The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Diagnostic performance of(18)F-FDG-PET/CT compared to standard skeletal survey for detecting bone destruction in smouldering multiple myeloma: time to move forward

Skeletal survey (SS) continues to be used in the community to detect bone disease in patients with multiple myeloma (MM). While the false-negative rate is high, the specificity of SS is less well characterised. Here, we compare the diagnostic accuracy of SS compared to(18)F-FDG-PET/CT (positron emission tomography/computed tomography) in 79 patients referred to our tertiary centre with a diagnosis of smouldering MM. SS had a specificity of 83 center dot 1% (95% confidence interval: 72 center dot 0-90 center dot 5%). This study reinforces the importance of using more specific imaging techniques to avoid inaccurate diagnosis that could lead to the risks associated with unnecessary therapy in patients with smouldering MM

Evaluation of Whole-Body MRI (WB-MRI) in Smoldering Multiple Myeloma (SMM)

Introduction Whole-body magnetic resonance imaging (WB-MRI), including multiplanar multisequence technique with diffusion weighted images, is a novel imaging technique being evaluated for patients with multiple myeloma (MM). WB-MRI is ideal for this population due to its high sensitivity for bone marrow signal changes and full anatomic coverage from vertex to mid-thighs. It is well established that patients with unequivocal focal lesions on MRI have worse outcomes. Currently the IMWG recommends that all patients with smoldering multiple myeloma (SMM) undergo WB-MRI (or whole spine MRI if WB-MRI is not available) to rule out two or more focal lesions which would classify the patient as having symptomatic myeloma requiring treatment. There is a clear benefit of using MRI for the detection of early focal myeloma lesions however less is known about findings in the SMM population. Detection of subtle findings such as one small focal lesion or heterogeneous bone marrow in WB-MRI has unknown clinical significance that needs to be further evaluated. This study aimed to evaluate the sensitivity of WB-MRI compared to other highly sensitive functional imaging modalities in patients with SMM both at baseline and after treatment. Methods Imaging of patients with WB-MRI performed at the National Institutes of Health Clinical Center Myeloma Program were reviewed and compared to whole spine MRI and 18F-FDG PET/CT completed at the same timepoint. The majority of patients were being evaluated for enrollment on clinical trials. Patients had undergone a WB-MRI with a 3-Tesla system either as a baseline study, after completion of induction treatment, or during follow up determined by the time DWI became available at our institution. The imaging protocol included sagittalT1 weighted (W) and Short tau inversion recovery (STIR) for spine and coronal, axial T1W and axial T2 TSE pulse sequences. The functional component included diffusion weighted imaging in the axial plane (b=0 and 900sec/mm2). Radiological interpretation was performed by two readers using myeloma response assessment and diagnosis system (My-RADS) {Messiou, 2019 #340}. WB-MRIs were categorized as positive if focal lesions or diffuse/heterogenous pattern of bone marrow infiltration were present. Similarly, 18F-FDG PET/CTs and whole spine MRIs were classified as positive if focal lesions or diffuse/heterogenous pattern of bone marrow were present. Results A total of 34 patients with SMM and 5 patients with relapsed refractory multiple myeloma (RRMM) had sequential WB-MRI and 18F-FDG PET/CT. Figure 1 summarizes the radiological data of the SMM population. Eleven of these patients had PET/CT, whole spine MRI, and WB-MRI at baseline. Twenty-five patients had PET/CT and WB-MRI completed after at least 8 cycles of treatment. Thirteen patients had consistently negative imaging at baseline, 7 of which also had negative imaging after treatment, while 2 patients were found to have new lesions seen on WB-MRI after treatment. Six patients had resolution of positive imaging seen at baseline after treatment. Among the 17 patients with a positive WB-MRI, 12 (71%; 95% CI 47% - 87%) had a negative correlating PET/CT. Among 5 patients with positive PET/CT at the same time point as a WB-MRI, only 1 (20%; 95% CI 2% - 64%) correlated to a negative WB-MRI. Figure 2 depicts findings from patients with RRMM for comparison. All imaging modalities showed multiple focal findings in all 5 patients. Conclusions This study depicts the high sensitivity of WB-MRI in the SMM population. Such a high sensitivity is especially needed in SMM and early myeloma when disease burden is lower and the decision for treatment is being considered. In comparison to the RRMM population where all three imaging modalities easily detect multiple focal lesions, WB-MRI tends to identify myeloma involvement in the SMM patients more than the other imaging techniques. This suggests the importance of utilizing WB-MRI when diagnosing SMM. In the SMM population, the prognostic significance of lesions that are discrepant between MRI and FDG PET/CT is not yet known. Further follow up is needed to evaluate any difference in hard endpoints such as progression free survival between patients with positive findings described by WB-MRI. Disclosures No relevant conflicts of interest to declare

Mars Shot for Nuclear Medicine, Molecular Imaging, and Molecularly Targeted Radiopharmaceutical Therapy

The Society of Nuclear Medicine and Molecular Imaging created the Value Initiative in 2017 as a major component of its strategic plan to further demonstrate the value of molecular imaging and molecularly targeted radiopharmaceutical therapy to patients, physicians, payers, and funding agencies. The research and discovery domain, 1 of 5 under the Value Initiative, has a goal of advancing the research and development of diagnostic and therapeutic nuclear medicine. Research and discovery efforts and achievements are essential to ensure a bright future for NM and to translate science to practice. Given the remarkable progress in the field, leaders from the research and discovery domain and society councils identified 5 broad areas of opportunity with potential for substantive growth and clinical impact. This article discusses these 5 growth areas, identifying specific areas of particularly high importance for future study and development. As there was an understanding that goals should be both visionary yet achievable, this effort was called the Mars shot for nuclear medicine

Pattern of failure in prostate cancer previously treated with radical prostatectomy and post-operative radiotherapy: a secondary analysis of two prospective studies using novel molecular imaging techniques

Abstract Background Prostate Membrane Specific Antigen (PSMA) positron emission tomography (PET) and multiparametric MRI (mpMRI) have shown high accuracy in identifying recurrent lesions after definitive treatment in prostate cancer (PCa). In this study, we aimed to outline patterns of failure in a group of post-prostatectomy patients who received adjuvant or salvage radiation therapy (PORT) and subsequently experienced biochemical recurrence, using 18F-PSMA PET/CT and mpMRI. Methods PCa patients with biochemical failure post-prostatectomy, and no evident site of recurrence on conventional imaging, were enrolled on two prospective trials of first and second generation 18F-PSMA PET agents (18F-DCFBC and 18F-DCFPyL) in combination with MRI between October 2014 and December 2018. The primary aim of our study is to characterize these lesions with respect to their location relative to previous PORT field and received dose. Results A total of 34 participants underwent 18F-PSMA PET imaging for biochemical recurrence after radical prostatectomy and PORT, with 32/34 found to have 18F-PSMA avid lesions. On 18F-PSMA, 17/32 patients (53.1%) had metastatic disease, 8/32 (25.0%) patients had locoregional recurrences, and 7/32 (21.9%) had local failure in the prostate fossa. On further exploration, we noted 6/7 (86%) of prostate fossa recurrences were in-field and were encompassed by 100% isodose lines, receiving 64.8–72 Gy. One patient had marginal failure encompassed by the 49 Gy isodose. Conclusions 18F-PSMA PET imaging demonstrates promise in identifying occult PCa recurrence after PORT. Although distant recurrence was the predominant pattern of failure, in-field recurrence was noted in approximately 1/5th of patients. This should be considered in tailoring radiotherapy practice after prostatectomy. Trial registration www.clinicaltrials.gov , NCT02190279 and NCT03181867. Registered July 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02190279 and June 8 2017, https://clinicaltrials.gov/ct2/show/NCT03181867

Mars Shot for Nuclear Medicine, Molecular Imaging, and Molecularly Targeted Radiopharmaceutical Therapy.

The Society of Nuclear Medicine and Molecular Imaging created the Value Initiative in 2017 as a major component of its strategic plan to further demonstrate the value of molecular imaging and molecularly targeted radiopharmaceutical therapy to patients, physicians, payers, and funding agencies. The research and discovery domain, 1 of 5 under the Value Initiative, has a goal of advancing the research and development of diagnostic and therapeutic nuclear medicine. Research and discovery efforts and achievements are essential to ensure a bright future for NM and to translate science to practice. Given the remarkable progress in the field, leaders from the research and discovery domain and society councils identified 5 broad areas of opportunity with potential for substantive growth and clinical impact. This article discusses these 5 growth areas, identifying specific areas of particularly high importance for future study and development. As there was an understanding that goals should be both visionary yet achievable, this effort was called the Mars shot for nuclear medicine

The Role of 18f-FDG-PET/CT in Characterizing Depth of Response in High Risk Smoldering Multiple Myeloma Patients Treated with Carfilzomib, Lenalidomide, and Dexamethasone (KRd)

Introduction A direct association exists between minimal residual disease (MRD) negativity and prolonged survival in multiple myeloma (MM) (Landgren et al, BMT 2016). 18F-fluoro-deoxy-glucose (FDG) positron emission tomography-computed tomography (PET/CT) is a recommended monitoring technique for patients with MM as persistence of FDG uptake after induction therapy, prior to maintenance, is an independent risk factor for progression. Therefore PET/CT and MRD detection in the bone marrow are complementary prognostic tools prior to initiation of maintenance therapy. In patients with smoldering multiple myeloma (SMM), the presence of a focal FDG-avid lesion without underlying osteolytic lesion on PET/CT is associated with rapid progression to MM. However, little is known about the prognostic value of PET/CT for SMM patients receiving treatment. Herein, we show that treatment of high risk (HR)-SMM with carfilzomib, lenalidomide, and dexamethasone with lenalidomide maintenance (KRd-R) leads to sustained remissions detected on PET/CT imaging. Methods Trial design including key results for KRd-R in HR-SMM (NCT01572480) has been submitted to the meeting separately (abstract ID: 136148). As part of the study design, all eligible patients had bone marrow biopsies with multicolor flow cytometry (MRD sensitivity, 10-5) and whole-body PET/CT performed at baseline and at key time points, including achievement of complete response (CR) or completion of KRd induction (8 cycles), after 1 and 2 years of -R maintenance, and annually thereafter. PET/CTs were evaluated by nuclear medicine radiologists blinded to flow cytometry and considered positive if at least one focal hypermetabolic (above background reference) lesion and/or heterogenous bone marrow involvement were present, as defined by the IMWG (Hillengass et al. Lancet Oncol 2019). Results As of data cutoff, 46 patients had completed at least 8 cycles of therapy and had 2 sequential PET/CTs performed. By the end of induction therapy, no patient developed progressive disease and the overall response rate was 100%. Approximately 72% of patients with baseline negative PET/CTs remained negative, 11% of patients had resolution of previous focal/heterogenous FDG avidity, 15% of patients had decrease or stable focal/ heterogenous lesions, and 2% developed new focal lesions. Table 1 shows the results at subsequent time points of one and two years of maintenance therapy. Throughout this time period, one patient developed a lytic lesion after 1 year of maintenance therapy. However, 3 patients had either resolution or decrease in focal/heterogenous lesions. Specifically, after 8 cycles of combination therapy, 33 patients (70.2%, 95% CI 55.9 - 81.4%) had a response of MRD negative CR based on bone marrow flow cytometry and 26 patients (55.3%; 95% CI 41.2-68.6%) had a negative PET/CT in addition to MRD negative CR (Table 2). Conclusions It is important to evaluate the tools used in MM response assessment specifically in the SMM population as more studies report results of treatment in this population. MRD information can be used as a biomarker to evaluate the efficacy of different treatment strategies. This study demonstrates an exceptionally high rate of concordance between MRD negativity by flow cytometry and negative PET/CT after 8 cycles of KRd. However, 15% of patients were MRD negative yet had positive findings on PET/CT. While these lesions were not biopsy proven, some resolved during maintenance therapy. Further follow-up is needed to determine whether early MRD negativity in bone marrow with negative PET/CT correlates to longer overall survival and decreased progression to MM compared to those patients with a positive PET/CT. The use of PET/CT imaging may increase our understanding in assessing depth response to treatment in HR-SMM patients and be an important outcome predictor. Disclosures Korde: Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Landgren:Adaptive: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Glenmark: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Research Funding; Janssen: Consultancy, Honoraria, Other: Independent Data Monitoring Committees for clinical trials, Research Funding; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; Takeda: Other: Independent Data Monitoring Committees for clinical trials, Research Funding; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Glenmark: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Seattle Genetics: Research Funding; Pfizer: Consultancy, Honoraria; Merck: Other; Karyopharma: Research Funding; Binding Site: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Cellectis: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Merck: Other