Publications by authors named "Jeffrey Meyer"

191 Publications

A double-blind placebo-controlled trial of minocycline on translocator protein distribution volume in treatment-resistant major depressive disorder.

Transl Psychiatry 2021 May 29;11(1):334. Epub 2021 May 29.

Brain Health Imaging Centre and Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.

Gliosis is implicated in the pathophysiology of many neuropsychiatric diseases, including treatment-resistant major depressive disorder (TRD). Translocator protein total distribution volume (TSPO V), a brain marker mainly reflective of gliosis in disease, can be measured using positron emission tomography (PET). Minocycline reduces gliosis and translocator protein binding in rodents, but this is not established in humans. Here, the ability of oral minocycline to reduce TSPO V was assessed in TRD. To determine whether oral minocycline, as compared to placebo, can reduce prefrontal cortex (PFC), anterior cingulate cortex (ACC), and insula TSPO V in TRD, twenty-one TRD participants underwent two [F]FEPPA PET scans to measure TSPO V. These were completed before and after either oral minocycline 100 mg bid or placebo which was administered in a randomized double-blinded fashion for 8 weeks. There was no significant difference between the minocycline and placebo groups on change in TSPO V within the PFC, ACC, and insula (repeated measures ANOVA, effect of group interaction, PFC: F = 0.28, P = 0.60; ACC: F = 0.54, P = 0.47; insula F = 1.6, P = 0.22). Oral minocycline had no significant effect on TSPO V which suggests that this dosage is insufficient to reduce gliosis in TRD. To target gliosis in TRD either alternative therapeutics or intravenous formulations of minocycline should be investigated. These results also suggest that across neuropsychiatric diseases in humans, it should be assumed that oral minocycline will not reduce TSPO V or gliosis unless empirically demonstrated.
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http://dx.doi.org/10.1038/s41398-021-01450-3DOI Listing
May 2021

Bone density and fracture risk following SBRT for non-spine bone metastases.

J Radiosurg SBRT 2021 ;7(3):199-206

Johns Hopkins University School of Medicine, Department of Radiation Oncology and Molecular Radiation Sciences, Baltimore, MD, USA.

Purpose/methods: This retrospective study evaluated local recurrence (LR) and fracture risk in non-spine bone metastases treated with SBRT.

Results: 181 lesions in 116 patients are reported. The median dose was 27 Gy (range 15-40) in 3 fractions (range 1-6). The cumulative incidence of LR was 2.8%, 7.2% and 12.5% at 6 mo, 1 yr and 2 yrs. Fractures occurred in 11 lesions (6%). Radioresistant histology and increasing PTV predicted for LR on univariate analysis, while rib location was associated with control. Increasing PTV remained a significant predictor for LR on multivariate analysis. Univariate predictors of fracture risk included female gender, lytic lesions and poorer KPS. Average CT-approximated L1 trabecular attenuation in patients with fracture was significantly lower than in patients without fracture (112.2 vs. 142.6 Hounsfield units).

Conclusion: In the largest series to date, we report excellent local control for SBRT to non-spine bone metastases and a novel relationship between CT-based bone quality assessment and fracture risk.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055232PMC
January 2021

Development, Practice Patterns, and Early Clinical Outcomes of a Multidisciplinary Liver Cancer Clinic.

Cancer Control 2021 Jan-Dec;28:10732748211009945

Department of Radiation Oncology and Molecular Radiation Sciences, 1500Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Multidisciplinary care has been associated with improved survival in patients with primary liver cancers. We report the practice patterns and real world clinical outcomes for patients presenting to the Johns Hopkins Hospital (JHH) multidisciplinary liver clinic (MDLC). We analyzed hepatocellular carcinoma (HCC, n = 100) and biliary tract cancer (BTC, n = 76) patients evaluated at the JHH MDLC in 2019. We describe the conduct of the clinic, consensus decisions for patient management based on stage categories, and describe treatment approaches and outcomes based on these categories. We describe subclassification of BCLC stage C into 2 parts, and subclassification of cholangiocarcinoma into 4 stages. A treatment consensus was finalized on the day of MDLC for the majority of patients (89% in HCC, 87% in BTC), with high adherence to MDLC recommendations (91% in HCC, 100% in BTC). Among patients presenting for a second opinion regarding management, 28% of HCC and 31% of BTC patients were given new therapeutic recommendations. For HCC patients, at a median follow up of 11.7 months (0.7-19.4 months), median OS was not reached in BCLC A and B patients. In BTC patients, at a median follow up of 14.2 months (0.9-21.1 months) the median OS was not reached in patients with resectable or borderline resectable disease, and was 11.9 months in patients with unresectable or metastatic disease. Coordinated expert multidisciplinary care is feasible for primary liver cancers with high adherence to recommendations and a change in treatment for a sizeable minority of patients.
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http://dx.doi.org/10.1177/10732748211009945DOI Listing
April 2021

Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial.

JAMA 2021 04;325(13):1277-1286

Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.

Importance: Aspirin and cyclooxygenase 2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. The effect of celecoxib, a COX-2 inhibitor, as treatment for nonmetastatic colon cancer is unknown.

Objective: To determine if the addition of celecoxib to adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) improves disease-free survival in patients with stage III colon cancer.

Design, Setting, And Participants: Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702 was a 2 × 2 factorial design, phase 3 trial conducted at 654 community and academic centers throughout the United States and Canada. A total of 2526 patients with stage III colon cancer were enrolled between June 2010 and November 2015 and were followed up through August 10, 2020.

Interventions: Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 vs 6 months with or without 3 years of celecoxib (400 mg orally daily; n = 1263) vs placebo (n = 1261). This report focuses on the results of the celecoxib randomization.

Main Outcomes And Measures: The primary end point was disease-free survival, measured from the time of randomization until documented recurrence or death from any cause. Secondary end points included overall survival, adverse events, and cardiovascular-specific events.

Results: Of the 2526 patients who were randomized (mean [SD] age, 61.0 years [11 years]; 1134 women [44.9%]), 2524 were included in the primary analysis. Adherence with protocol treatment, defined as receiving celecoxib or placebo for more than 2.75 years or continuing treatment until recurrence, death, or unacceptable adverse events, was 70.8% for patients treated with celecoxib and 69.9% for patients treated with placebo. A total of 337 patients randomized to celecoxib and 363 to placebo experienced disease recurrence or died, and with 6 years' median follow-up, the 3-year disease-free survival was 76.3% for celecoxib-treated patients vs 73.4% for placebo-treated patients (hazard ratio [HR] for disease recurrence or death, 0.89; 95% CI, 0.76-1.03; P = .12). The effect of celecoxib treatment on disease-free survival did not vary significantly according to assigned duration of adjuvant chemotherapy (P for interaction = .61). Five-year overall survival was 84.3% for celecoxib vs 81.6% for placebo (HR for death, 0.86; 95% CI, 0.72-1.04; P = .13). Hypertension (any grade) occurred while treated with FOLFOX in 14.6% of patients in the celecoxib group vs 10.9% of patients in the placebo group, and a grade 2 or higher increase in creatinine levels occurred after completion of FOLFOX in 1.7% vs 0.5% of patients, respectively.

Conclusions And Relevance: Among patients with stage III colon cancer, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant chemotherapy did not significantly improve disease-free survival.

Trial Registration: ClinicalTrials.gov Identifier: NCT01150045.
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http://dx.doi.org/10.1001/jama.2021.2454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025124PMC
April 2021

Fiducial-based image-guided SBRT for pancreatic adenocarcinoma: Does inter-and intra-fraction treatment variation warrant adaptive therapy?

Radiat Oncol 2021 Mar 19;16(1):53. Epub 2021 Mar 19.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, 401 N. Broadway, Suite 1440, Baltimore, MD, 21231, USA.

Purpose: Variation in target positioning represents a challenge to set-up reproducibility and reliability of dose delivery with stereotactic body radiation therapy (SBRT) for pancreatic adenocarcinoma (PDAC). While on-board imaging for fiducial matching allows for daily shifts to optimize target positioning, the magnitude of the shift as a result of inter- and intra-fraction variation may directly impact target coverage and dose to organs-at-risk. Herein, we characterize the variation patterns for PDAC patients treated at a high-volume institution with SBRT.

Methods: We reviewed 30 consecutive patients who received SBRT using active breathing coordination (ABC). Patients were aligned to bone and then subsequently shifted to fiducials. Inter-fraction and intra-fraction scans were reviewed to quantify the mean and maximum shift along each axis, and the shift magnitude. A linear regression model was conducted to investigate the relationship between the inter- and intra-fraction shifts.

Results: The mean inter-fraction shift in the LR, AP, and SI axes was 3.1 ± 1.8 mm, 2.9 ± 1.7 mm, and 3.5 ± 2.2 mm, respectively, and the mean vector shift was 6.4 ± 2.3 mm. The mean intra-fraction shift in the LR, AP, and SI directions were 2.0 ± 0.9 mm, 2.0 ± 1.3 mm, and 2.3 ± 1.4 mm, respectively, and the mean vector shift was 4.3 ± 1.8 mm. A linear regression model showed a significant relationship between the inter- and intra-fraction shift in the AP and SI axis and the shift magnitude.

Conclusions: Clinically significant inter- and intra-fraction variation occurs during treatment of PDAC with SBRT even with a comprehensive motion management strategy that utilizes ABC. Future studies to investigate how these variations could lead to variation in the dose to the target and OAR should be investigated. Strategies to mitigate the dosimetric impact, including real time imaging and adaptive therapy, in select cases should be considered.
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http://dx.doi.org/10.1186/s13014-021-01782-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980583PMC
March 2021

Geometric Reproducibility of Fiducial Markers and Efficacy of a Patient-Specific Margin Design Using Deep Inspiration Breath Hold for Stereotactic Body Radiation Therapy for Pancreatic Cancer.

Adv Radiat Oncol 2021 Mar-Apr;6(2):100655. Epub 2021 Jan 22.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University of School of Medicine, Baltimore, Maryland.

Purpose: In patients undergoing stereotactic body radiation therapy (SBRT) for pancreatic adenocarcinoma, the reproducibility of tumor positioning between deep-inspiration breath holds is unclear. We characterized this variation with fiducials at simulation and treatment and investigated whether a patient-specific breath-hold (PSBH) margin would help account for intrafraction variation at treatment.

Methods And Materials: We analyzed 20 consecutive patients with pancreatic cancer who underwent SBRT with deep-inspiration breath holds. At simulation, 3 additional breath-hold scans were acquired immediately after the contrast-enhanced planning computed tomography (CT) scan and used to quantify the mean and maximum variations in the simulation fiducial position ( and ), as well as to design the internal target volume (ITV) incorporating a PSBH margin.

Results: At treatment, a mean of 5 breath-hold cone beam CT (CBCT) scans were acquired per fraction for each patient to quantify the mean and maximum variations in the treatment fiducial position ( and ). Various planning target volume (PTV) margins on the gross tumor volume (GTV) versus ITV were evaluated using CBCT scans, with the goal of >95% of fiducials being covered at treatment. The and were 0.9 ± 0.5 mm and 1.5 ± 0.8 mm in the left-right (LR) direction, 0.9 ± 0.4 mm and 1.4 ± 0.4 mm in the anteroposterior (AP) direction, and 1.5 ± 0.9 mm and 2.1 ± 1.0 mm in the superoinferior (SI) direction, respectively. The and were 1.2 ± 0.4 mm and 2.0 ± 0.7 mm in the LR direction, 1.1 ± 0.4 mm and 1.8 ± 0.6 mm in the AP direction, and 1.9 ± 1.0 mm and 3.1 ± 1.4 mm in the SI direction, respectively. The ITV was increased by 21.0% ± 8.6% compared with the GTV alone. The PTV margin necessary to encompass >95% of the fiducial locations was 2 mm versus 4 mm in both LR and AP and 4 mm versus 6 mm in SI for the ITV and the GTV, respectively.

Conclusions: The interbreath-hold variation is not insignificant, especially in the SI direction. Acquiring multiple breath-hold CT scans at simulation can help quantify the reproducibility of the interbreath hold and design a PSBH margin for treatment.
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http://dx.doi.org/10.1016/j.adro.2021.100655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940819PMC
January 2021

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging.

Acta Pharm Sin B 2021 Feb 25;11(2):373-393. Epub 2020 Aug 25.

Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA.

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.
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http://dx.doi.org/10.1016/j.apsb.2020.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893127PMC
February 2021

Inflammation, Obsessive-Compulsive Disorder, and Related Disorders.

Authors:
Jeffrey Meyer

Curr Top Behav Neurosci 2021 Feb 24. Epub 2021 Feb 24.

Campbell Family Mental Health Research Institute, CAMH, Toronto, ON, Canada.

Initial reports supporting the possibility of inflammation in the brain in obsessive-compulsive disorder (OCD) evolved from the models of Sydenham's Chorea, and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS), which implicated excessive autoimmune responses following exposure to group A B-hemolytic streptococcal infections. Subsequently, this model was expanded to Pediatric Autoimmune Neuropsychiatric Syndrome (PANS) which applied the same concept but included other infections. A critical shortcoming of this model was that it was attributable to a small minority of OCD cases. The relationship between inflammation and OCD was more broadly demonstrated through translocator protein (TSPO) positron emission tomography imaging, a method that detects gliosis, an important component of brain inflammation, in neuropsychiatric diseases, including morphological activation and proliferation of microglia and to some extent astroglia. This method identified greater TSPO binding in the cortico-striatal-thalamo-cortical circuit in OCD, providing a direct brain measure of an important component of inflammation. To identify OCD cases with prominent elevations in TSPO binding in clinical research settings with lower cost peripheral markers, a promising approach is to apply blood serum biomarkers of inflammatory molecules produced by activated microglia and astroglia (gliosis). Such measures may aid stratification in future clinical trials. Several inflammatory-modifying interventions, including celecoxib, minocycline, and n-acetylcysteine, have been tested as treatments in randomized double-blind placebo controlled clinical trials and there is a tendency toward positive results, although these medications are not optimized for brain penetration and sample sizes for most trials were small. Future clinical trials of medications that target gliosis in OCD should apply larger sample sizes, ideally incorporating stratification approaches to enrich samples for the presence of gliosis.
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http://dx.doi.org/10.1007/7854_2020_210DOI Listing
February 2021

The Effect of Oral L-cysteine on Breast Milk and Plasma Cysteine Concentrations.

Neuropsychiatr Dis Treat 2020 21;16:3163-3172. Epub 2020 Dec 21.

CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.

Purpose: Greater oxidative signaling is implicated in major depressive disorder; hence, there is considerable interest in developing oral supplements with anti-oxidant properties to prevent or treat mood disorders, such as postpartum depression. L-cysteine is a precursor for glutathione, an important antioxidant in the brain. So, developing L-cysteine as a dietary supplement may be useful, provided oral supplementation substantially raises its concentration in blood plasma yet does not affect its total concentration in breast milk. This study assessed the effect of oral L-cysteine on its concentration in breast milk and blood plasma of breastfeeding mothers.

Participants And Methods: Twenty-four health breastfeeding women were randomly assigned to 0, 1.5, or 3 g of oral L-cysteine. Free and total cysteine in breast milk; and free cysteine in plasma were measured. While breast milk is the gold standard, measurement of infant formulas provides indices of nutritional intake considered safe. Therefore, free cysteine was also measured in six different formulas.

Results: Total cysteine in breast milk was not affected by oral L-cysteine (Repeated Measures of ANOVA (rANOVA), intervention effect: =0.75). Free cysteine levels in breast milk did rise (rANOVA, intervention effect: =0.017), but were within the range of common infant formulas. There was no significant effect of L-cysteine supplementation on free cysteine levels in plasma (rANOVA, intervention effect: =0.25), although a post hoc analysis found a trend towards greater plasma cysteine 30 minutes after oral supplementation ((14)=-1.69, =0.11, 3g versus no-dose).

Conclusion: The negligible effect of oral cysteine administration on its total concentration in breast milk was favorable, but the minimal effect on its blood plasma concentration more strongly argues against further development of oral L-cysteine in postpartum, as well as other conditions.
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http://dx.doi.org/10.2147/NDT.S255205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762443PMC
December 2020

Long-Term Results of a Phase 1 Dose-Escalation Trial and Subsequent Institutional Experience of Single-Fraction Stereotactic Ablative Radiation Therapy for Liver Metastases.

Int J Radiat Oncol Biol Phys 2021 Apr 16;109(5):1387-1395. Epub 2020 Dec 16.

Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas.

Purpose: We report long-term outcomes from our phase 1 dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR pooled with our subsequent single institutional experience with patients treated postprotocol at the highest dose level (40 Gy) established from the phase 1 study.

Methods And Materials: Patients with liver metastases from solid tumors located outside of the central liver zone were treated with single-fraction SABR on a phase 1 dose escalation trial. At least 700 cc of normal liver had to receive <9.1 Gy. Seven patients with 10 liver metastases received the initial prescription dose of 35 Gy, and dose was then escalated to 40 Gy for 7 more patients with 7 liver metastases. An additional 19 postprotocol patients with 22 liver metastases were treated to 40 Gy in a single fraction. Patients were followed for toxicity and underwent serial imaging to assess local control.

Results: Median imaging follow-up for the combined cohort (n = 33, 39 lesions) was 25.9 months; 38.9 months for protocol patients and 20.2 months for postprotocol patients. Median lesion size was 2.0 cm (range, 0.5-5.0 cm). There were no dose-limiting toxicities observed for protocol patients, and only 3 grade 2 toxicities were observed in the entire cohort, with no grade ≥3 toxicities attributable to treatment. Four-year actuarial local control of irradiated lesions in the entire cohort was 96.6%, 100% in the protocol group and 92.9% in the subsequent patients. Two-year overall survival for all treated patients was 82.0%.

Conclusions: For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy was safe and well-tolerated, and shows excellent local control with long-term follow-up; results in subsequent patients treated with single-fraction SABR doses of 40 Gy confirmed our earlier results.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.012DOI Listing
April 2021

Long-Term Results of a Phase 1 Dose-Escalation Trial and Subsequent Institutional Experience of Single-Fraction Stereotactic Ablative Radiation Therapy for Liver Metastases.

Int J Radiat Oncol Biol Phys 2021 Apr 16;109(5):1387-1395. Epub 2020 Dec 16.

Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, Texas.

Purpose: We report long-term outcomes from our phase 1 dose-escalation study to determine the maximum tolerated dose of single-fraction liver SABR pooled with our subsequent single institutional experience with patients treated postprotocol at the highest dose level (40 Gy) established from the phase 1 study.

Methods And Materials: Patients with liver metastases from solid tumors located outside of the central liver zone were treated with single-fraction SABR on a phase 1 dose escalation trial. At least 700 cc of normal liver had to receive <9.1 Gy. Seven patients with 10 liver metastases received the initial prescription dose of 35 Gy, and dose was then escalated to 40 Gy for 7 more patients with 7 liver metastases. An additional 19 postprotocol patients with 22 liver metastases were treated to 40 Gy in a single fraction. Patients were followed for toxicity and underwent serial imaging to assess local control.

Results: Median imaging follow-up for the combined cohort (n = 33, 39 lesions) was 25.9 months; 38.9 months for protocol patients and 20.2 months for postprotocol patients. Median lesion size was 2.0 cm (range, 0.5-5.0 cm). There were no dose-limiting toxicities observed for protocol patients, and only 3 grade 2 toxicities were observed in the entire cohort, with no grade ≥3 toxicities attributable to treatment. Four-year actuarial local control of irradiated lesions in the entire cohort was 96.6%, 100% in the protocol group and 92.9% in the subsequent patients. Two-year overall survival for all treated patients was 82.0%.

Conclusions: For selected patients with liver metastases, single-fraction SABR at doses of 35 and 40 Gy was safe and well-tolerated, and shows excellent local control with long-term follow-up; results in subsequent patients treated with single-fraction SABR doses of 40 Gy confirmed our earlier results.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.012DOI Listing
April 2021

Neuroinflammation in psychiatric disorders: PET imaging and promising new targets.

Lancet Psychiatry 2020 12 21;7(12):1064-1074. Epub 2020 Oct 21.

Molecular Imaging Branch, National Institute of Mental Health, Bethesda, MD, USA. Electronic address:

Neuroinflammation is a multifaceted physiological and pathophysiological response of the brain to injury and disease. Given imaging findings of 18 kDa translocator protein (TSPO) and the development of radioligands for other inflammatory targets, PET imaging of neuroinflammation is at a particularly promising stage. This Review critically evaluates PET imaging results of inflammation in psychiatric disorders, including major depressive disorder, schizophrenia and psychosis disorders, substance use, and obsessive-compulsive disorder. We also consider promising new targets that can be measured in the brain, such as monoamine oxidase B, cyclooxygenase-1 and cyclooxygenase-2, colony stimulating factor 1 receptor, and the purinergic P2X7 receptor. Thus far, the most compelling TSPO imaging results have arguably been found in major depressive disorder, for which consistent increases have been observed, and in schizophrenia and psychosis, for which patients show reduced TSPO levels. This pattern highlights the importance of validating brain biomarkers of neuroinflammation for each condition separately before moving on to patient stratification and treatment monitoring trials.
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http://dx.doi.org/10.1016/S2215-0366(20)30255-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893630PMC
December 2020

Are There Therapeutic Benefits of Cannabinoid Products in Adult Mental Illness?

Can J Psychiatry 2021 Feb 11;66(2):185-194. Epub 2020 Sep 11.

Department of Psychiatry, University of Calgary, Alberta, Canada.

A position statement developed by the Canadian Psychiatric Association's (CPA) Research Committee and approved by the CPA's Board of Directors on May 13, 2020.
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http://dx.doi.org/10.1177/0706743720945525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918871PMC
February 2021

Feasibility and Outcome of Routine Use of Concurrent Chemoradiation in HIV-positive Patients With Squamous Cell Anal Cancer.

Am J Clin Oncol 2020 10;43(10):701-708

Departments of Radiation Oncology.

Objectives: Clinical concerns about hematologic toxicities in human immunodeficiency virus (HIV)+ patients with squamous cell anal cancer (SCAC) may lead to de-escalation of treatment intensity. The objective of this study is to evaluate clinical outcomes including toxicity following standard concurrent curative-intent chemoradiation for HIV+ and HIV- patients with SCAC.

Materials And Methods: Among 97 evaluable patients treated between 2009 and 2016 (median age 52.2 y), 43 (44.3%) were HIV+ and 54 (55.7%) HIV-. The majority of the radiation was delivered using intensity-modulated radiation therapy and chemotherapy consisting primarily (93%) of 5-fluorouracil and mitomycin C. Clinical outcomes assessed included toxicity, locoregional control (LRC), distant metastasis (DM), progression-free survival (PFS), colostomy-free survival (CFS), overall survival (OS), and cause-specific survival (CSS).

Results: With a median follow-up of 45 months, HIV+ patients exhibited a trend toward reduced OS compared with HIV- patients (4 y OS 61.2% vs. 78.3%; HR 2.09; 95% CI, 0.97-4.52; P=0.055) on univariable analysis, but HIV status was not significant after adjusting for additional parameters on multivariable analysis. Toxicity rates, LRC, CFS, PFS, freedom from DM, and CSS were similar between the 2 cohorts. On multivariable analysis, tumor size >5 cm impacted all clinical outcomes (trend for LRC) except CFS. Radiation treatment extension beyond 7 days was found to negatively impact LRC and CSS. Male sex was associated with worse CFS.

Conclusions: Radiation therapy with concurrent 5-fluorouracil and mitomycin C chemotherapy is reasonably well-tolerated as curative treatment for HIV+ patients with SCAC, and no significant difference in outcomes was noted relative to HIV- patients.
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http://dx.doi.org/10.1097/COC.0000000000000736DOI Listing
October 2020

Excess tau PET ligand retention in elderly patients with major depressive disorder.

Mol Psychiatry 2020 Jul 1. Epub 2020 Jul 1.

Department of Functional Brain Imaging Research, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.

Depression is one of the common psychiatric disorders in old age. Major depressive disorder (MDD) has been identified as a risk factor or prodrome for neurodegenerative dementias, suggesting neuropathological overlaps and a continuum between MDD and neurodegenerative disorders. In this study, we examined tau and amyloid-β (Aβ) accumulations in the brains of MDD and healthy controls using positron emission tomography (PET) to explore pathological substrates of this illness. Twenty MDD and twenty age-matched, healthy controls were examined by PET with a tau radioligand, [C]PBB3, and an Aβ radioligand, [C]PiB. Radioligand retentions were quantified as a standardized uptake value ratio (SUVR). We also assessed clinical manifestations of the patients using the 17-item Hamilton Depression Scale, the Geriatric Depression Scale, and psychotic symptoms. Mean cortical [C]PBB3 SUVRs in MDD patients were significantly higher than those of healthy controls. These values were higher in MDD patients with psychotic symptoms than in those without any. The present findings indicate that tau depositions may underlie MDD, and especially in patients with psychotic symptoms. PET detection of tau accumulations may provide mechanistic insights into neuronal dysfunctions in these cases and could serve as predictions of their clinical consequences.
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http://dx.doi.org/10.1038/s41380-020-0766-9DOI Listing
July 2020

Serotonin transporter protein in autopsied brain of chronic users of cocaine.

Psychopharmacology (Berl) 2020 Sep 3;237(9):2661-2671. Epub 2020 Jun 3.

Human Brain Laboratory, Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Rationale: The long-held speculation that the brain serotonin system mediates some behavioral effects of the psychostimulant cocaine is supported in part by the high affinity of cocaine for the serotonin transporter (SERT) and by reports that the serotonin transporter (SERT), estimated by SERT binding, is increased in brain of human chronic cocaine users. Excessive SERT activity and consequent synaptic serotonin deficiency might cause a behavioral (e.g., mood) abnormality in chronic users of the drug.

Objective And Methods: Previous studies focused on changes in SERT binding, which might not necessarily reflect changes in SERT protein. Therefore, we compared levels of SERT protein, using a quantitative Western blot procedure, in autopsied brain (striatum, cerebral cortices) of chronic human cocaine users (n = 9), who all tested positive for the drug/metabolite in brain, to those in control subjects (n = 15) and, as a separate drug of abuse group, in chronic heroin users (n = 11).

Results: We found no significant difference in protein levels of SERT or the serotonin synthesizing enzyme tryptophan hydroxylase-2 among the control and drug abuse groups. In the cocaine users, no significant correlations were observed between SERT and brain levels of cocaine plus metabolites, or with levels of serotonin or its metabolite 5-hydroxyindoleacetic acid.

Conclusion: Our postmortem data suggest that a robust increase in striatal/cerebral cortical SERT protein is not a common characteristic of chronic, human cocaine users.
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http://dx.doi.org/10.1007/s00213-020-05562-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502513PMC
September 2020

Minocycline and celecoxib as adjunctive treatments for bipolar depression: a multicentre, factorial design randomised controlled trial.

Lancet Psychiatry 2020 06 20;7(6):515-527. Epub 2020 May 20.

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Background: Several small studies suggest that the adjunctive use of anti-inflammatory agents might improve depressive symptoms in bipolar disorder. However, there are few well designed, appropriately powered clinical trials assessing the efficacy of these novel treatment strategies. We aimed to assess the efficacy of adjunctive minocycline or celecoxib in this setting.

Methods: This double-blind, 12-week, randomised, placebo-controlled trial was done in four outpatient psychiatric clinics in Pakistan. Eligible participants were adults (aged 18-65 years) with DSM-5 bipolar disorder (type I or II) and a major depressive episode. In a 2 × 2 factorial design, participants were randomly assigned (1:1:1:1) to receive either active minocycline plus active celecoxib, active minocycline plus placebo celecoxib, placebo minocycline plus active celecoxib, or placebo minocycline plus placebo celecoxib. The primary outcome was the mean change from baseline to week 12 in score on the 17-item Hamilton Depression Rating Scale (HAMD-17), assessed in all randomised participants (missing data were imputed and assumed to be missing at random). The trial was registered with ClinicalTrials.gov, NCT02703363.

Findings: 266 (17%) of 1542 patients assessed between May 1, 2016, and March 31, 2019, were randomly assigned to receive minocycline plus celecoxib (n=68), minocycline plus placebo (n=66), celecoxib plus placebo (n=66), or placebo plus placebo (n=66). From baseline to week 12, depressive symptoms as per HAMD-17 reduced in all four groups (from 24·5-25·2 to 11·3-12·8), but these reductions did not differ significantly between the groups. In terms of main effects, reductions in HAMD-17 did not differ for patients treated with minocycline (mean adjusted difference vs non-minocycline 1·48 [95% CI -0·41 to 3·36]; p=0·123) or for celecoxib (mean adjusted difference vs non-celecoxib -0·74 [-2·61 to 1·14]; p=0·443). Rates of serious adverse effects did not differ between groups (31 participants had a manic switch, two self-harmed, and one died in a motor vehicle accident).

Interpretation: We found no evidence that minocycline or celecoxib was superior to placebo for the treatment of bipolar depression. This large trial casts doubt on the potential therapeutic benefits of adjunctive anti-inflammatory drugs for the acute management of bipolar depression.

Funding: Stanley Medical Research Institute.
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http://dx.doi.org/10.1016/S2215-0366(20)30138-3DOI Listing
June 2020

Translocator Protein Distribution Volume Predicts Reduction of Symptoms During Open-Label Trial of Celecoxib in Major Depressive Disorder.

Biol Psychiatry 2020 10 29;88(8):649-656. Epub 2020 Mar 29.

Brain Health Imaging Centre and Campbell Family Mental Health Research Institute, the Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Gliosis is common among neuropsychiatric diseases, but the relationship between gliosis and response to therapeutics targeting effects of gliosis is largely unknown. Translocator protein total distribution volume (TSPO V), measured with positron emission tomography, mainly reflects gliosis in neuropsychiatric disease. Here, the primary objective was to determine whether TSPO V in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) predicts reduction of depressive symptoms following open-label celecoxib administration in treatment-resistant major depressive disorder.

Methods: A total of 41 subjects with treatment-resistant major depressive disorder underwent one [F]FEPPA positron emission tomography scan to measure PFC and ACC TSPO V. Open-label oral celecoxib (200 mg, twice daily) was administered for 8 weeks. Change in symptoms was measured with the 17-item Hamilton Depression Rating Scale (HDRS).

Results: Cumulative mean change in HDRS scores between 0 and 8 weeks of treatment was plotted against PFC and ACC TSPO V, showing a significant nonlinear relationship. At low TSPO V values, there was no reduction in HDRS scores, but as TSPO V values increased, there was a reduction in HDRS scores that then plateaued. This was modeled with a 4-parameter sigmoidal model in which PFC and ACC TSPO V accounted for 84% and 92% of the variance, respectively.

Conclusions: Celecoxib administration in the presence of gliosis labeled by TSPO V is associated with greater reduction of symptoms. Given the predictiveness of TSPO V on symptom reduction, this personalized medicine approach of matching a marker of gliosis to medication targeting effects of gliosis should be applied in early development of novel therapeutics, in particular for treatment-resistant major depressive disorder.
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http://dx.doi.org/10.1016/j.biopsych.2020.03.007DOI Listing
October 2020

Minocycline as adjunctive treatment for treatment-resistant depression: study protocol for a double blind, placebo-controlled, randomized trial (MINDEP2).

BMC Psychiatry 2020 04 15;20(1):173. Epub 2020 Apr 15.

Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Background: Available evidence suggests that adjunctive treatment with immunomodulatory medications may be effective in the treatment of major depressive disorder (MDD). A pilot trial of the tetracycline minocycline as adjunctive treatment in treatment-resistant depression (TRD), produced promising results, however, a larger scale trial is needed to confirm the antidepressant actions of this drug.

Methods: This is a 12-week double blind, placebo-controlled, randomized trial of minocycline as an add-on to standard antidepressants for adults (age > 18) with DSM-5 major depressive episode, who have failed to respond to at least two adequate trials of antidepressant treatment. It is a parallel-arm study with 50 participants in each group. The primary outcome measure is change in 17-item Hamilton Depression Rating Scale (HRSD-17) total scores from baseline to week 12. Secondary measures include the Clinical Global Impression (CGI) scale, World Health Organization Quality of Life Short Version (WHOQOL-BREF) and the Generalized Anxiety Disorder scale (GAD-7). Peripheral inflammatory biomarkers will be collected at baseline, week 6 and 12.

Discussion: If minocycline is well tolerated and effective in reducing depressive symptoms in patients with TRD, it would warrant genuine consideration as a treatment option for TRD. Additionally, if results demonstrate that minocycline has antidepressant properties, and that changes in inflammatory status are associated with its antidepressant action, it will inform the development of individualized treatment for a subset of patients with MDD.

Trial Registration: Clinicaltrials.gov identifier: NCT03947827. Registered 13th May, 2019.
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http://dx.doi.org/10.1186/s12888-020-02553-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161279PMC
April 2020

Evaluation of a Novel Absorbable Radiopaque Hydrogel in Patients Undergoing Image Guided Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Adenocarcinoma.

Pract Radiat Oncol 2020 Nov - Dec;10(6):e508-e513. Epub 2020 Mar 7.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland. Electronic address:

Purpose: We assessed the feasibility and safety of placing a radiopaque hydrogel in the pancreaticoduodenal groove via endoscopic ultrasound guidance in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC).

Methods And Materials: Hydrogel injections were done at time of fiducial placement to form blebs in the pancreaticoduodenal groove. Patients subsequently underwent simulation computed tomography (sim-CT) followed by hypofractionated stereotactic body radiotherapy (SBRT; 33 Gy in 5 fractions). Four to 8 weeks after SBRT, patients underwent CT re-evaluation for surgical candidacy and assessment of hydrogel location and size. Hydrogel placement was considered successful if identified in the pancreaticoduodenal groove on sim-CT scan. Stability was evaluated using equivalence testing analyses, with a null hypothesis of the presence of a ≥20% mean percentage change in volume and ≥2 mm change in the median and mean interbleb surface distance with a P value <.05 required to reject the null hypothesis and conclude equivalence. For patients undergoing pancreaticoduodenectomy, hydrogel sites were histologically examined for location and local inflammatory reactions.

Results: Hydrogel placement was successful in 6 of the 6 evaluable patients. The average changes in median and mean interbleb distances were -0.43 mm and -0.35 mm, respectively, with P < .05. The average change in volume from sim-CT to post-SBRT CT was -1.0%, with P < .05. One patient experienced grade 3 nausea after fiducial/hydrogel placement, with no other adverse events to date.

Conclusions: These data demonstrate feasibility and safety of injecting a hydrogel marker in the pancreaticoduodenal groove in patients with BR/LAPC and set the stage for a follow-up clinical trial to place hydrogel as a spacer between the pancreatic tumor and dose-limiting, radiosensitive duodenum.
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http://dx.doi.org/10.1016/j.prro.2020.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483342PMC
March 2020

Microglia imaging in methamphetamine use disorder: a positron emission tomography study with the 18 kDa translocator protein radioligand [F-18]FEPPA.

Addict Biol 2021 01 4;26(1):e12876. Epub 2020 Feb 4.

Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Activation of brain microglial cells, microgliosis, has been linked to methamphetamine (MA)-seeking behavior, suggesting that microglia could be a new therapeutic target for MA use disorder. Animal data show marked brain microglial activation following acute high-dose MA, but microglial status in human MA users is uncertain, with one positron emission tomography (PET) investigation reporting massively and globally increased translocator protein 18 kDa (TSPO; [C-11](R)-PK11195) binding, a biomarker for microgliosis, in MA users. Our aim was to measure binding of a second-generation TSPO radioligand, [F-18]FEPPA, in brain of human chronic MA users. Regional total volume of distribution (V ) of [F-18]FEPPA was estimated with a two-tissue compartment model with arterial plasma input function for 10 regions of interest in 11 actively using MA users and 26 controls. A RM-ANOVA corrected for TSPO rs6971 polymorphism was employed to test significance. There was no main effect of group on [F-18]FEPPA V (P = .81). No significant correlations between [F-18]FEPPA V and MA use duration, weekly dosage, blood MA concentrations, regional brain volumes, and self-reported craving were observed. Our preliminary findings, consistent with our earlier postmortem data, do not suggest substantial brain microgliosis in MA use disorder but do not rule out microglia as a therapeutic target in MA addiction. Absence of increased [F-18]FEPPA TSPO binding might be related to insufficient MA dose or blunting of microglial response following repeated MA exposure, as suggested by some animal data.
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http://dx.doi.org/10.1111/adb.12876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398821PMC
January 2021

Replicating predictive serum correlates of greater translocator protein distribution volume in brain.

Neuropsychopharmacology 2020 05 4;45(6):925-931. Epub 2019 Nov 4.

Research Imaging Centre and Campbell Family Mental Health Research Institute at the Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.

Greater activation of glia, a key component of neuroinflammation, is an important process to target in neuropsychiatric illnesses. However, the magnitude of gliosis varies across cases so low-cost predictors are needed to stratify subjects for clinical trials. Here, several such blood serum measures were assessed in relation to TSPO V, an index of translocator protein density, measured with positron emission tomography. Blood serum concentration of several products known to be synthesized by activated microglia (and to some extent astroglia) [prostaglandin E (PGE), prostaglandin F alpha (PGF), and tumor necrosis factor alpha (TNF)], controlled by an index of peripheral inflammation [C-reactive protein (CRP)] and TSPO V were measured in 3 cohorts: prefrontal cortex TSPO V of 20 subjects with major depressive episodes (MDEs) from major depressive disorder (MDD); and 56 subjects with treatment resistant MDEs from MDD; and dorsal caudate TSPO V of 20 subjects with obsessive-compulsive disorder. Ln(PGE/CRP) and ln(TNF/CRP) consistently correlated with TSPO V (R = 0.36 to 0.11, p = 0.0030 to p = 0.0076). Assessment of threshold serum values to predict highly elevated TSPO V, demonstrated that a positive predictive value (PPV) of 80% was possible while retaining 40% of participant samples and that receiver operating curves (ROC) ranged from 75 to 81%. Post-hoc selection of ln(CRP) was more predictive (R = 0.23 to 0.39, p = 0.0058 to p = 0.00013; ROC > 80%). Systematic assessment of selected peripheral inflammatory markers is promising for developing low cost predictors of TSPO V. Marker thresholds with high PPV will improve subject stratification for clinical trials of glial targeting therapeutics.
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http://dx.doi.org/10.1038/s41386-019-0561-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162884PMC
May 2020

Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin.

Lancet Psychiatry 2020 01 24;7(1):93-108. Epub 2019 Oct 24.

Department of Psychiatry and Psychotherapy II, Ulm University, Bezirkskrankenhaus Günzburg, Günzburg, Germany.

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.
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http://dx.doi.org/10.1016/S2215-0366(19)30290-1DOI Listing
January 2020

Considerations of target surface area and the risk of radiosurgical toxicity.

PLoS One 2019 21;14(10):e0224047. Epub 2019 Oct 21.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.

Objective: The goal of this study was to explore conceptual benefits of characterizing delineated target volumes based on surface area and to utilize the concept for assessing risk of therapeutic toxicity in radiosurgery.

Methods And Materials: Four computer-generated targets, a sphere, a cylinder, an ellipsoid and a box, were designed for two distinct scenarios. In the first scenario, all targets had identical volumes, and in the second one, all targets had identical surface areas. High quality stereotactic radiosurgery plans with at least 95% target coverage and selectivity were created for each target in both scenarios. Normal brain volumes V12Gy, V14Gy and V16Gy corresponding to received dose of 12 Gy, 14 Gy and 16 Gy, respectively, were computed and analyzed. Additionally, V12Gy and V14Gy volumes and values for seven prospective toxicity variables were recorded for 100 meningioma patients after Gamma Knife radiosurgery. Multivariable stepwise linear regression and best subset linear regression analyses were performed in two statistical software packages, SAS/STAT and R, respectively.

Results: In a phantom study, for the constant volume targets, the volumes of 12 Gy, 14 Gy and 16 Gy isodose clouds were the lowest for the spherical target as an expected corollary of the isoperimetric inequality. For the constant surface area targets, a conventional wisdom is confirmed, as the target volume increases the corresponding volumes V12Gy, V14Gy and V16Gy also increase. In the 100-meningioma patient cohort, the best univariate model featured tumor surface area as the most significantly associated variable with both V12Gy and V14Gy volumes, corresponding to the adjusted R2 values of 0.82 and 0.77, respectively. Two statistical methods converged to matching multivariable models.

Conclusions: In a univariate model, target surface area is a better predictor of spilled dose to normal tissue than target largest dimension or target volume itself. In complex multivariate models, target surface area is an independent variable for modeling radiosurgical normal tissue toxicity risk.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0224047PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802845PMC
March 2020

In Vivo Imaging of Translocator Protein in Long-term Cannabis Users.

JAMA Psychiatry 2019 12;76(12):1305-1313

Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Importance: Cannabis is the most commonly used illicit drug in the world. Cannabinoids have been shown to modulate immune responses; however, the association of cannabis with neuroimmune function has never been investigated in vivo in the human brain.

Objective: To investigate neuroimmune activation or 18-kDa translocator protein (TSPO) levels in long-term cannabis users, and to evaluate the association of brain TSPO levels with behavioral measures and inflammatory blood biomarkers.

Design, Setting, And Participants: This cross-sectional study based in Toronto, Ontario, recruited individuals from January 1, 2015, to October 30, 2018. Participants included long-term cannabis users (n = 24) and non-cannabis-using controls (n = 27). Cannabis users were included if they had a positive urine drug screen for only cannabis and if they used cannabis at least 4 times per week for the past 12 months and/or met the criteria for cannabis use disorder. All participants underwent a positron emission tomography scan with [18F]FEPPA, or fluorine F 18-labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide.

Main Outcomes And Measures: Total distribution volume was quantified across regions of interest. Stress and anxiety as well as peripheral measures of inflammatory cytokines and C-reactive protein levels were also measured.

Results: In total, 24 long-term cannabis users (mean [SD] age, 23.1 [3.8] years; 15 men [63%]) and 27 non-cannabis-using controls (mean [SD] age, 23.6 [4.2] years; 18 women [67%]) were included and completed all study procedures. Compared with the controls, cannabis users had higher [18F]FEPPA total distribution volume (main group effect: F1,48 = 6.5 [P = .01]; ROI effect: F1,200 = 28.4 [P < .001]; Cohen d = 0.6; 23.3% higher), with a more prominent implication for the cannabis use disorder subgroup (n = 15; main group effect: F1,39 = 8.5 [P = .006]; ROI effect: F1,164 = 19.3 [P < .001]; Cohen d = 0.8; 31.5% higher). Greater TSPO levels in the brain were associated with stress and anxiety and with higher circulating C-reactive protein levels in cannabis users.

Conclusions And Relevance: The results of this study suggest that TSPO levels in cannabis users, particularly in those with cannabis use disorder, are higher than those in non-cannabis-using controls. The findings emphasize the need for more complementary preclinical systems for a better understanding of the role of cannabinoids and TSPO in neuroimmune signaling.
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http://dx.doi.org/10.1001/jamapsychiatry.2019.2516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751758PMC
December 2019

Enhancing liver tumor localization accuracy by prior-knowledge-guided motion modeling and a biomechanical model.

Quant Imaging Med Surg 2019 Jul;9(7):1337-1349

Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Background: Pre-treatment liver tumor localization remains a challenging task for radiation therapy, mostly due to the limited tumor contrast against normal liver tissues, and the respiration-induced liver tumor motion. Recently, we developed a biomechanical modeling-based, deformation-driven cone-beam CT estimation technique (Bio-CBCT), which achieved substantially improved accuracy on low-contrast liver tumor localization. However, the accuracy of Bio-CBCT is still affected by the limited tissue contrast around the caudal liver boundary, which reduces the accuracy of the boundary condition that is fed into the biomechanical modeling process. In this study, we developed a motion modeling and biomechanical modeling-guided CBCT estimation technique (MM-Bio-CBCT), to further improve the liver tumor localization accuracy by incorporating a motion model into the CBCT estimation process.

Methods: MM-Bio-CBCT estimates new CBCT images through deforming a prior high-quality CT or CBCT volume. The deformation vector field (DVF) is solved by iteratively matching the digitally-reconstructed-radiographs (DRRs) of the deformed prior image to the acquired 2D cone-beam projections. Using the same solved DVF, the liver tumor volume contoured on the prior image can be transferred onto the new CBCT image for automatic tumor localization. To maximize the accuracy of the solved DVF, MM-Bio-CBCT employs two strategies for additional DVF optimization: (I) prior-knowledge-guided liver boundary motion modeling with motion patterns extracted from a prior 4D imaging set like 4D-CTs/4D-CBCTs, to improve the liver boundary DVF accuracy; and (II) finite-element-analysis-based biomechanical modeling of the liver volume to improve the intra-liver DVF accuracy. We evaluated the accuracy of MM-Bio-CBCT on both the digital extended-cardiac-torso (XCAT) phantom images and real liver patient images. The liver tumor localization accuracy of MM-Bio-CBCT was evaluated and compared with that of the purely intensity-driven 2D-3D deformation technique, the 2D-3D deformation technique with motion modeling, and the Bio-CBCT technique. Metrics including the DICE coefficient and the center-of-mass-error (COME) were assessed for quantitative evaluation.

Results: Using limited-view 20 projections for CBCT estimation, the average (± SD) DICE coefficients between the estimated and the 'gold-standard' liver tumors of the XCAT study were 0.57±0.31, 0.78±0.26, 0.83±0.21, and 0.89±0.11 for 2D-3D deformation, 2D-3D deformation with motion modeling, Bio-CBCT and MM-Bio-CBCT techniques, respectively. Using 20 projections for estimation, the patient study yielded average DICE results of 0.63±0.21, 0.73±0.13 and 0.78±0.12, and 0.83±0.09, correspondingly. The MM-Bio-CBCT localized the liver tumor to an average COME of ~2 mm for both the XCAT and the liver patient studies.

Conclusions: Compared to Bio-CBCT, MM-Bio-CBCT further improves the accuracy of liver tumor localization. MM-Bio-CBCT can potentially be used towards pre-treatment liver tumor localization and intra-treatment liver tumor location verification to achieve substantial radiotherapy margin reduction.
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http://dx.doi.org/10.21037/qims.2019.07.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685812PMC
July 2019

Sequential short-course radiation therapy and chemotherapy in the neoadjuvant treatment of rectal adenocarcinoma.

Radiat Oncol 2019 Aug 19;14(1):147. Epub 2019 Aug 19.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: There is continued debate regarding the optimal combinations of radiation therapy and chemotherapy in the preoperative treatment of locally advanced rectal adenocarcinomas. We report our single-institution experience of feasibility and early oncologic outcomes of short-course preoperative radiation therapy (5 Gy X 5 fractions) followed by consolidation neoadjuvant chemotherapy.

Methods: We reviewed the records of 26 patients with locally advanced rectal adenocarcinoma. All patients underwent short course radiotherapy (5 Gy X 5 fractions) followed by chemotherapy [either modified infusional and bolus 5-fluorouracail and oxalipatin (mFOLFOX6) or capecitabine and oxaliplatin] prior to consideration for surgery. A full course of chemotherapy was defined as at least 8 weeks of chemotherapy.

Results: There were five clinical (c) T2, 16 cT3, and five cT4 rectal tumors, with 88% cN+. Twenty-five patients received a median of 4 cycles (range 3 to 8) of mFOLFOX6 (with one cycle defined as a two-week period); one patient received 3 cycles of capecitabine and oxaliplatin. All patients completed SCRT; 81% completed the full course of neoadjuvant chemotherapy with 19% requiring dose reductions in chemotherapy, most commonly due to neuropathy. Nineteen patients underwent post-treatment endoscopic evaluation, and nine patients were noted to achieve a complete clinical response (CCR). Six of the nine patients who achieved CCR opted for a non-operative approach of watch-and-wait. Twenty patients underwent surgical resection; pathologic complete response was observed in seven (35%) of these twenty. The main radiation-associated toxicity was proctitis with CTCAE Grade 2 proctitis observed in seven patients (27%). Post-operative Clavien-Dindo Grade 3 complications within 30 days of surgery were identified in six patients (30%), with no Grade 4 or 5 adverse events. Median length of hospital stay was 4.5 days (range 2-16 days); three patients were readmitted within a 30 day period.

Conclusions: Short course preoperative radiotherapy followed by neoadjuvant chemotherapy was well-tolerated and achieved oncologic outcomes that compare favorably with short-course radiation therapy alone or long-course chemoradiotherapy. This regimen is associated with high rates of clinical and pathologic complete response.
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http://dx.doi.org/10.1186/s13014-019-1358-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700789PMC
August 2019

Radiation treatment planning with embedded dose escalation.

Radiat Oncol 2019 Aug 14;14(1):145. Epub 2019 Aug 14.

Dept. of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, 401 N Broadway St. Weinberg Suite 1440, Baltimore, MD, 21231, USA.

Background: Heterogeneous target doses are a common by-product from attempts to improve normal tissue sparing in radiosurgery treatment planning. These regions of escalated dose within the target may increase tumor control probability (TCP). Purposely embedding hot spots within tumors during optimization may also increase the TCP. This study discusses and compares five optimization approaches that not only eliminate homogeneity constraints, but also maximize heterogeneity and internal dose escalation.

Methods: Co-planar volumetric modulated arc therapy (VMAT) plans were produced for virtual spherical targets with 2-8 cm diameters, minimum target dose objectives of 25 Gy, and objectives to minimize normal tissue dose. Five other sets of plans were produced with additional target dose objectives: 1) minimum dose-volume histogram (DVH) objective on 10% of the target 2) minimum dose objective on a sub-structure within the target, and 3-5) minimum generalized equivalent uniform dose (gEUD) objectives assuming three different volume-effect parameters. Plans were normalized to provide equivalent maximum OAR dose and were compared in terms of target D0.1 cc, ratio of V12.5 Gy to PTV volume (R50%), monitor units per 5 Gy fraction (MU), and mean multi-leaf collimator (MLC) segment size. All planning approaches were also applied to a clinical patient dataset and compared.

Results: Mean ± standard deviation metrics achievable using the baseline and experimental approaches 1-5) included D0.1 cc: 27.7 ± 0.8, 64.6 ± 10.5, 56.5 ± 10.3, 48.9 ± 5.7, 44.8 ± 5.0, and 37.4 ± 4.5 Gy. R50%: 4.64 ± 3.27, 5.15 ± 2.32, 4.83 ± 2.64, 4.42 ± 1.83, 4.45 ± 1.88, and 4.21 ± 1.75. MU: 795 ± 27, 1988 ± 222, 1766 ± 259, 1612 ± 112, 1524 ± 90, and 1362 ± 146. MLC segment size: 4.7 ± 1.6, 2.3 ± 0.7, 2.6 ± 0.8, 2.7 ± 0.7, 2.7 ± 0.8, and 2.8 ± 0.8 cm.

Conclusions: The DVH-based approach provided the highest embedded doses for all target diameters and patient example with modest increases in R50%, achieved by decreasing MLC segment size while increasing MU. These results suggest that embedding doses > 220% of tumor margin dose is feasible, potentially improving TCP for solid tumors.
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http://dx.doi.org/10.1186/s13014-019-1348-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693221PMC
August 2019