Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells.

In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens. In a phase 1 trial of 25 patients with recurrent glioblastoma multiforme, cytotoxic lymphocytes homed to the tumor, with tumor regression ongoing in three patients for 14, 22, and 27 months, respectively. No treatment-related adverse effects were observed. This proof-of-principle study shows that tumor-reactive effector cells can be generated ex vivo by exposure to antigens induced by DNA demethylation, providing a novel, minimally invasive therapeutic strategy for treating cancer.

Intra-arterial nimodipine for cerebral vasospasm after subarachnoid haemorrhage: Influence on clinical course and predictors of clinical outcome.

Intra-arterial nimodipine (IAN) has shown a promising effect on cerebral vasospasm (CV) after aneurysmal subarachnoid haemorrhage. At our institution, Rigshospitalet, IAN treatment has been used since 2009, but the short- and long-term clinical efficacy of IAN has not yet been assessed. The purpose was to evaluate the efficacy and clinical outcome of IAN treatment of symptomatic CV, and to assess the predictors of clinical outcome. Medical records of 25 patients undergoing a total of 41 IAN treatment sessions were retrospectively reviewed. Data on angiographic results, blood-flow velocities and the clinical condition before and after the IAN treatment were recorded. Predictors of the clinical outcome were assessed with a linear regression model. Positive angiographic response was achieved in 95.1% of 41 IAN treatment sessions. Flow-velocity measurements showed no relationship with angiographic responses of IAN. The immediate clinical improvement was observed in three patients (12%). Five patients (20%) had a favourable outcome at discharge and at three-month follow-up; 10 patients (40%) had a moderate to poor outcome; and the rest (40%) died. Increased number of affected vessels and number of procedures carried out per patient, and a trend toward an increased delay time from symptomatic CV to confirming angiographic CV and thus instituting IAN treatment predicted the poor clinical outcome. IAN treatment appears to be effective in reversing angiographic CV. However, it is not always effective in reversing clinical deterioration, as several other factors including treatment delay affect the clinical course.

Thrombectomy assisted by carotid stenting in acute ischemic stroke management: benefits and harms.

Extracranial carotid artery occlusion or high-grade stenosis with concomitant intracranial embolism causes severe ischemic stroke and shows poor response rates to intravenous thrombolysis (IVT). Endovascular therapy (EVT) utilizing thrombectomy assisted by carotid stenting was long considered risky because of procedural complexities and necessity of potent platelet inhibition-in particular following IVT. This study assesses the benefits and harms of thrombectomy assisted by carotid stenting and identifies factors associated with clinical outcome and procedural complications. Retrospective single-center analysis of 47 consecutive stroke patients with carotid occlusion or high-grade stenosis and concomitant intracranial embolus treated between September 2011 and December 2014. Benefits included early improvement of stroke severity (NIHSS ≥ 10) or complete remission within 72 h and favorable long-term outcome (mRS ≤ 2). Harms included complications during and following EVT. Mean age was 64.3 years (standard deviation ±12.5), 40 (85%) patients received IVT initially. Median NIHSS was 16 (inter-quartile range 14-19). Mean time from stroke onset to recanalization was 311 min (standard deviation ±78.0). Early clinical improvement was detected in 22 (46%) patients. Favorable outcome at 3 months occurred in 32 (68%) patients. Expedited patient management was associated with favorable clinical outcome. Two (4%) patients experienced symptomatic hemorrhage. Eight (17%) patients experienced stent thrombosis. Four (9%) patients died. Thrombectomy assisted by carotid stenting seems beneficial and reasonably safe with a promising rate of favorable outcome. Nevertheless, adverse events and complications call for additional clinical investigations prior to recommendation as clinical standard. Expeditious patient management is central to achieve good clinical outcome.

Patient reported outcome in posttraumatic pituitary deficiency: results from The Danish National Study on posttraumatic hypopituitarism.

OBJECTIVE: Posttraumatic pituitary hormone deficiency is often suggested. The impact of these predominantly mild and often irreproducible deficiencies on outcome is less clear. The aim of the present study was to describe patient reported outcome in a national a priori unselected cohort of patients with traumatic brain injury (TBI) in relation to deficiencies identified upon pituitary assessment. DESIGN AND METHODS: We conducted a nationwide population-based cohort study. Participants were Danish patients with a head trauma diagnosis recorded in the Danish Board of Health diagnostic code registry; 439 patients (and 124 healthy controls) underwent assessment of anterior pituitary function 2.5 years (median) after TBI. Questionnaires on health-related quality of life (QoL) (SF36, EuroQoL-5D, QoL assessment of GH deficiency in adults) and fatigue (MFI-20) were completed in parallel to pituitary assessment. RESULTS: Patients with TBI had significant detriments in QoL. Impairment (mainly physical scales) related to pituitary deficiency, although only partially confirmed after adjustment for demographic differences. Hypogonadotropic hypogonadism related to several QoL scores. Increasing impairments were observed with declining total testosterone concentrations (men), but not free testosterone concentrations or any other hormone concentrations. Total testosterone was not independently related to impaired QoL and fatigue, after adjustment for demographics, and treatment with antidiabetics, opioids, antidepressants, and anticonvulsants. CONCLUSIONS: Only a very limited relationship between pituitary hormone deficiencies and QoL/fatigue was demonstrated. Due to the dominating influence of concurrent comorbidities, pituitary deficiencies were not independently related to QoL/fatigue. Causality is still to be shown, and whether substitution therapy could be of additional relevance in selected patients needs to be proven.

Transient global amnesia after cerebral angiography still occurs: Case report and literature review.

Transient global amnesia is considered a very rare complication of diagnostic cerebral angiography, and has been reported only in a limited number of case reports more than 15 years ago. We describe a patient experiencing transient global amnesia following cerebral digital subtraction angiography. While the condition by definition is self-limiting, its differential diagnoses may cause severe morbidity and/or mortality if left untreated. It is therefore important to build and maintain awareness of transient global amnesia as a possible complication of cerebral angiography.

[Pseudo aneurysm in arteria carotis interna treated with stent]. / Pseudoaneurisme på arteria carotis interna behandlet med stent.

Extracranial internal carotid artery aneurysms (EACIAs) are rare. Untreated they have a high stroke rate. Traditionally the treatment has been surgery or endovascular intervention with coils. Both are associated with relatively high complication rates. Another treatment option is endovascular intervention with covered stent, which provides one-step closure of the aneurysm. As in the case story it can be complicated with in-stent occlusion. Therefore we recommend balloon occlusion test before treatment of EACIAs with covered stent.

Major stroke in a 19-year-old patient with a univentricular heart.

Patients with univentricular heart malformations are at increased risk of suffering from thromboembolic events. We present a case of a 19-year-old woman born with a univentricular heart who suffered a major stroke while being treated with only salicylic acid. At least 20% of patients with univentricular hearts have been reported to experience thromboembolic events, of which 25% are fatal. Despite the high incidence of thromboembolic events, no consensus has been reached regarding the role of long-term anti-thrombotic treatment in this group of patients. This lack of consensus warrants future studies that compare the different therapeutic strategies.

[Computer tomography angiography of the cerebral and cervical vessels]. / Computertomografiangiografi af hjernens og halsens kar.

Due to the high temporal and spatial resolution in multislice computed tomography it is possible to perform high-quality computer tomography angiography (CTA) of the cerebral and cervical vessels. Compared to digital subtraction angiography (DSA), a method that is still considered to be the golden standard, CTA is faster and can be performed using a minimal invasive technique. In this paper we outline the clinical indications for performing CTA (aneurysms, stroke, vasospasms, arterio-venous malformations, dissection). Examples of scan protocols are given both for angiography of the cerebral vessels alone and for angiography of the cervical and cerebral vessels in combination. Postprocessing methods for evaluating the images in 2D and 3D are described. Finally CTA is compared to other modalities (DSA, magnetic resonance angiography and Doppler ultrasound).

Treatment of intracranial aneurysms. Reconstruction of the parent artery with flow-diverting (Silk) stent.

INTRODUCTION: Since the flow diverters (FDs) have been introduced it is possible to treat aneurysms that are considered difficult or impossible to treat with usual endovascular or surgical methods. It is still uncertain which aneurysms are suitable for this new treatment. We present the periprocedural complications, immediate result, late complications, imaging follow-up at 6 and 12 months and clinical follow-up at 2-23 months. METHODS: Twenty-two patients with 26 wide-necked or blister-like aneurysms had 23 treatments with implantation of a Silk stent. Eleven patients had re-canalizations, and 11 patients were either untreated or had been treated for another aneurysm. RESULTS: Periprocedural complications were seen in four treatments (17%). However, none of these had clinical consequences. Mortality and morbidity rates were 1 of 22 (5%) and 1 of 22 (5%), respectively. Clinical outcome was unchanged in 16 patients (72%), 3 patients improved (14%) and 3 patients worsened (14%). The end-of-procedure angiography did not show complete occlusion of any of the aneurysms, but at 6 months follow-up angiography, 17 of 25 aneurysms (68%) were completely occluded, and at 12 months, 18 of 21 aneurysms (86%) were occluded. CONCLUSION: The effect of the Silk FD in terms of occlusion of the aneurysms seems to occur mainly during the first 6 months after placement but continues during the following time. Most delayed complications occur immediately after discontinuing the anticoagulation medication. Considering the complexity of the aneurysms treated, the rate of complications is acceptable.

[Maternal post partum arteriovenous fistula with objective tinnitus]. / Arteriovenøs fistel med objektiv tinnitus efter fødsel.

This case-report describes an otherwise healthy younger woman with post partum onset of objective pulsatile tinnitus. Neuroradiological examination revealed a dural fistula that was later closed using endovascular coiling technique, after which the patient's tinnitus disappeared. At 6-month follow-up the patient was symptom-free. This case report emphasises the importance of examining for objective tinnitus in patients complaining of tinnitus, as the causes of objective pulsatile tinnitus can frequently be treated successfully.

Serotonin transporters in dopamine transporter imaging: a head-to-head comparison of dopamine transporter SPECT radioligands 123I-FP-CIT and 123I-PE2I.

UNLABELLED: Current SPECT radioligands available for in vivo imaging of the dopamine transporter (DAT) also show affinity for monoamine transporters other than DAT, especially the serotonin transporter (SERT). The effect of this lack of selectivity for in vivo imaging is unknown. In this study, we compared the SPECT radioligands (123)I-2-ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ((123)I-FP-CIT) and (123)I-N-(3-iodoprop-2E-enyl)-2-ß-carbomethoxy-3ß-(4-methylphenyl) nortropane ((123)I-PE2I), which has a 10-fold higher selectivity than (123)I-FP-CIT for DAT versus SERT [corrected]. METHODS: Sixteen healthy individuals were scanned in random order with both radioligands. The radioligands were administered according to standard recommendations: (123)I-FP-CIT was given as a bolus injection, and the ratio between the striatum and reference tissue was measured after 3 h. (123)I-PE2I was administered in a bolus-infusion setup, and the nondisplaceable binding potential (BP(ND)) was measured after 2 h. To assess the contribution of SERT to the overall SPECT signal, SERT was blocked by intravenous citalopram in 6 of the individuals. RESULTS: The striatum-to-reference ratio - 1 of (123)I-FP-CIT was on average 18% higher than the striatal BP(ND) of (123)I-PE2I. Equal doses of radioactivity resulted in 3 times higher counting rates for (123)I-FP-CIT than for (123)I-PE2I, both in target and in reference brain regions. Citalopram infusion led to significant reductions in both striatal (22.8% ± 20.4%, P < 0.05) and thalamic (63.0% ± 47.9%, P < 0.05) (123)I-FP-CIT binding ratios, whereas BP(ND) of (123)I-PE2I was unaltered. Likewise, blocking of SERT led to increased (21% ± 30.1%, P < 0.001) plasma (123)I-FP-CIT, probably as a result of significant blocking of peripheral SERT binding sites. By contrast, plasma (123)I-PE2I remained stable. CONCLUSION: (123)I-FP-CIT and (123)I-PE2I had approximately the same target-to-background ratios, but per injected megabecquerel, (123)I-FP-CIT gave rise to 3-fold higher cerebral counting rates. We found that (123)I-FP-CIT, but not (123)I-PE2I, brain images have a highly interindividual but significant signal contribution from SERT. Whether the SERT signal contribution is of clinical importance needs to be established in future patient studies.

MRI-guided region-of-interest delineation is comparable to manual delineation in dopamine transporter SPECT quantification in patients: a reproducibility study.

UNLABELLED: A particularly sensitive step in the quantification of SPECT images of the dopamine transporter (DAT) is a correct delineation of the region of interest (ROI). In this study, we primarily compared the reproducibility of the following different approaches for ROI delineation in SPECT images of the DAT: the use of manual delineation (MD) on high-count striatal slides directly on the SPECT image, ROI delineation based on individual MR images (MRD), and oversized striatal ROIs-that is, the striatal volume of interest (SVI), as described previously. We also assessed the ability of the different approaches to identify striatal pathology in patients with parkinsonism. METHODS: Eight patients with highly variable reductions in cerebral DAT availability were SPECT-scanned twice with (123)I-labeled N-(3-iodoprop-(2E)-enyl)-2beta-carboxymethoxy-3beta-(4'-methylphenyl) nortropane bolus infusion setup and once with an MRI scanner. For SPECT/MRI coregistration, we used external fiducial markers visible on both MRI and SPECT. With the MD and MRD methods, the outcome parameters for DAT availability were the binding potentials and the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BP(ND)). For the SVI method, the outcome parameter was the specific binding ratio (SBR). RESULTS: No statistically significant difference in striatal BP(ND) intraobserver reproducibility was seen among any of the 3 methods. The intraobserver reproducibility average +/- SD for MD was 7.0% +/- 4.1%; for MRD, 5.7% +/- 5.4%; and for SVI, 6.7% +/- 6.0%. Mean intrasubject variability, as determined from the test-retest scans, did not differ with the 3 delineation methods used. The average (+/-SD) intrasubject variability of striatal BP(ND) was 11.9% +/- 10.0% with MD and 14.6% +/- 15.3% with MRD. With the SVI method, the intrasubject variability of striatal specific binding ratio was 10.0% +/- 10.2%. BP(ND) values obtained with the MD and MRD methods were similar (paired t test, P > 0.4). CONCLUSION: In patients with reduced striatal DAT binding, the reproducibility of the outcome from ROI MD is comparable to both that obtained by delineation of ROI on individual MR images, followed by coregistration to the SPECT image, and that obtained with the SVI-based approach.

Hypopituitarism is uncommon after aneurysmal subarachnoid haemorrhage.

OBJECTIVE: Aneurysmal subarachnoid haemorrhage (SAH) has recently been reported as a common cause of chronic hypopituitarism, and introduction of routine neuroendocrine screening has been advocated. We aimed at estimating the risk of hypopituitarism after SAH using strict criteria including confirmatory testing in case of suggested insufficiency. DESIGN: Cross-sectional evaluation with a nested prospective subgroup. Patients and measurements Endocrine evaluation was performed at a median of 14 months (range 11-26) post-SAH in 62 patients with SAH and 30 healthy controls. Twenty-six patients were followed prospectively (median 7 days, and 12 months post-SAH). Endocrine evaluation included baseline evaluation, which was combined with an insulin tolerance test (ITT) or, if contraindicated, GHRH + arginine tests and a standard ACTH test at evaluation 1-2 years post-SAH. Pituitary insufficiencies were confirmed by re-evaluation. RESULTS: Early post-SAH hormone alterations mimicking central hypogonadism were present in 58% of the patients and associated with a worse clinical state (P < 0.05). One to 2 years post-SAH, initial neuroendocrine evaluation identified seven patients (11%) with abnormal results; three had free T4 and TSH suggestive of central hypothyroidism, three men had testosterone below 10 nm, and one had an insufficient GH and cortisol response to the ITT. None of these abnormalities was confirmed upon confirmatory testing. CONCLUSION: In the largest reported cohort of patients with SAH to date, with early and late endocrine evaluation, none of the patients had chronic hypopituitarism. Based on these findings, the introduction of routine neuroendocrine screening is not justified, and the data suggest the importance of using strict diagnostic criteria in patients with a low pretest probability of hypopituitarism.

Modified condylotomy versus conventional conservative treatment in painful reciprocal clicking--a preliminary prospective study in eight patients.

Modified condylotomy may be relevant in severe painful reciprocal clicking of the temporomandibular joint (TMJ) where conservative treatment is insufficient. The effect of the modified condylotomy was analyzed and compared with conventional nonsurgical treatment in a randomized pilot study of eight patients, 19-44 years of age, with severe painful reciprocal clicking. Before and after treatment, assessments were performed by subjective reports, clinical recordings, and blinded evaluations of radiography and magnetic resonance imaging (MRI). Based on the clinical evaluations before treatment, all conditions were disc displacements with reduction and arthralgia (Research diagnostic criteria for temporomandibular disorders), but based on MRI, one patient had disc displacement without reduction and another had normal disc position. The treatment effect was significantly better and the disorders were significantly more reduced with condylotomy than with conventional nonsurgical treatment (P < 0.05, Mann-Whitney U test). In the surgical group, the clicking and locking had disappeared, the pain during function was significantly reduced (P < 0.05, Friedman ANOVA), and in two patients the disc position was normalized. The clicking still persisted in the nonsurgical patients and the disc position was unchanged. Our conclusion is that modified condylotomy is a promising option to reduce symptoms and signs in severe painful reciprocal clicking.

Anterior cervical discectomy with or without fusion with ray titanium cage: a prospective randomized clinical study.

STUDY DESIGN: A prospective randomized clinical study. OBJECTIVE: To compare 2 surgical methods in the treatment of cervical radiculopathy caused by hard or soft disc herniation; namely, simple discectomy versus discectomy with an additional interbody fusion with a Ray titanium cage. SUMMARY OF BACKGROUND DATA: Although an interbody fusion after anterior decompressive surgery for hard or soft disc herniation is widely accepted, there is no scientific evidence that convincingly demonstrates that insertion of graft material for interbody fusion is necessary after discectomy and decompression of the nervous elements have been performed. To date, no randomized studies have compared simple discectomy with discectomy followed by an interbody fusion with a titanium cage. METHODS: Eighty-six patients with symptoms of nerve root compression at 1 level were randomly allocated to either discectomy followed by fusion with a Ray titanium cage (40 patients) or to discectomy alone (46 patients). Clinical and radiologic follow-up was performed 3, 12, and 24 months after surgery. RESULTS: There was no statistically significant difference between the 2 groups concerning self-reported satisfaction or severity of pain in the neck and arm. Two years after the operation, 86.1% of the patients treated with cage stated a good outcome versus 76.7% in the discectomy group (P = 0.44). The rate of fusion was 83.3% in the cage group versus 81.0% in the discectomy group (P = 0.30). Furthermore, after 2 years, also the rates of new adjacent disc degeneration or spondylosis were the same in both groups. CONCLUSION: This study showed no statistically significant difference between simple discectomy and discectomy followed by interbody fusion with a titanium cage in the surgical treatment of cervical radiculopathy caused by disc herniation.

Evaluation of the Serotonin Transporter Ligand 123I-ADAM for SPECT Studies on Humans.

UNLABELLED: Imaging serotonin transporters in the living human brain is important in several fields, such as normal psychophysiology, mood disorders, eating disorders, and neurodegenerative disorders. The aim of this study was to compare different kinetic and semiquantitative methods for assessing serotonin transporters using (123)I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) in humans: an arterial plasma input model, simplified and Logan reference tissue models, and standardized uptake value ratios. METHODS: Nine subjects were scanned with dynamic (123)I-ADAM SPECT (mean age, 31 y; range, 24-43 y), and metabolite-corrected arterial input was measured. Tissue reference models (simplified reference tissue model, Logan reference tissue model, and ratio method) were validated against the outcome of a 1-tissue-compartment model, and performance with decreasing scan length was evaluated. The specificity of (123)I-ADAM binding was investigated in a blocking experiment. RESULTS: Binding estimates from the simplified reference tissue and Logan reference tissue models correlated tightly with full kinetic modeling when based on a 240- or 360-min dynamic acquisition (r = 0.99); however, there were slight underestimations (3%-5%), especially in high-binding regions. Application of the ratio method to data from 200 to 240 min overestimated specific binding (on average, by 10% +/- 28%) and correlated only moderately with estimates from the 1-tissue-compartment model (r = 0.94). With an acquisition time of 0-120 min, the Logan model still yielded an acceptable outcome when a fixed clearance rate constant (k2') from the cerebellum was applied. Intravenously injected citalopram was not associated with a decrease in cerebellar binding. A lipophilic metabolite that did not seem to bind specifically to serotonin transporter was seen in 2 of 7 subjects. CONCLUSION: Serotonin transporter binding with (123)I-ADAM SPECT can be assessed with the Logan model based on a 120-min acquisition when a constant k2' is applied. This model, because it allows for more accurate and less biased binding estimates and thus reduces the required sample size, is advantageous over the ratio method used in clinical studies so far. A single blocking experiment supported the use of the cerebellum as a reference region.

Reproducibility of [123I]PE2I binding to dopamine transporters with SPECT.

PURPOSE: The iodinated cocaine derivative [(123)I]PE2I is a new selective ligand for in vivo studies of the dopamine transporter (DAT) with SPECT. Recently, a bolus/infusion (B/I) protocol for [(123)I]PE2I measurements of DAT density was established [Pinborg LH et al. J Nucl Med 2005;46:1119-271]. The aims of this study were, firstly, to evaluate the test-retest variability using the B/I protocol and, secondly, to evaluate the B/I approach in a new group of healthy subjects using two outcome parameters, BP(1) (C(ROI)/C(plasma)) and BP(2) (C(ROI)/C(REF)). METHODS: Seven healthy subjects were subjected to [(123)I]PE2I SPECT scanning twice. For both studies, the two outcome parameters BP(1) and BP(2) were calculated based on two different methods for region of interest (ROI) delineation, namely manual delineation and probability map-based automatic delineation with MRI co-registration. RESULTS: With manual delineation, striatal test-retest variability (absolute difference between first and second scan as a percentage of the mean) of BP(1) and BP(2) was 13.9% (range 1.8-35.7%) and 4.1% (range 0.5-9.7%) respectively. The probability map-based automatic delineation resulted in striatal test-retest variability of 17.2% (range 4.3-40.5%) and 5.2% (range 0.1-10.9%) respectively. The B/I approach provided stable brain activity from 120 to 180 min post injection in both high- and low-count regions with a mean % change/hour in striatal BP(2) of 10.6. CONCLUSION: [(123)I]PE2I SPECT with the B/I approach yields a highly reproducible measure of striatal dopamine transporter binding. The appropriateness of a B/I protocol with a B/I ratio of 2.7 h (i.e. with a bolus worth 2.7 h of infusion) was confirmed in an independent sample of healthy subjects.

Three-dimensional reconstruction of TMJ MR images: a technical note and case report.

MR images of the temporomandibular joint at occlusion and at various stages of mouth opening were registered and reconstructed three-dimensionally before and after a modified condylotomy in a patient with painful disk displacement. Following the condylotomy, the condyle/disk relationship had become normalized in all three planes of space at closed mouth and during mouth opening. The post-operative distances of the condylar and diskal paths had increased when compared with the preoperative distances. The three-dimensional visualizing method may, besides providing diagnostic advantages, be a valuable tool for qualitative and quantitative documentation of the efficiency of different treatment methods for normalization of the disk/condyle relationship in patients with TMJ disk displacement.