-specific event-free survival (EFS). RESULTS: High PET score was associated with inferior EFS, before (P < .001) and after adjustment (P = .01) for baseline risk stratification. Only patients with a postchemotherapy PET score of 5 (uptake ≥ three times maximum liver uptake) had an increased risk of progression or HL-related death (hazard ratio, 9.4 v score of 3; 95% CI, 2.8 to 31.3 and hazard ratio, 6.7 v score of 4; 95% CI, 1.4 to 31.7). Patients with a PET score of 5 also had inferior progression-free and overall survival. There was no association between European Organisation for Research and Treatment of Cancer or German Hodgkin Study Group risk group and EFS, before or after adjusting for PET score (all P > .4). CONCLUSION: In RAPID, a positive PET scan did not carry uniform prognostic weight; only a PET score of 5 was associated with inferior outcomes. This suggests that in future trials involving patients without B symptoms or mediastinal bulk, a score of 5 rather than a positive PET result should be used to guide treatment escalation in early-stage HL.

Continuous monitoring devices and seizure patterns by glucose, time and lateralized seizure onset.

OBJECTIVES: To investigate if glucose levels influence seizure patterns. MATERIALS AND METHODS: In a patient with RNS/NeuroPace implanted bi-temporally and type 1 diabetes mellitus, seizure event times and onset locations were matched to continuous tissue glucose. RESULTS: Left focal seizure (LFS, n = 22) glucoses averaged 169 mg/dL, while right focal seizure (RFS, n = 23) glucoses averaged 131 mg/dL (p = 0.03). LFS occurred at mean time 17:02 while RFS occurred at 04:23. LFS spread to the contralateral side (n = 19) more than RFS (n = 2). CONCLUSION: Seizure onset laterality and spread vary with glucose and time of seizure.

Pilot data on responsive epilepsy neurostimulation, measures of sleep apnea and continuous glucose measurements.

OBJECTIVES: To match responsive neurostimulator (RNS) and polysomnographic data to determine if RNS detections and stimulations correlate with measurements of sleep disordered breathing and continuous glucose measurements (CGM). MATERIALS AND METHODS: In a patient with an RNS with detection/stimulation leads implanted bi-temporally detection-stimulation counts were matched by time with coinciding polysomnogram and CGM data. RESULTS: Temporal dispersion of RNS DSC were independent of measures of sleep apnea, hypopnea or glucose. CONCLUSION: Hippocampal nighttime responsive neurostimulation therapies did not appear to worsen measures of normal or abnormal sleep.

Differences between stance and foot preference evident in Osprey (Pandion haliaetus) fish holding during movement.

BACKGROUND: Skateboarders, snowboarders, and surfers all show stance preferences for which foot is forward while moving. We are unaware of other animals than humans with a stance preference, perhaps excepting Osprey, who fly their caught fish beneath them in a foot-forward stance. We hypothesize there should be no difference between left foot forward, right foot back (conventional) versus right foot forward left foot back (goofy) stances or for fish holding with unilateral left or right foot. Online, publicly available, convenience images of Osprey catching fish were accessed and assessed by five independent reviewers using different Internet search engines or online photo series. Stance preference and footedness were tested using chi-square analysis. RESULTS: Stance preferences were evident with the left foot forward (conventional stance) on average 64-78% of the time (all p < 0.02). No difference in foot preference for either one-foot grabs of fish during flight or for non-flight nest/perch fish holding was evident. CONCLUSION: Flight stance of Osprey holding fish shows a lateralized preference in a proportion similar to skateboarders of surfers. We discuss stance preferences in the setting of complex movements and potential flight and survival advantages for Osprey.