Intracranial arterial calcifications as a prognostic factor for subsequent major adverse cardiovascular events (MACE)

Background

Intracranial arterial calcifications (ICAC) are often detected on unenhanced CT of patients with an age > 60. However, association with the subsequent occurrence of major adverse cardiovascular events (MACE) has not yet been evaluated.

Purpose

This study aimed at evaluating the association of ICAC with subsequent MACE and overall mortality.

Methods

In this retrospective, IRB approved study, we included 175 consecutive patients (89 males, mean age 78.3 ± 8.5 years) of age > 60 years who underwent an unenhanced CT of the head due to minor trauma or neurological disorders. Presence of ICAC was determined in seven intracranial arteries using a semi-quantitative scale, which resulted in the calcified plaque score (CPS). Clinical follow-up information was obtained by questionnaires and telephone interviews. MACE was defined as myocardial infarction or revascularization, stroke or death due to cardiovascular event.

Results

Mean follow-up time was 39.8 ± 7.8 months, resulting in 579.7 patient-years of follow-up. Overall, 36 MACE occurred during follow-up (annual event rate = 6.2%/year). Mean CPS was significantly higher in subjects with MACE during follow-up compared to subjects without MACE (p < 0.01). In 15 patients CPS was 0; in none of these patients MACE was registered. Kaplan–Meier-analysis revealed that patients with a low plaque burden (CPS < 5) had a significant longer MACE-free and overall survival than patients with a high plaque burden (CPS ≥ 5) (p < 0.01).

Conclusion

Patients with ICAC have an increased risk for future cardio- or cerebrovascular events. Therefore, ICAC might be a prognostic factor to determine the risk for these events in older patients.

     

Influence of olfactory bulbectomy and subsequent imipramine treatment on 5-hydroxytryptaminergic presynapses in the rat frontal cortex: behavioural correlates

1. Alterations of 5-hydroxytryptaminergic mechanisms are thought to play a special role in the pathogenesis of depression and antidepressant treatments are assumed to restore these changes.
2. We have used one of the most reliable models of depression, the olfactory bulbectomized rat to study the long term consequences of this manipulation and of subchronic imipramine treatment on two parameters of 5-hydroxytryptaminergic presynapses, 5-hydroxytryptamine (5-HT) transporter density and tryptophan hydroxylase apoenzyme concentration, in the frontal cortex as well as on active avoidance learning several weeks after bulbectomy.
3. The B_max value of [³H]-paroxetine binding and the concentration of the 5-HT synthesizing enzyme were both significantly elevated in the frontal cortex of bulbectomized rats compared to sham-operated controls.
4. Imipramine treatment, either by daily injections or by subcutaneous implantation of slow release imipramine-containing polymers reduced the elevated tryptophan hydroxylase apoenzyme levels in the frontal cortex of bulbectomized, but not of sham-operated control rats and restored the deficient learning performance of bulbectomized rats.
5. Both effects were more pronounced after continuous drug administration by imipramine-releasing polymers compared to daily i.p. injections.
6. These findings indicate that bulbectomy leads to a compensatory 5-hydroxytryptaminergic hyperinnervation of the frontal cortex. Chronic antidepressant treatment seems to attenuate the increased output of the 5-hydroxytryptaminergic projections in the frontal cortex through the destabilization of the rate limiting enzyme of 5-HT synthesis of the 5-hydroxytryptaminergic nerve endings in this brain region.

     

Evaluation of post-operative complications associated with repeat resection and BCNU wafer implantation in recurrent glioblastoma

Background

Patients with glioblastoma treated with BCNU wafer implantation for recurrence frequently receive frontline chemoradiotherapy with temozolomide as part of the Stupp protocol. A retrospective investigation was conducted of surgical complications in a cohort of these patients treated at a single institution.

Methods

We searched our institutional database for patients treated between January 2006 and October 2012 who had recurrent glioblastoma previously treated with open surgery followed by the Stupp protocol and then underwent repeat resection with or without BCNU wafers for recurrent disease. Rates of select post-operative complications within 3 months of surgery were estimated.

Results

We identified 95 patients with glioblastoma who underwent resection followed by the Stupp protocol as frontline treatment. At disease recurrence (first and second recurrence), 63 patients underwent repeat resection with BCNU wafer implantation and 32 without implantation. Generally, BCNU wafer use was associated with minor to moderate increases in rates of select complications versus non-implantation—wound healing abnormalities (14.2 vs. 6.2 %), cerebrospinal fluid leak (7.9 vs. 3.1 %), hydrocephalus requiring ventriculoperitoneal shunt (6.3 vs. 9.3 %), chemical meningitis (3.1 vs. 0 %), cerebral infections (3.1 vs. 0 %), cyst formation (3.1 vs. 3.1 %), cerebral edema (4.7 vs. 0 %), and empyema formations (1.5 vs. 0 %). Performance status was well maintained post-operatively in both groups. Median progression-free survival from the time of first recurrence was 6.0 and 5.0 months, respectively.

Conclusions

The use of the Stupp protocol as frontline therapy in patients with glioblastoma does not preclude the use of BCNU wafers at the time of progression.     

Variability of stimulus detection,form discrimination,and color recognition with suprathreshold campimetry in brain-damaged patients

Background: Optic neuritis (ON) is a common manifestation of multiple sclerosis. It occurs because of the immune-mediated inflammation of the optic nerve. Some vascular factors that could influence the blood flow in the ophthalmic artery (OA) have been suggested in the pathogenesis of ON as well. The purpose of our study was to evaluate blood flow velocities and resistance (RI) and pulsatile (PI) indexes in the OA in patients with acute unilateral ON. Materials and methods: Orbital color Doppler imaging was performed in 27 consecutive patients during acute unilateral ON prior to corticosteroid treatment. ON was diagnosed on the basis of clinical presentation, acute unilateral loss of vision, and assessment of visual evoked potentials (VEP). The peak-systolic velocity (PSV) and the end-diastolic velocity (EDV) and RI and PI were measured in the OA on both sides. We compared results from affected and unaffected orbits, using the paired t-test. We also measured the same parameters in the middle cerebral arteries (MCA) on both sides. Results: The PSV (p < 0.0001), RI (p < 0.0001), and PI (p < 0.0001) in the OA on the side affected by acute ON were significantly higher compared to the unaffected side. There was no difference in EDV in the OA between affected and unaffected sides (p > 0.05). All the parameters in the MCA on both sides were normal. Conclusion: Pathophysiological changes during acute unilateral ON influence the orbital hemodynamics as documented by increased PSV, RI, and PI in the OA on the side affected by ON.     

Genomic profiling reveals distinctive molecular relapse patterns in IDH1/2 wild‐type glioblastoma

Molecular changes associated with the progression of glioblastoma after standard radiochemotherapy remain poorly understood. We compared genomic profiles of 27 paired primary and recurrent IDH1/2 wild‐type glioblastomas by genome‐wide array‐based comparative genomic hybridization. By bioinformatic analysis, primary and recurrent tumor profiles were normalized and segmented, chromosomal gains and losses identified taking the tumor cell content into account, and difference profiles deduced. Seven of 27 (26%) pairs lacked DNA copy number differences between primary and recurrent tumors (equal pairs). The recurrent tumors in 9/27 (33%) pairs contained all chromosomal imbalances of the primary tumors plus additional ones, suggesting a sequential acquisition of and/or selection for aberrations during progression (sequential pairs). In 11/27 (41%) pairs, the profiles of primary and recurrent tumors were divergent, i.e., the recurrent tumors contained additional aberrations but had lost others, suggesting a polyclonal composition of the primary tumors and considerable clonal evolution (discrepant pairs). Losses on 9p21.3 harboring the CDKN2A/B locus were significantly more common in primary tumors from sequential and discrepant (nonequal) pairs. Nonequal pairs showed ten regions of recurrent genomic differences between primary and recurrent tumors harboring 46 candidate genes associated with tumor recurrence. In particular, copy numbers of genes encoding apoptosis regulators were frequently changed at progression. In summary, approximately 25% of IDH1/2 wild‐type glioblastoma pairs have stable genomic imbalances. In contrast, approximately 75% of IDH1/2 wild‐type glioblastomas undergo further genomic aberrations and alter their clonal composition upon recurrence impacting their genomic profile, a process possibly facilitated by 9p21.3 loss in the primary tumor. © 2014 Wiley Periodicals, Inc.     

Fatty acid patterns early after premature birth, simultaneously analysed in mothers' food, breast milk and serum phospholipids of mothers and infants

Background  

The supply of long-chain polyunsaturated fatty acids via the placenta is interrupted in premature infants, making them exclusively dependent on breast milk, which varies in fatty acid (FA) concentrations depending on the mother's diet.     

“Whose data is it anyway?” The implications of putting small area-level health and social data online

Data from electronic patient management systems, routine national health databases, and social administrative systems have increased significantly over the past decade. These data are increasingly used to create maps and analyses communicating the geography of health and illness. The results of these analyses can be easily disseminated on the web often without due consideration for the identification, access, ethics, or governance, of these potentially sensitive data. Lack of consideration is currently proving a deterrent to many organisations that might otherwise provide data to central repositories for invaluable social science and medical research. We believe that exploitation of such data is needed to further our understanding of the determinants of health and inequalities. Therefore, we propose a geographical privacy-access continuum framework, which could guide data custodians in the efficient dissemination of data while retaining the confidentiality of the patients/individuals concerned. We conclude that a balance of restriction and access is needed allowing linkage of multiple datasets without disclosure, enabling researchers to gather the necessary evidence supporting policy changes or complex environmental and behavioural health interventions.     

Monoclonal antibodies directed against the T-cell activation molecule CD137 (interleukin-A or 4-1BB) block human lymphocyte-mediated suppression of tumor xenografts in severe combined immunodeficient mice

A monoclonal antibody specific for the human analog of the murine T-cell activation molecule 4-1BB was generated and is shown here to react selectively with activated human CD4+ and CD8+ T lymphocytes. Treatment of these T cells in a one-way mixed lymphocyte culture with the anti-h4-1BB antibody enhanced the cell proliferation of the allostimulated lymphocytes. Previous studies in the mouse have shown that treatment of tumor-bearing mice with antibodies to 4-1BB augments anti-tumor immunity that is mediated by both CD4+ and CD8+ T cells. The authors consider the possibility that a similar approach may be efficacious for human cancer immunotherapy. This question was addressed by evaluating the effect of an anti-h4-1BB monoclonal antibody on human lymphocyte-mediated suppression of a human tumor xenograft in SCID mice. Mice treated with a control antibody and co-injected with the tumor and peripheral blood lymphocytes exhibited a lymphocyte dose-dependent suppression of tumor growth. In mice treated with the anti-h4-1BB antibody, the lymphocyte-mediated tumor suppression was completely eliminated and tumors grew progressively (as was observed in mice inoculated with tumors without lymphocytes). This monoclonal antibody specific for anti-h4-1BB, which augments the proliferation of allostimulated cells in vitro, blocks T-cell anti-tumor activity in vivo. These results suggest that although 4-1BB plays a role in the human peripheral blood lymphocyte-mediated suppression of tumor growth, antibodies to this molecule on human cells fail to stimulate anti-tumor activity, as was observed in tumor-bearing mice treated with an antibody to murine 4-1BB.     

A phase 1b randomised,placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma

Background Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM.Methods Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored.Results The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK.Conclusions With personalised dosing, nabiximols had acceptable safety and tolerability with no drug–drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial.Clinical trial registration ClinicalTrials.gov: Part 1– NCT01812603; Part 2– NCT01812616.Subject terms: CNS cancer, Drug development, CNS cancer, Pharmaceutics