Publications by authors named "Peter de Boer"

82 Publications

Correction: Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study.

Transl Psychiatry 2020 Oct 19;10(1):352. Epub 2020 Oct 19.

Stress, Psychiatry and Immunology Laboratory & Perinatal Psychiatry, King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, Maurice Wohl Clinical Neuroscience Institute, King's College London, SE5 9RT, London, UK.

We have corrected this Article post-publication, because Dr. Cattaneo's affiliation details were originally incorrect (she was affiliated with three institutions but is in fact only linked to one: Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia). These changes reflect in both the PDF and HTML versions of this Article.
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http://dx.doi.org/10.1038/s41398-020-01044-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572382PMC
October 2020

Whole-blood expression of inflammasome- and glucocorticoid-related mRNAs correctly separates treatment-resistant depressed patients from drug-free and responsive patients in the BIODEP study.

Transl Psychiatry 2020 07 23;10(1):232. Epub 2020 Jul 23.

Stress, Psychiatry and Immunology Laboratory & Perinatal Psychiatry, King's College London, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, Maurice Wohl Clinical Neuroscience Institute, King's College London, SE5 9RT, London, UK.

The mRNA expression signatures associated with the 'pro-inflammatory' phenotype of depression, and the differential signatures associated with depression subtypes and the effects of antidepressants, are still unknown. We examined 130 depressed patients (58 treatment-resistant, 36 antidepressant-responsive and 36 currently untreated) and 40 healthy controls from the BIODEP study, and used whole-blood mRNA qPCR to measure the expression of 16 candidate mRNAs, some never measured before: interleukin (IL)-1-beta, IL-6, TNF-alpha, macrophage inhibiting factor (MIF), glucocorticoid receptor (GR), SGK1, FKBP5, the purinergic receptor P2RX7, CCL2, CXCL12, c-reactive protein (CRP), alpha-2-macroglobulin (A2M), acquaporin-4 (AQP4), ISG15, STAT1 and USP-18. All genes but AQP4, ISG15 and USP-18 were differentially regulated. Treatment-resistant and drug-free depressed patients had both increased inflammasome activation (higher P2RX7 and proinflammatory cytokines/chemokines mRNAs expression) and glucocorticoid resistance (lower GR and higher FKBP5 mRNAs expression), while responsive patients had an intermediate phenotype with, additionally, lower CXCL12. Most interestingly, using binomial logistics models we found that a signature of six mRNAs (P2RX7, IL-1-beta, IL-6, TNF-alpha, CXCL12 and GR) distinguished treatment-resistant from responsive patients, even after adjusting for other variables that were different between groups, such as a trait- and state-anxiety, history of childhood maltreatment and serum CRP. Future studies should replicate these findings in larger, longitudinal cohorts, and test whether this mRNA signature can identify patients that are more likely to respond to adjuvant strategies for treatment-resistant depression, including combinations with anti-inflammatory medications.
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http://dx.doi.org/10.1038/s41398-020-00874-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376244PMC
July 2020

Deep learning-based reconstruction of in vivo pelvis conductivity with a 3D patch-based convolutional neural network trained on simulated MR data.

Magn Reson Med 2020 11 21;84(5):2772-2787. Epub 2020 Apr 21.

Department of Radiotherapy, University Medical Center Utrecht, Utrecht, The Netherlands.

Purpose: To demonstrate that mapping pelvis conductivity at 3T with deep learning (DL) is feasible.

Methods: 210 dielectric pelvic models were generated based on CT scans of 42 cervical cancer patients. For all dielectric models, electromagnetic and MR simulations with realistic accuracy and precision were performed to obtain and transceive phase (ϕ ). Simulated and ϕ served as input to a 3D patch-based convolutional neural network, which was trained in a supervised fashion to retrieve the conductivity. The same network architecture was retrained using only ϕ in input. Both network configurations were tested on simulated MR data and their conductivity reconstruction accuracy and precision were assessed. Furthermore, both network configurations were used to reconstruct conductivity maps from a healthy volunteer and two cervical cancer patients. DL-based conductivity was compared in vivo and in silico to Helmholtz-based (H-EPT) conductivity.

Results: Conductivity maps obtained from both network configurations were comparable. Accuracy was assessed by mean error (ME) with respect to ground truth conductivity. On average, ME < 0.1 Sm for all tissues. Maximum MEs were 0.2 Sm for muscle and tumour, and 0.4 Sm for bladder. Precision was indicated with the difference between 90 and 10 conductivity percentiles, and was below 0.1 Sm for fat, bone and muscle, 0.2 Sm for tumour and 0.3 Sm for bladder. In vivo, DL-based conductivity had median values in agreement with H-EPT values, but a higher precision.

Conclusion: Anatomically detailed, noise-robust 3D conductivity maps with good sensitivity to tissue conductivity variations were reconstructed in the pelvis with DL.
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http://dx.doi.org/10.1002/mrm.28285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402024PMC
November 2020

Characterisation of the pharmacodynamic effects of the P2X7 receptor antagonist JNJ-54175446 using an oral dexamphetamine challenge model in healthy males in a randomised, double-blind, placebo-controlled, multiple ascending dose trial.

J Psychopharmacol 2020 Sep 4;34(9):1030-1042. Epub 2020 Apr 4.

Janssen Research and Development, a Division of Janssen Pharmaceutica N.V., Beerse, Belgium.

Background: This is the first report of the pharmacodynamic (PD) effects of the selective, potent and brain-penetrant P2X7 receptor (P2X7R) antagonist JNJ-54175446. Activation of the P2X7R, an adenosine triphosphate-gated ion channel, leads to the production of pro-inflammatory cytokines, which have been linked to neuroinflammation and play a role in the pathogenesis of mood disorders. Previous clinical studies with JNJ-54175446 demonstrated peripheral target engagement of JNJ-54175446 by assessing ex vivo lipopolysaccharide (LPS)-stimulated cytokine production. Blood-brain barrier penetration and a clear dose-receptor occupancy relationship was demonstrated using positron emission tomography.

Aims: The objectives of this double-blind, placebo-controlled, translational study were to assess the safety and tolerability of administering multiple doses of JNJ-54175446 and to explore its PD effects using a dexamphetamine challenge.

Methods: Subjects ( = 64) were randomised to either JNJ-54175446 (50-450 mg;  = 48) or placebo ( = 16) and underwent a baseline oral 20 mg dexamphetamine challenge followed by 11 consecutive days q.d. dosing with JNJ-54175446/placebo and a randomised crossover dexamphetamine/placebo challenge.

Results: At all doses tested, JNJ-54175446 was well tolerated and suppressed the ex vivo LPS-induced release of cytokines. At doses ⩾100 mg, JNJ-54175446 attenuated dexamphetamine-induced increases in locomotion and enhanced the mood-elevating effects of dexamphetamine, suggesting that a dose that is approximately twice as high is needed to obtain a central PD response compared to the dose needed for maximum peripheral occupancy.

Conclusion: Overall, the observed pharmacological profile of JNJ-54175446 in the dexamphetamine challenge paradigm is compatible with a potential mood-modulating effect.
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http://dx.doi.org/10.1177/0269881120914206DOI Listing
September 2020

Immune and Neuroendocrine Trait and State Markers in Psychotic Illness: Decreased Kynurenines Marking Psychotic Exacerbations.

Front Immunol 2019 17;10:2971. Epub 2020 Jan 17.

Faculty of Medicine and Health Sciences, Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Antwerp, Belgium.

Different patterns of immune system upregulation are present in the acute vs. post-treatment states of psychotic illness. We explored the existence of state and trait markers in the peripheral immune system and two immune-associated neuroendocrine pathways (IDO and GTP-CH1 pathway) in a longitudinal sample of psychosis patients. We also evaluated the association of these markers with neuropsychiatric symptomatology. Plasma concentrations of peripheral blood markers were measured in a transdiagnostic group of 49 inpatients with acute psychosis and 52 matched healthy control subjects. Samples were obtained in patients within 48 h after hospital admission for an acute psychotic episode (before initiation of antipsychotics), after 1-2 weeks and again after 8 weeks of treatment. Kynurenine, kynurenic acid (KA), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), phenylalanine, tyrosine, nitrite, and neopterin were measured using HPLC and LC-MS/MS analysis. Concentrations of CRP, CCL2 (MCP1) and cytokines were determined with multiplex immunoassay. PANSS interviews and cognitive tests were performed at baseline and follow-up. Mixed model analyses were used to identify trait and state markers. Patients had significantly higher plasma concentrations of CRP, CCL2, IL1RA, and lower concentrations of KA and KA/Kyn at all time points (F7.5-17.5, all < 0.001). Increased concentrations of IL6, IL8, IL1RA, TNFα, and CCL2 and decreased QA and 3-HK (F8.7-21.0, all < 0.005) were found in the acute psychotic state and normalized after treatment. Low nitrite concentrations at admission rose sharply after initiation of antipsychotic medication (F42.4, < 0.001). PANSS positive scale scores during the acute episode correlated with pro-inflammatory immune markers ( ≥ |0.5|), while negative scale scores correlated inversely with IDO pathway markers ( ≥ |0.4|). Normalization of KA and 3-HK levels between admission and follow-up corresponded to a larger improvement of negative symptoms ( = 0.5, < 0.030) A reverse association was found between relative improvement of SDST scores and decreasing KA levels ( = 0.5, < 0.010). The acute psychotic state is marked by state-specific increases of immune markers and decreases in peripheral IDO pathway markers. Increased CRP, CCL2, and IL1RA, and decreased KA and KA/Kyn are trait markers of psychotic illness.
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http://dx.doi.org/10.3389/fimmu.2019.02971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978914PMC
December 2020

Peripheral Blood Cell-Stratified Subgroups of Inflamed Depression.

Biol Psychiatry 2020 07 2;88(2):185-196. Epub 2019 Dec 2.

Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom; Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge, United Kingdom.

Background: Depression has been associated with increased inflammatory proteins, but changes in circulating immune cells are less well defined.

Methods: We used multiparametric flow cytometry to count 14 subsets of peripheral blood cells in 206 depression cases and 77 age- and sex-matched controls (N = 283). We used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity.

Results: Depression cases, compared with controls, had significantly increased immune cell counts, especially neutrophils, CD4 T cells, and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis of cases demonstrated significant associations between the severity of depressive symptoms and increased myeloid and CD4 T-cell counts. Depression cases were partitioned into 2 subgroups by forced binary clustering of cell counts: the inflamed depression subgroup (n = 81 out of 206; 39%) had increased monocyte, CD4, and neutrophil counts; increased C-reactive protein and interleukin-6; and more severe depression than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified 4 subgroups of depression cases, 2 of which (n = 38 and n = 100; 67% collectively) were associated with increased inflammatory proteins and more severe depression but differed in terms of myeloid and lymphoid cell counts. Results were robust to potentially confounding effects of age, sex, body mass index, recent infection, and tobacco use.

Conclusions: Peripheral immune cell counts were used to distinguish inflamed and uninflamed subgroups of depression and to indicate that there may be mechanistically distinct subgroups of inflamed depression.
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http://dx.doi.org/10.1016/j.biopsych.2019.11.017DOI Listing
July 2020

Neuroendocrine and Inflammatory Effects of Childhood Trauma Following Psychosocial and Inflammatory Stress in Women with Remitted Major Depressive Disorder.

Brain Sci 2019 Dec 13;9(12). Epub 2019 Dec 13.

Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Wilrijk 2610, Belgium.

The dysregulation of the inflammatory and neuroendocrine systems seen in major depressive disorder (MDD) may persist after remission and this is associated with a higher risk of relapse. This vulnerable subgroup may be characterized by a history of childhood trauma. In a single-blind randomized placebo-controlled crossover study, 21 women with remitted recurrent MDD and 18 healthy controls were exposed to psychosocial stress (Trier social stress test) or inflammatory stress (typhoid vaccine), or both, to investigate the effects of childhood trauma on the neuroendocrine and inflammatory responses. Childhood trauma was assessed using the Childhood Trauma Questionnaire and participants were dichotomized into a traumatized and non-traumatized group. Serum adrenocorticotropic hormone (ACTH), cortisol, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were measured at regular intervals after each intervention. The effects of trauma, time, and intervention on these parameters were modeled by fitting linear mixed models. Childhood trauma in itself did not have a main effect on the outcome measurements. However, an interactional effect of trauma with stressor type was found in the remitted MDD group: trauma was associated with higher cortisol levels only after adding immunological to psychosocial stress, and with lower TNF-α levels in response to vaccination. This suggests the existence of a vulnerable trauma-associated MDD endophenotype.
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http://dx.doi.org/10.3390/brainsci9120375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956125PMC
December 2019

Correction to: The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder.

Transl Psychiatry 2019 Oct 2;9(1):240. Epub 2019 Oct 2.

Janssen Research and Development, Division of Janssen Pharmaceutica N.V., Beerse, Belgium.

In the original Article, Tables two and three had formatting issues which affected their clarity. This has been corrected in the PDF and HTML versions of this Article.
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http://dx.doi.org/10.1038/s41398-019-0585-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775147PMC
October 2019

Ketamine effects on default mode network activity and vigilance: A randomized, placebo-controlled crossover simultaneous fMRI/EEG study.

Hum Brain Mapp 2020 01 18;41(1):107-119. Epub 2019 Sep 18.

Clinical Neuroscience Research Group, Experimental and Clinical Research Center (ECRC), Department of Anesthesiology and Operative Intensive Care Medicine (CCM, CVK), Charité - Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.

In resting-state functional connectivity experiments, a steady state (of consciousness) is commonly supposed. However, recent research has shown that the resting state is a rather dynamic than a steady state. In particular, changes of vigilance appear to play a prominent role. Accordingly, it is critical to assess the state of vigilance when conducting pharmacodynamic studies with resting-state functional magnetic resonance imaging (fMRI) using drugs that are known to affect vigilance such as (subanesthetic) ketamine. In this study, we sought to clarify whether the previously described ketamine-induced prefrontal decrease of functional connectivity is related to diminished vigilance as assessed by electroencephalography (EEG). We conducted a randomized, double-blind, placebo-controlled crossover study with subanesthetic S-Ketamine in N = 24 healthy, young subjects by simultaneous acquisition of resting-state fMRI and EEG data. We conducted seed-based default mode network functional connectivity and EEG power spectrum analyses. After ketamine administration, decreased functional connectivity was found in medial prefrontal cortex whereas increased connectivities were observed in intraparietal cortices. In EEG, a shift of energy to slow (delta, theta) and fast (gamma) wave frequencies was seen in the ketamine condition. Frontal connectivity is negatively related to EEG gamma and theta activity while a positive relationship is found for parietal connectivity and EEG delta power. Our results suggest a direct relationship between ketamine-induced functional connectivity changes and the concomitant decrease of vigilance in EEG. The observed functional changes after ketamine administration may serve as surrogate end points and provide a neurophysiological framework, for example, for the antidepressant action of ketamine (trial name: 29JN1556, EudraCT Number: 2009-012399-28).
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http://dx.doi.org/10.1002/hbm.24791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268043PMC
January 2020

The selective orexin-2 antagonist seltorexant (JNJ-42847922/MIN-202) shows antidepressant and sleep-promoting effects in patients with major depressive disorder.

Transl Psychiatry 2019 09 3;9(1):216. Epub 2019 Sep 3.

Janssen Research and Development, Division of Janssen Pharmaceutica N.V., Beerse, Belgium.

Excessive arousal has a role in the pathophysiology of major depressive disorder (MDD). Seltorexant (JNJ-42847922/MIN-202) is a selective antagonist of the human orexin-2 receptor (OX2R) that may normalize excessive arousal and thereby attenuate depressive symptoms. In this study, the effects of night-time arousal suppression on depressive symptoms were investigated. 47 MDD patients with a total Inventory of Depressive Symptomatology (IDS) score of ≥30 at screening were included in a randomized, double-blind, diphenhydramine-, and placebo-controlled multicentre study. Symptoms of depression were rated using the 17-item Hamilton Depression Rating Scale (HDRS). Effects on sleep were evaluated by polysomnography and by the Leeds Sleep Evaluation Questionnaire (LSEQ). To investigate the safety and tolerability of seltorexant, vital signs, suicidal ideation and adverse events were monitored. At baseline the severity of depressive symptoms correlated with sleep efficiency (SE), wake after sleep onset (WASO), duration of stage 2 sleep, and ruminations. Ten days of treatment with seltorexant (and not diphenhydramine) resulted in a significant improvement of core depressive symptoms compared to placebo; the antidepressant efficacy of seltorexant was maintained with continued treatment up to 28 days. Compared to placebo, the antidepressant efficacy of seltorexant coincided with an overall increase in (left posterior) EEG power and a relative increase in delta- and decrease in theta-, alpha- and beta power during stage 2 sleep. Treatment with seltorexant was associated with mild, self-limiting adverse drug reactions. Seltorexant affected core symptoms of depression in the absence of overt changes in the hypnogram; in contrast, diphenhydramine was not efficacious.
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http://dx.doi.org/10.1038/s41398-019-0553-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722075PMC
September 2019

A mood state-specific interaction between kynurenine metabolism and inflammation is present in bipolar disorder.

Bipolar Disord 2020 02 30;22(1):59-69. Epub 2019 Aug 30.

Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Objectives: Cytokines are thought to contribute to the pathogenesis of psychiatric symptoms by kynurenine pathway activation. Kynurenine metabolites affect neurotransmission and can cause neurotoxicity. We measured inflammatory markers in patients with bipolar disorder (BD) and studied their relation to kynurenine metabolites and mood.

Methods: Patients with BD suffering from an acute mood episode were assigned to the depressive (n = 35) or (hypo)manic (n = 32) subgroup. Plasma levels of inflammatory markers [cytokines, C-reactive protein] and kynurenine metabolites [tryptophan (TRP), kynurenine (KYN), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KYNA)] were measured on 6 time points during 8 months follow-up. Biological marker levels in patients were compared to controls (n = 35) and correlated to scores on mood scales. Spearman correlations and linear mixed models were used for statistical analysis.

Results: Twenty patients of the manic subgroup, 29 of the depressive subgroup, and 30 controls completed the study. The manic subgroup had a rapid remission of mood symptoms, but in the depressive subgroup subsyndromal symptoms persisted. No differences in inflammation were found between groups. A strong correlation between tumor necrosis factor-α and KYN, KYN/TRP, 3-HK and QA (ρ > 0.60) was specific for the manic group, but only at baseline (during mania). The depressive subgroup had a lower neuroprotective ratio (KYNA/3-HK, P = .0004) and a strong association between interferon-y and kynurenine pathway activation (P < .0001). KYNA was low in both patient groups versus controls throughout the whole follow-up (P = .0008).

Conclusions: Mania and chronic depressive symptoms in BD are accompanied by a strong interaction between inflammation and a potentially neurotoxic kynurenine metabolism.
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http://dx.doi.org/10.1111/bdi.12814DOI Listing
February 2020

Prospective validation of craniocaudal tumour size on MR imaging compared to histoPAthology in patients with uterine cervical cancer: The MPAC study.

Clin Transl Radiat Oncol 2019 Sep 15;18:9-15. Epub 2019 Jun 15.

Department of Radiation Oncology, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Purpose: To determine the accuracy of MRI in detecting craniocaudal tumour extension, compared to histopathology, of the hysterectomy specimen in patients with early-stage uterine cervical cancer. Three complementary methods were investigated.

Materials And Methods: Thirty-four patients with early-stage cervical cancer had pre-operative MRI, followed by radical hysterectomy or trachelectomy. 1) craniocaudal tumour extension was measured on MRI by two radiologists and compared to microscopy by a pathologist, 2) to compensate for changes in uterine shape between pre-operative MRI and the surgical specimen, craniocaudal tumour extensions were directly compared and appreciated as being a part of a 3-dimensional tumour by a radiation oncologist and resident, and 3) tumour size on MRI was compared macroscopically after digital non-rigid registration of the uterus, uterine cavity and tumour of both modalities.

Results: The craniocaudal tumour extension measured on histopathology minus MRI gives: 1) on average +3 mm difference when measured by a radiologist compared to the microscopic extension (range -13 to +15 mm), 2) -0.2 mm (range -11 to +6.0 mm) when evaluated on MRI by a radiation oncologist compared to the macroscopic tumour; 3) after non-rigid organ registration, a margin of 10 mm around the tumour on MRI would be needed to cover 95% of the tumour in 90% of the patients.

Conclusions: Results indicate that microscopic tumour extension towards the uterine fundus is within a margin of 10 mm around the visible tumour on MRI. The major source of measurement uncertainty is post-surgical change of organ shape and form.
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http://dx.doi.org/10.1016/j.ctro.2019.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610701PMC
September 2019

Cervical cancer apparent diffusion coefficient values during external beam radiotherapy.

Phys Imaging Radiat Oncol 2019 Jan 14;9:77-82. Epub 2019 Mar 14.

Department of Radiation Oncology, University Medical Centre Utrecht, The Netherlands.

Background And Purpose: Apparent diffusion coefficient (ADC) reflects micro-enviromental changes and therefore might be useful in predicting recurrence prior to brachytherapy. The purpose of this study is to evaluate change in ADC of the primary tumour and pathologic lymph nodes during treatment and to correlate this with clinical outcome.

Material And Methods: Twenty patients were included who received chemoradiation for locally advanced cervical cancer between July 2016 and November 2017. All patients underwent magnetic resonance imaging (MRI) prior to treatment, and three MRIs in weeks 1/2, 3 and 4 of treatment, including T2 and diffusion weighted imaging (values 0, 200, 800 s/mm) for determining an ADC-map. Primary tumour was delineated on T2 and ADC-map and pathologic lymph nodes were delineated only on ADC-map.

Results: At time of analysis median follow-up was 15 (range 7-22) months. From MRI one to four, primary tumour on ADC-map showed a significant signal increase of 0.94 (range 0.74-1.46) × 10 mm/s to 1.13 (0.98-1.49) × 10 mm/s (p < 0.001). When tumour was delineated on T2, ADC-value signal increase (in tumour according to T2) was similar. All 46 delineated pathologic lymph nodes showed an ADC-value increase on average from 0.79 (range 0.33-1.12) × 10 mm/s to 1.14 (0.59-1.75) × 10 mm/s (p < 0.001). The mean tumour/suspected lymph node volumes decreased respectively 51/40%. Four patients developed relapse (one local and three nodal), without clear relation with ΔADC. However, the median volume decrease of the primary tumour was substantially lower in the failing patients compared to the group without relapse (19 vs. 57%).

Conclusions: ADC values can be acquired using T2-based tumour delineations unless there are substantial shifts between ADC-mapping and T2 acquisition. It remains plausible that ΔADC is a predictor for response to EBRT. However, the correlation in this study was not statistically significant.
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http://dx.doi.org/10.1016/j.phro.2019.03.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807732PMC
January 2019

The selective orexin-2 receptor antagonist seltorexant improves sleep: An exploratory double-blind, placebo controlled, crossover study in antidepressant-treated major depressive disorder patients with persistent insomnia.

J Psychopharmacol 2019 02 15;33(2):202-209. Epub 2019 Jan 15.

6 Neuroscience Development, Janssen Research and Development, San Diego, CA, USA.

Background: Insomnia is common in patients with major depressive disorder. Although antidepressants improve mood, insomnia often persists as a result of physiological hyperarousal. The orexin-2 receptor is increasingly being recognized as a new target for the treatment of persistent insomnia in major depressive disorder .

Aim: This exploratory study investigated the effects of seltorexant on objective sleep parameters and subjective depressive symptoms in antidepressant treated major depressive disorder patients with persistent insomnia.

Methods: Twenty male and female patients received a single dose of 10, 20, 40 mg seltorexant and placebo with a washout period of seven days in a double-blind four-way crossover study. Effects on latency to persistent sleep, total sleep time and sleep efficiency were assessed with polysomnography. Subjective changes in mood were explored by the Quick Inventory of Depressive Symptomatology Self-Report. Safety was recorded and suicidal ideation and behavior were assessed with the Columbia Suicide Severity Rating Scale.

Results: Latency to persistent sleep was significantly shorter for all doses of seltorexant compared to placebo. Placebo least square mean was 61.05 min with least square mean ratios treatment/placebo (80% confidence interval) of 0.32 (0.24-0.44), 0.15 (0.11-0.2) and 0.17 (0.12-0.23) 19.69, 9.2, 10.15 for 10, 20 and 40 mg seltorexant respectively, (all p<0.001). Total sleep time was significantly longer for all doses of seltorexant compared to placebo. Sleep efficiency was significantly improved. The Quick Inventory of Depressive Symptomatology Self-Report demonstrated a trend to mood-improvement for the 40 mg group.

Conclusions: Seltorexant showed a statistically significant, dose-dependent decrease in latency to persistent sleep, and increase in total sleep time and sleep efficiency combined with a tendency toward subjectively improved mood.
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http://dx.doi.org/10.1177/0269881118822258DOI Listing
February 2019

State-associated changes in longitudinal [F]-PBR111 TSPO PET imaging of psychosis patients: Evidence for the accelerated ageing hypothesis?

Brain Behav Immun 2019 03 29;77:46-54. Epub 2018 Nov 29.

Collaborative Antwerp Psychiatric Research Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; University Psychiatric Hospital Antwerp, Campus Duffel, Duffel, Belgium.

Objective: To determine whether state-associated changes in microglial activity, measured with translocator-protein positron emission tomography (TSPO PET), can be identified in psychosis patients through longitudinal evaluation of their regional tracer uptake over the clinical course from acute psychosis to post-treatment follow-up, and comparison to healthy controls. We also evaluated the relation between tracer uptake, clinical symptoms and peripheral immunological markers.

Method: Second-generation radioligand [F]-PBR111 TSPO PET-CT was used for longitudinal dynamic imaging in 14 male psychosis patients and 17 male age-matched healthy control subjects. Patients were first scanned during an acute psychotic episode followed by a second scan after treatment. Prior genotyping of subjects for the rs6917 polymorphism distinguished high- and mixed-affinity binders. The main outcome was regional volume of distribution (V), representing TSPO binding. Plasma concentrations of CRP, cytokines and kynurenines were measured at each timepoint.

Results: We found a significant three-way interaction between time of scan, age and cohort (cortical grey matter F6.50, p.020). Age-dependent differences in V existed between cohorts during the psychotic state, but not at follow-up. Patients' relative change in V over time correlated with age (cortical grey matter Pearson's r.574). PANSS positive subscale scores correlated with regional V during psychosis (cortical grey matter r.767). Plasma CRP and quinolinic acid were independently associated with lower V.

Conclusions: We identified a differential age-dependent pattern of TSPO binding from psychosis to follow-up in our cohort of male psychosis patients. We recommend future TSPO PET studies in psychosis patients to differentiate between clinical states and consider potential age-related effects.
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http://dx.doi.org/10.1016/j.bbi.2018.11.318DOI Listing
March 2019

Digging deeper in the differential effects of inflammatory and psychosocial stressors in remitted depression: Effects on cognitive functioning.

J Affect Disord 2019 02 6;245:356-363. Epub 2018 Nov 6.

Faculty of Medicine and Health Sciences, Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp - Campus "Drie Eiken", Universiteitsplein 1, 2610 Antwerp, Belgium; Psychiatric Hospital Duffel, Stationsstraat 22C, 2570 Duffel, Belgium. Electronic address:

Background: Major Depressive Disorder (MDD) covers a wide spectrum of symptoms, including cognitive dysfunction, which can persist during remission. Both inflammatory states and psychosocial stress play a role in MDD pathogenesis.

Methods: The effects of inflammatory (i.e., Salmonella typhi vaccine) and psychosocial stressor (i.e., Trier Social Stress Test), as well as their combination were investigated on cognition in women (aged 25-45 years, n = 21) with (partially) remitted MDD and healthy controls (n = 18) in a single-blind placebo-controlled study. In a crossover design, patients received on the first day one of the aforementioned interventions and on the other day a placebo, or vice versa, with a washout period of 7-14 days. Short-term and verbal memory, working memory, attention, verbal fluency, information processing speed, psychomotor function, and measures of attentional bias to emotions were measured. Exploratory analyses were performed to assess the correlation between biomarkers of inflammation and the Hypothalamic-Pituitary-Adrenal axis and cognitive functioning.

Results: In patients, inflammatory stress decreased information processing speed and verbal memory, and increased working memory; after psychosocial stress, there was an increase in attention. There was also an increased negative attentional bias in patients after inflammatory stress. Neither stressor had any effect in controls.

Limitiations: Limitations are the relatively small sample size and antidepressant use by a part of the participants. The effects of the stressors were also measured a relatively short period after administration.

Conculsion: Patients were sensitive to the cognitive effects of inflammation and psychosocial stress on cognition, while controls were not.
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http://dx.doi.org/10.1016/j.jad.2018.11.020DOI Listing
February 2019

Clinical pharmacokinetics, pharmacodynamics, safety, and tolerability of JNJ-54175446, a brain permeable P2X7 antagonist, in a randomised single-ascending dose study in healthy participants.

J Psychopharmacol 2018 12 27;32(12):1341-1350. Epub 2018 Sep 27.

1 Janssen Research and Development, Beerse, Belgium.

Background: Central nervous system-derived interleukin-1β plays a role in mood disorders. P2X7 receptor activation by adenosine-triphosphate leads to the release of interleukin-1β.

Aims: This first-in-human study evaluated safety, tolerability, pharmacokinetics and pharmacodynamics of a novel central nervous system-penetrant P2X7 receptor antagonist, JNJ-54175446, in healthy participants.

Methods: The study had three parts: an ascending-dose study in fasted participants (0.5-300 mg JNJ-54175446); an ascending-dose study in fed participants (50-600 mg); and a cerebrospinal fluid study (300 mg). Target plasma concentrations were based on estimated plasma effective concentration (EC) (105 ng/mL) and EC (900 ng/mL) values for central nervous system P2X7 receptor binding.

Results: Seventy-seven participants received a single oral dose of JNJ-54175446 ( n=59) or placebo ( n=18). Area under the curve of concentration time extrapolated to infinity (AUC) increased dose-proportionally; maximum concentration (C) of plasma (C) increased less than dose-proportionally following single doses of JNJ-54175446. Because food increases bioavailability of JNJ-54175446, higher doses were given with food to evaluate safety at higher exposures. The highest C reached (600 mg, fed) was 1475±163 ng/mL. JNJ-54175446 C in cerebrospinal fluid, a proxy for brain penetration, was seven times lower than in total plasma; unbound C and C were comparable (88.3±35.7 vs 114±39 ng/mL). JNJ-54175446 inhibited lipopolysaccharide/3'-O-(4-benzoylbenzoyl)-ATP-induced interleukin-1β release from peripheral blood in a dose-dependent manner (inhibitory concentration (IC):82 ng/mL; 95% confidence interval: 48-94). Thirty-three of 59 (55.9%) participants reported at least one treatment-emergent adverse event; the most common adverse event being headache (11/59, 18.6%).

Conclusion: Plasma exposure of JNJ-54175446 was dose-dependent. No serious adverse events occurred. Single-dose administration of JNJ-54175446>10 mg attenuated ex-vivo lipopolysaccharide-induced interleukin-1β release in peripheral blood. Passive brain penetration of JNJ-54175446 was confirmed.
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http://dx.doi.org/10.1177/0269881118800067DOI Listing
December 2018

Multiple daytime administration of the selective orexin-2 receptor antagonist JNJ-42847922 induces somnolence in healthy subjects without residual central effects.

J Psychopharmacol 2018 12 5;32(12):1330-1340. Epub 2018 Sep 5.

1 Department of Experimental Medicine Neuroscience, Janssen Research and Development, Beerse, Belgium.

Background: Pharmacokinetics, pharmacodynamics and general safety and tolerability of JNJ-42847922, a selective orexin-2 receptor antagonist, were assessed in healthy subjects.

Methods: Five consecutive cohorts of healthy subjects were enrolled and received doses of 5-60 mg orally once daily over 10 days of JNJ-42847922 ( n=6) or placebo ( n=2). Concentrations of drug in plasma and urine were measured over 24 h after dosing on Days 1, 5 and 10. Observed- and self-reported somnolence was used to evaluate the principal pharmacodynamic effect of JNJ-42847922. A test battery to assess vigilance state, sedation and alertness was assessed at 4, 6 and 8 h after dosing. Safety assessments included recording of adverse events, vital signs, electrocardiograms, clinical laboratory assessments and suicidality per Columbia Suicide Severity Rating Scale.

Results: JNJ-42847922 was rapidly absorbed after the morning dose administration. The median t ranged from 0.5-1.5 h and mean t values from 2-3 h. At JNJ-42847922 dose levels ⩾20 mg, mean C and mean area under the curve, values increased less than dose proportionally. At doses ⩾20 mg, JNJ-42847922 consistently induced somnolence on all study days. At four hours post-dose administration, dose levels >5 mg JNJ-42847922 were identified as sedating by the Addiction Research Center Inventory-49. Except for a mild decrease in attention (Bond and Lader Visual Analogue Scale Factor 1) at dose levels >10 mg at four hours post-dose, no clinically relevant changes in other central measures have been observed. JNJ-42847922 was well tolerated.
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http://dx.doi.org/10.1177/0269881118791521DOI Listing
December 2018

Pharmacological fMRI: Effects of subanesthetic ketamine on resting-state functional connectivity in the default mode network, salience network, dorsal attention network and executive control network.

Neuroimage Clin 2018 1;19:745-757. Epub 2018 Jun 1.

Experimental and Clinical Research Center (ECRC), Dept. of Anesthesiology and Intensive Care Medicine, Charité - University Medicine Berlin, Germany; Pharmaimage Biomarker Solutions GmbH, Berlin, Germany; Pharmaimage Biomarker Solutions Inc., Boston, USA.

Background: Subanesthetic dosages of the NMDAR antagonist, S-Ketamine, can cause changes in behavior in healthy subjects, which are similar to the state acute psychosis and are relevant in translational schizophrenia research. Functional magnetic resonance imaging (fMRI) can be used for non-hypothesis-driven analysis of brain connectivity. The correlation between clinical behavioral scores and neuroimaging can help to characterize ketamine effects on healthy brains in resting state.

Method: seventeen healthy, male subjects (mean: 27.42 years, SD: 4.42) were administered an infusion with S-Ketamine (initial bolus 1 mg/kg and continuous infusion of 0.015625 mg/kg/min with dosage reduction -10%/10 min) or saline in a randomized, double-blind, cross-over study. During infusion, resting state connectivity was measured and analyzed with a seed-to-voxel fMRI analysis approach. The seed regions were located in the posterior cingulate cortex, intraparietal sulcus, dorsolateral prefrontal cortex and fronto-insular cortex. Receiver operating characteristics (ROC) were calculated to assess the accuracy of the ketamine-induced functional connectivity changes. Bivariate Pearson correlation was used for correlation testing of functional connectivity changes with changes of clinical scores (PANSS, 5D-ASC).

Results: In the executive network (ECN), ketamine significantly increases the functional connectivity with parts of the anterior cingulum and superior frontal gyrus, but no significant correlations with clinical symptoms were found. Decreased connectivity between the salience network (SN) and the calcarine fissure was found, which is significantly correlated with negative symptoms (PANSS) (R2 > 0.4).

Conclusion: Decreased ketamine-induced functional connectivity in the salience network may qualify as accurate and highly predictive biomarkers for ketamine induced negative symptoms.
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http://dx.doi.org/10.1016/j.nicl.2018.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040604PMC
January 2019

Markers of Inflammation and Monoamine Metabolism Indicate Accelerated Aging in Bipolar Disorder.

Front Psychiatry 2018 14;9:250. Epub 2018 Jun 14.

Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

A mild pro-inflammatory status accompanies bipolar disorder (BD). Inflammation can cause a shift in monoamine metabolism, thereby activating more cytotoxic pathways. The extent to which low-grade inflammation in BD interacts with monoamine metabolism and how this accords to aging and clinical course is unknown. We evaluated the presence of alterations in inflammation and monoamine metabolism in BD throughout different mood states and the role of aging therein. Sixty-seven patients with BD were included during an acute mood episode, either depressive ( = 29), (hypo)manic ( = 29), or mixed ( = 9). Plasma levels of inflammatory markers [tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-y), interleukin-6 (IL-6), and C-reactive protein (CRP)] and markers of monoamine metabolism (neopterin, tryptophan, kynurenine, phenylalanine, and tyrosine) were measured repeatedly during a follow-up of 8 months. Levels in patients were compared to controls ( = 35) and correlated to HDRS-17 and YMRS scores. Spearman correlations and linear mixed model analysis were used for statistical analysis. Forty-nine patients and 30 controls (age range: 22-62 years) completed the study. No significant differences in inflammatory markers were found between patients and controls overall. Tryptophan, tyrosine, and phenylalanine levels were lower in patients. In both patients and controls, markers of inflammation correlated only weakly with markers of monoamine metabolism, but correlations representative for activity of cytotoxic pathways in monoamine metabolism were more pronounced in patients. In patients, but not in controls, older age was associated with increases in inflammatory markers (IL-6, CRP, neopterin) and the kynurenine/tryptophan ratio. None of the biological markers correlated significantly with mood symptom severity. Our data suggest an increased susceptibility of patients with BD to develop a pro-inflammatory state and to shift monoamine metabolism toward more cytotoxic pathways. These findings are in support of the theory of neuroprogression and accelerated aging in BD. Since associations between biological markers and clinical characteristics are limited, it remains to be determined if alterations in biological markers are due to a disease effect or rather are a consequence of confounding factors.
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http://dx.doi.org/10.3389/fpsyt.2018.00250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010913PMC
June 2018

Evaluation of T2-W MR imaging and diffusion-weighted imaging for the early post-treatment local response assessment of patients treated conservatively for cervical cancer: a multicentre study.

Eur Radiol 2019 Jan 25;29(1):309-318. Epub 2018 Jun 25.

Department of Radiology, University Hospitals Leuven, Leuven, Belgium.

Objectives: To compare MR imaging with or without DWI and clinical response evaluation (CRE) in the local control evaluation of cervical carcinoma after radiotherapy.

Methods: In a multicentre university setting, we prospectively included 107 patients with primary cervical cancer treated with radiotherapy. Sensitivity and specificity for CRE and MR imaging (with pre-therapy MR imaging as reference) (2 readers) were evaluated using cautious and strict criteria for identifying residual tumour. Nested logistic regression models were constructed for CRE, subsequently adding MR imaging with and without DWI as independent variables, as well as the pre- to post-treatment change in apparent diffusion coefficient (delta ADC).

Results: Using cautious criteria, CRE and MR imaging with DWI (reader 1/reader 2) have comparable high specificity (83% and 89%/95%, respectively), whereas MR imaging without DWI showed significantly lower specificity (63%/53%) than CRE. Using strict criteria, CRE and MR imaging with DWI both showed very high specificity (99% and 92%/95%, respectively), whereas MR imaging without DWI showed significantly lower specificity (89%/77%) than CRE. All sensitivities were not significantly different. Addition of MR imaging with DWI to CRE has statistically significant incremental value in identifying residual tumour (reader 1: estimate, 1.06; p = 0.001) (reader 2: estimate, 0.62; p = 0.02). Adding the delta ADC did not have significant incremental value in detecting residual tumour.

Conclusions: DWI significantly increases the specificity of MR imaging in the detection of local residual tumour. Furthermore, MR imaging with DWI has significant incremental diagnostic value over CRE, whereas adding the delta ADC has no incremental diagnostic value.

Key Points: • If MR imaging is used for response evaluation, DWI should be incorporated • MR imaging with DWI has diagnostic value comparable/complementary to clinical response evaluation • Inter-reader agreement is moderate to fair for two experienced radiologist readers • Quantitative measurements of ADC early post-therapy have limited diagnostic value.
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http://dx.doi.org/10.1007/s00330-018-5510-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291430PMC
January 2019

A randomized Phase 2 study to evaluate the orexin-2 receptor antagonist seltorexant in individuals with insomnia without psychiatric comorbidity.

J Psychopharmacol 2018 06 31;32(6):668-677. Epub 2018 May 31.

12 Minerva Neurosciences, Waltham, MA, USA.

Background: Seltorexant is a potent and selective antagonist of the orexin-2 receptor that is being developed for the treatment of insomnia and major depressive disorder.

Aims: The primary objective was to investigate the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity. Secondary objectives included evaluation of total sleep time, latency to persistent sleep, and wake after sleep onset. Subjects received 40 mg of seltorexant for five days during Period 1 and placebo during Period 2 or vice versa in this randomized, two-way crossover study. Objective sleep parameters were evaluated by polysomnography over 8 h on Day 1/2 (single dose) and on Day 5/6 (multiple doses). Subjective sleep parameters were assessed by questionnaires.

Results: Twenty-seven subjects completed the study. The mean changes in sleep efficiency (% (SD)) of seltorexant from placebo at Day 1/2 were 5.8 (9.2), and 7.9 (9.8) at Day 5/6 ( p < 0.001 at both time points); in total sleep time (min (SD)) 27.7 (44.3) and 37.9 (47.1), respectively; in latency to persistent sleep (min (SD)) -18.8 (21.3) and -29.9 (27.7), respectively; and in wake after sleep onset (min (SD)) -11.1 (36.4) and -11.3 (46.5). The most common adverse events were headache and somnolence.

Conclusions: Sleep efficiency was increased with seltorexant treatment compared with placebo. Treatment with seltorexant resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset. There were no unexpected safety findings.
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http://dx.doi.org/10.1177/0269881118773745DOI Listing
June 2018

Treatment-resistant depression and peripheral C-reactive protein.

Br J Psychiatry 2019 01 16;214(1):11-19. Epub 2018 May 16.

Immuno-Psychiatry, Immuno-Inflammation Therapeutic Area Unit,GlaxoSmithKline R&D,Stevenage,UK,Cambridgeshire and Peterborough NHS Foundation Trust,Cambridge,UKandDepartment of Psychiatry,University of Cambridge,UK.

Background: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations.

Method: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes.

Results: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood.

Conclusions: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.
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http://dx.doi.org/10.1192/bjp.2018.66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124647PMC
January 2019

Target tailoring and proton beam therapy to reduce small bowel dose in cervical cancer radiotherapy : A comparison of benefits.

Strahlenther Onkol 2018 03 3;194(3):255-263. Epub 2017 Nov 3.

Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Purpose: The aim of the study was to investigate the potential clinical benefit from both target tailoring by excluding the tumour-free proximal part of the uterus during image-guided adaptive radiotherapy (IGART) and improved dose conformity based on intensity-modulated proton therapy (IMPT).

Methods: The study included planning CTs from 11 previously treated patients with cervical cancer with a >4-cm tumour-free part of the proximal uterus on diagnostic magnetic resonance imaging (MRI). IGART and robustly optimised IMPT plans were generated for both conventional target volumes and for MRI-based target tailoring (where the non-invaded proximal part of the uterus was excluded), yielding four treatment plans per patient. For each plan, the V, V, V and D for bladder, sigmoid, rectum and bowel bag were compared, and the normal tissue complication probability (NTCP) for ≥grade 2 acute small bowel toxicity was calculated.

Results: Both IMPT and MRI-based target tailoring resulted in significant reductions in V, V, V and D for bladder and small bowel. IMPT reduced the NTCP for small bowel toxicity from 25% to 18%; this was further reduced to 9% when combined with MRI-based target tailoring. In four of the 11 patients (36%), NTCP reductions of >10% were estimated by IMPT, and in six of the 11 patients (55%) when combined with MRI-based target tailoring. This >10% NTCP reduction was expected if the V for bowel bag was >275 cm and >200 cm, respectively, during standard IGART alone.

Conclusions: In patients with cervical cancer, both proton therapy and MRI-based target tailoring lead to a significant reduction in the dose to surrounding organs at risk and small bowel toxicity.
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http://dx.doi.org/10.1007/s00066-017-1224-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5847034PMC
March 2018

Neurotrophic and inflammatory markers in bipolar disorder: A prospective study.

Psychoneuroendocrinology 2017 Oct 5;84:143-150. Epub 2017 Jul 5.

Collaborative Antwerp Psychiatric Research Institute (CAPRI), Department of Biomedical Sciences, University of Antwerp, Belgium; University Psychiatric Hospital Duffel, VZW Emmaüs, Duffel, Belgium.

Altered neurotrophic signaling is thought to impair neuroplasticity in bipolar disorder (BD). Brain-derived neurotrophic factor (BDNF) is proposed as a neurotrophic marker in BD. However, the current evidence for its use in monitoring disease activity and illness progression is conflicting and an exploration of additional neurotrophic markers is needed. This prospective case-control study investigated mood-specific changes in potential neurotrophic markers and their association to inflammatory activity. Patients with BD were included during an acute mood episode, either depressive (n=35) or (hypo)manic (n=32). Fifty-nine patients (88%) and 29 healthy controls (97%) completed the study. Peripheral blood levels of BDNF, vascular endothelial growth factor A (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and tumor necrosis factor alpha (TNF-α) were measured at baseline and after 2 months. Biomarker levels in patients were compared to controls and correlated to HDRS-17 and YMRS total scores and the PANSS positive subscale scores. Linear mixed model analysis revealed no significant differences in neurotrophic markers between patients and controls. We found significantly increased TNF-α levels in patients and a subsequent normalization during euthymia. None of the biomarkers strongly correlated to mood symptom severity. Despite standardized methodological practices, BDNF and VEGF levels had a wide distribution range. We need a better understanding of methodological aspects influencing the analysis of neurotrophic factors to improve future research on markers for mood state monitoring and illness progression in BD.
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http://dx.doi.org/10.1016/j.psyneuen.2017.07.003DOI Listing
October 2017

Dosimetric advantages of a clinical daily adaptive plan selection strategy compared with a non-adaptive strategy in cervical cancer radiation therapy.

Acta Oncol 2017 May 20;56(5):667-674. Epub 2017 Feb 20.

a Department of Radiation Oncology , Academic Medical Center, University of Amsterdam , Amsterdam , The Netherlands.

Background: Radiation therapy (RT) using a daily plan selection adaptive strategy can be applied to account for interfraction organ motion while limiting organ at risk dose. The aim of this study was to quantify the dosimetric consequences of daily plan selection compared with non-adaptive RT in cervical cancer.

Material And Methods: Ten consecutive patients who received pelvic irradiation, planning CTs (full and empty bladder), weekly post-fraction CTs and pre-fraction CBCTs were included. Non-adaptive plans were generated based on the PTV defined using the full bladder planning CT. For the adaptive strategy, multiple PTVs were created based on both planning CTs by ITVs of the primary CTVs (i.e., GTV, cervix, corpus-uterus and upper part of the vagina) and corresponding library plans were generated. Daily CBCTs were rigidly aligned to the full bladder planning CT for plan selection. For daily plan recalculation, selected CTs based on initial similarity were deformably registered to CBCTs. Differences in daily target coverage (D > 95%) and in V, V, V, D and D for rectum, bladder and bowel were assessed.

Results: Non-adaptive RT showed inadequate primary CTV coverage in 17% of the daily fractions. Plan selection compensated for anatomical changes and improved primary CTV coverage significantly (p < 0.01) to 98%. Compared with non-adaptive RT, plan selection decreased the fraction dose to rectum and bowel indicated by significant (p < 0.01) improvements for daily V, V, V, D and D. However, daily plan selection significantly increased the bladder V, V, D and D.

Conclusions: In cervical cancer RT, a non-adaptive strategy led to inadequate target coverage for individual patients. Daily plan selection corrected for day-to-day anatomical variations and resulted in adequate target coverage in all fractions. The dose to bowel and rectum was decreased significantly when applying adaptive RT.
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http://dx.doi.org/10.1080/0284186X.2017.1287949DOI Listing
May 2017

Differential Effects of Inflammatory and Psychosocial Stress on Mood, Hypothalamic-Pituitary-Adrenal Axis, and Inflammation in Remitted Depression.

Neuropsychobiology 2016 27;74(3):150-158. Epub 2017 Apr 27.

Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Background/aims: Major depressive disorder (MDD) is highly recurrent. This may be due to increased stress sensitivity after remission. Both inflammatory and psychosocial stressors are implicated in the pathogenesis of MDD, but the additive or differential effect is unclear.

Methods: We conducted a single-blind placebo-controlled study to investigate the effects of inflammatory stress (i.e., typhoid vaccination), psychosocial stress (i.e., Trier Social Stress Test [TSST]), or a combination of both in women (25-45 years old) with (partially) remitted recurrent MDD (n = 21) and healthy female controls (n = 18). We evaluated the effect on mood measured by the Profile of Mood States, markers of the hypothalamic-pituitary-adrenal (HPA) axis activity, and inflammatory system activation. The study was performed during 2 testing days, separated by a washout of 7-14 days. In a crossover design, subjects received one of the interventions on one day and placebo on the other.

Results: A lowering of mood was seen in patients (β [95% CI] = -4.79 [-6.82 to -2.75], p < 0.001) only after vaccination, but not after the TSST or the combination; this effect was not observed in controls. Controls experienced a significantly different response on adrenocorticotropic hormone (ACTH) after vaccination, with a general rise in ACTH not observed in patients. In both groups, the TSST activated the HPA axis and suppressed the inflammatory parameters.

Conclusions: There is a differential effect of inflammatory and psychosocial stress on mood and HPA axis activation in patients with remitted recurrent MDD. This may be an interesting treatment target in MDD.
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http://dx.doi.org/10.1159/000466698DOI Listing
February 2018

Patterns of care survey: Radiotherapy for women with locally advanced cervical cancer.

Radiother Oncol 2017 05 20;123(2):306-311. Epub 2017 Apr 20.

Department of Radiation Oncology, Academic Medical Centre (AMC) - University of Amsterdam, The Netherlands.

Background And Purpose: Regarding latest developments, the need of a radiotherapy 'Patterns of Care' survey was expressed by the Dutch National Platform Radiotherapy for Gynaecological Cancer (LPRGT). Therefore, this study investigated current practice for cervical cancer in all 16 radiation oncology centres in the Netherlands specialised in gynaecological oncology.

Material And Methods: A structured 'patterns of care' questionnaire was completed and followed by an in-depth interview with radiation oncologists from all radiotherapy centres specialised in gynaecological oncology. Specific topics addressed were: definition of target volumes, treatment preparation, imaging for treatment planning, treatment planning, and image-guided adaptive radiotherapy for external beam radiotherapy and brachytherapy.

Results: Current radiotherapy practice in the Netherlands for cervical cancer appears to be in accordance with international standards. However, at the time of the survey some differences were revealed that might have relevant clinical impact. For instance: 1) Half of the centres acquired positron emission tomography combined with CT (PET-CT) for staging and target delineation for every patient, 2) The definition of upper border of the para-aortal lymph node area and dose prescription for external beam radiotherapy varied between the centres, and 3) 12 centres used a single treatment plan for delivering EBRT, and four used a plan-of-the-day strategy with a library of 3-4 treatment plans.

Conclusions: Most differences were found at the cutting edge of clinical evidence. However, the majority of these uncertainties are topics being addressed in current and planned (inter)national studies.
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http://dx.doi.org/10.1016/j.radonc.2017.04.005DOI Listing
May 2017

PET-Guided Stereotactic Irradiation of Prostate Cancer Lymph Node Metastases.

J Nucl Med 2017 01 18;58(1):183-184. Epub 2016 Aug 18.

VU Medical Center Meibergdreef 9 Amsterdam, 1105AZ, The Netherlands E-mail:

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http://dx.doi.org/10.2967/jnumed.116.181149DOI Listing
January 2017

Implicit motor sequence learning in schizophrenia and in old age: reduced performance only in the third session.

Exp Brain Res 2016 12 9;234(12):3531-3542. Epub 2016 Aug 9.

Collaborative Antwerp Psychiatric Research Institute, University of Antwerp, Campus Drie Eiken - gebouw R - D.R.328, Universiteitsplein 1 (R Building, 3th Floor), 2610, Antwerp, Belgium.

Although there still is conflicting evidence whether schizophrenia is a neurodegenerative disease, cognitive changes in schizophrenia resemble those observed during normal aging. In contrast to extensively demonstrated deficits in explicit learning, it remains unclear whether implicit sequence learning is impaired in schizophrenia and normal aging. Implicit sequence learning was investigated using a computerized drawing task, the 'implicit pattern learning task (IPLT)' in 30 stable patients with schizophrenia, 30 age-matched controls and 30 elderly subjects on two consecutive days and after 1 week (sessions 1, 2 and 3). Fixed sequence trials were intermixed with random trials, and sequence learning was assessed by subtraction of the response time in fixed sequence trials from random trials. Separate analyses of response times and movement accuracy (i.e., directional errors) were performed. Explicit sequence knowledge was assessed using three different awareness tasks. All groups learned equally during sessions 1 and 2. In session 3, control subjects showed significantly larger learning scores than patients with schizophrenia (p = .012) and elderly subjects (p = .021). This group difference is mainly expressed in movement time and directional errors. Patients with schizophrenia demonstrated less subjective sequence awareness, and both patients with schizophrenia and elderly subjects had less explicit sequence recall. Explicit recall was positively correlated with task performance in all groups. After a short 24 h interval, all subjects showed similar improvements in implicit sequence learning. However, no benefit of prior task exposure 1 week later was observed in patients with schizophrenia and elderly subjects compared to controls. As patients with schizophrenia and elderly both display less explicit sequence recall, the control group superiority after 1 week could be explained by an explicit learning component. The few patients with schizophrenia and elderly subjects who had some sequence recall could possibly utilize this explicit knowledge to improve their task performance but did this by distinct mechanisms.
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http://dx.doi.org/10.1007/s00221-016-4751-0DOI Listing
December 2016