Mechanics and functional consequences of nuclear deformations.

As the home of cellular genetic information, the nucleus has a critical role in determining cell fate and function in response to various signals and stimuli. In addition to biochemical inputs, the nucleus is constantly exposed to intrinsic and extrinsic mechanical forces that trigger dynamic changes in nuclear structure and morphology. Emerging data suggest that the physical deformation of the nucleus modulates many cellular and nuclear functions. These functions have long been considered to be downstream of cytoplasmic signalling pathways and dictated by gene expression. In this Review, we discuss an emerging perspective on the mechanoregulation of the nucleus that considers the physical connections from chromatin to nuclear lamina and cytoskeletal filaments as a single mechanical unit. We describe key mechanisms of nuclear deformations in time and space and provide a critical review of the structural and functional adaptive responses of the nucleus to deformations. We then consider the contribution of nuclear deformations to the regulation of important cellular functions, including muscle contraction, cell migration and human disease pathogenesis. Collectively, these emerging insights shed new light on the dynamics of nuclear deformations and their roles in cellular mechanobiology.

Interferon-ε is a tumour suppressor and restricts ovarian cancer.

High-grade serous ovarian cancers have low survival rates because of their late presentation with extensive peritoneal metastases and frequent chemoresistance1, and require new treatments guided by novel insights into pathogenesis. Here we describe the intrinsic tumour-suppressive activities of interferon-ε (IFNε). IFNε is constitutively expressed in epithelial cells of the fallopian tube, the cell of origin of high-grade serous ovarian cancers, and is then lost during development of these tumours. We characterize its anti-tumour activity in several preclinical models: ovarian cancer patient-derived xenografts, orthotopic and disseminated syngeneic models, and tumour cell lines with or without mutations in Trp53 and Brca genes. We use manipulation of the IFNε receptor IFNAR1 in different cell compartments, differential exposure status to IFNε and global measures of IFN signalling to show that the mechanism of the anti-tumour activity of IFNε involves direct action on tumour cells and, crucially, activation of anti-tumour immunity. IFNε activated anti-tumour T and natural killer cells and prevented the accumulation and activation of myeloid-derived suppressor cells and regulatory T cells. Thus, we demonstrate that IFNε is an intrinsic tumour suppressor in the female reproductive tract whose activities in models of established and advanced ovarian cancer, distinct from other type I IFNs, are compelling indications of potential new therapeutic approaches for ovarian cancer.

Advances in Chromatin and Chromosome Research: Perspectives from Multiple Fields.

Nucleosomes package genomic DNA into chromatin. By regulating DNA access for transcription, replication, DNA repair, and epigenetic modification, chromatin forms the nexus of most nuclear processes. In addition, dynamic organization of chromatin underlies both regulation of gene expression and evolution of chromosomes into individualized sister objects, which can segregate cleanly to different daughter cells at anaphase. This collaborative review shines a spotlight on technologies that will be crucial to interrogate key questions in chromatin and chromosome biology including state-of-the-art microscopy techniques, tools to physically manipulate chromatin, single-cell methods to measure chromatin accessibility, computational imaging with neural networks and analytical tools to interpret chromatin structure and dynamics. In addition, this review provides perspectives on how these tools can be applied to specific research fields such as genome stability and developmental biology and to test concepts such as phase separation of chromatin.

Transcription inhibition suppresses nuclear blebbing and rupture independently of nuclear rigidity.

Chromatin plays an essential role in the nuclear mechanical response and determining nuclear shape, which maintain nuclear compartmentalization and function. However, major genomic functions, such as transcription activity, might also impact cell nuclear shape via blebbing and rupture through their effects on chromatin structure and dynamics. To test this idea, we inhibited transcription with several RNA polymerase II inhibitors in wild-type cells and perturbed cells that presented increased nuclear blebbing. Transcription inhibition suppressed nuclear blebbing for several cell types, nuclear perturbations and transcription inhibitors. Furthermore, transcription inhibition suppressed nuclear bleb formation, bleb stabilization and bleb-based nuclear ruptures. Interestingly, transcription inhibition did not alter the histone H3 lysine 9 (H3K9) modification state, nuclear rigidity, and actin compression and contraction, which typically control nuclear blebbing. Polymer simulations suggested that RNA polymerase II motor activity within chromatin could drive chromatin motions that deform the nuclear periphery. Our data provide evidence that transcription inhibition suppresses nuclear blebbing and rupture, in a manner separate and distinct from chromatin rigidity.

CTCF is essential for proper mitotic spindle structure and anaphase segregation.

Mitosis is an essential process in which the duplicated genome is segregated equally into two daughter cells. CTCF has been reported to be present in mitosis and has a role in localizing CENP-E, but its importance for mitotic fidelity remains to be determined. To evaluate the importance of CTCF in mitosis, we tracked mitotic behaviors in wild-type and two different CTCF CRISPR-based genetic knockdowns. We find that knockdown of CTCF results in prolonged mitoses and failed anaphase segregation via time-lapse imaging of SiR-DNA. CTCF knockdown did not alter cell cycling or the mitotic checkpoint, which was activated upon nocodazole treatment. Immunofluorescence imaging of the mitotic spindle in CTCF knockdowns revealed disorganization via tri/tetrapolar spindles and chromosomes behind the spindle pole. Imaging of interphase nuclei showed that nuclear size increased drastically, consistent with failure to divide the duplicated genome in anaphase. Long-term inhibition of CNEP-E via GSK923295 recapitulates CTCF knockdown abnormal mitotic spindles with polar chromosomes and increased nuclear sizes. Population measurements of nuclear shape in CTCF knockdowns do not display decreased circularity or increased nuclear blebbing relative to wild-type. However, failed mitoses do display abnormal nuclear morphologies relative to successful mitoses, suggesting that population images do not capture individual behaviors. Thus, CTCF is important for both proper metaphase organization and anaphase segregation which impacts the size and shape of the interphase nucleus likely through its known role in recruiting CENP-E.

Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies.

PURPOSE: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [18F]PI-2620 tau-positron-emission-tomography (PET) imaging with [123I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability. METHODS: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [18F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies. RESULTS: In patients with 4R-tauopathies, [18F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (ß = - 0.464, p = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [18F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (ß = 0.078, p = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [18F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (ß = - 0.522, p = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies. CONCLUSION: Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function.

Noninvasive In Vivo Thrombus Imaging in Patients With Ischemic Stroke or Transient Ischemic Attack-Brief Report.

BACKGROUND: 18F-GP1 is a novel positron-emitting radiotracer that is highly specific for activated platelets and thrombus. In a proof-of-concept study, we aimed to determine its potential clinical application in establishing the role and origin of thrombus in ischemic stroke. METHODS: Eleven patients with recent ischemic stroke (n=9) or transient ischemic attack (n=2) underwent 18F-GP1 positron emission tomography and computed tomography angiography at a median of 11 (range, 2-21) days from symptom onset. 18F-GP1 uptake (maximum target-to-background ratio) was assessed in the carotid arteries and brain. RESULTS: 18F-GP1 uptake was identified in 10 of 11 patients: 4 in the carotid arteries only, 3 in the brain only, and 3 in both the brain and carotid arteries. In those with carotid uptake, 4 participants had >50% stenosis and 3 had nonstenotic disease. One case had bilateral stenotic disease (>70%), but only the culprit carotid artery demonstrated 18F-GP1 uptake. The average uptake was higher in the culprit (median maximum target-to-background ratio, 1.55 [interquartile range, 1.26-1.82]) compared with the contralateral nonculprit carotid artery (maximum target-to-background ratio, 1.22 [1.19-1.6]). In those with brain 18F-GP1 uptake (maximum target-to-background ratio, 6.45 [4.89-7.65]), areas of acute infarction on computed tomography correlated with brain 18F-GP1 uptake in 6 cases. Ex vivo autoradiography of postmortem infarcted brain tissue showed focal uptake corresponding to intraluminal thrombus within the culprit vessel and downstream microvasculature. There was also evidence of diffuse uptake within some of the infarcted brain tissue reflecting parenchymal petechial hemorrhage. CONCLUSIONS: 18F-GP1 positron emission tomography and computed tomography angiography is a novel noninvasive method of identifying in vivo cerebrovascular thrombosis, which holds major promise in understanding the role and origin of thrombosis in stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03943966.

Evaluation of Fluoroscopically Guided Transforaminal Selective Nerve Root Sleeve Injections for Lumbar Spinal Stenosis With Radiculopathy Utilizing Patient Reported Outcome Measurement Information System as an Outcome Measure.

OBJECTIVE: To evaluate the therapeutic effect of transforaminal selective nerve root sleeve injections (TFSNRIs) in a specific subset of patients with clinical symptoms and presentation consistent with spinal stenosis. DESIGN: Retrospective review. SETTING: Tertiary academic spine center. PARTICIPANTS: A total of 176 patients with radicular leg pain with or without low back pain as well as ≥3 clinical features of spinal stenosis and corroborative radiographic features of spinal stenosis on lumbar spine magnetic resonance imaging without confounding spinal pathology (N=176). INTERVENTIONS: Fluoroscopically guided transforaminal selective nerve root sleeve injections. MAIN OUTCOME MEASURES: Patient Reported Outcome Measurement Information System (PROMIS) Physical Function (PF) v1.2/v2.0, Pain Interference (PI) v1.1, and PROMIS (D) v1.0 were collected at baseline and post-procedure short term (<3-months) and long-term (6-12 month) follow-up. Statistical analysis comparing baseline and postprocedural PROMIS scores was performed. Differences were compared with previously established minimal clinically important differences in the spine population. RESULTS: For patients with spinal stenosis treated with TFSNRI, no statistically significant improvement was observed short- and long-term follow-up in PROMIS PF (P=.97, .77) and PROMIS Depression (P=.86, .85) scores. At short-term follow-up, PROMIS PI scores did significantly improve (P=.01) but the average difference of pre- and post-procedure scores did not reach clinical significance. No significant difference in PROMIS PI was noted at long-term follow-up (.75). CONCLUSIONS: Although a statistically significant difference was observed for improvement in pain, in this retrospective study, TFSNRI did not provide clinically significant improvement in patients' function, pain, or depression for lumbar spinal stenosis at short- and long-term follow-up.

Flow capabilities of arterial and drainage cannulae during venoarterial extracorporeal membrane oxygenation: A simulation model.

BACKGROUND: Large cannulae can increase cannula-related complications during venoarterial extracorporeal membrane oxygenation (VA ECMO). Conversely, the ability for small cannulae to provide adequate support is poorly understood. Therefore, we aimed to evaluate a range of cannula sizes and VA ECMO flow rates in a simulated patient under various disease states. METHODS: Arterial cannulae sizes between 13 and 21 Fr and drainage cannula sizes between 21 and 25 Fr were tested in a VA ECMO circuit connected to a mock circulation loop simulating a patient with severe left ventricular failure. Systemic and pulmonary hypertension, physiologically normal, and hypotension were simulated by varying systemic and pulmonary vascular resistances (SVR and PVR, respectively). All cannula combinations were evaluated against all combinations of SVR, PVR, and VA ECMO flow rates. RESULTS: A 15 Fr arterial cannula combined with a 21 Fr drainage cannula could provide >4 L/min of total flow and a mean arterial pressure of 81.1 mmHg. Changes in SVR produced marked changes to all measured parameters, while changes to PVR had minimal effect. Larger drainage cannulae only increased maximum circuit flow rates when combined with larger arterial cannulae. CONCLUSION: Smaller cannulae and lower flow rates could sufficiently support the simulated patient under various disease states. We found arterial cannula size and SVR to be key factors in determining the flow-delivering capabilities for any given VA ECMO circuit. Overall, our results challenge the notion that larger cannulae and high flows must be used to achieve adequate ECMO support.

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study.

INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-ß (Aß) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aß-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.

Use of Sutureless Valve in Aortic Root Enlargement.

AIM: The small aortic annulus is a surgical challenge in patients undergoing aortic valve replacement which may lead to patient prosthesis mismatch. Management options include aortic root enlargement, aortic root replacement, and the use of sutureless valves. In this case series, we report our results with aortic root enlargement, sutureless valve implantation, and benchtop modelling of the radial forces exerted. METHODS: Five patients underwent aortic root enlargement and insertion of the Perceval valve as part of the management strategy to enlarge their effective orifice area. We further investigate this strategy with a benchtop model to quantify the radial forces exerted by the Perceval valve on the aortic annulus. Radial and hoop forces on the aortic annulus and inner ring of the Perceval valve were recorded using a Mylar force tester. RESULTS: Five female patients with native annulus between 18mm-20mm underwent root enlargement and insertion of a Perceval S valve. The postoperative course was uncomplicated for all patients except for one who required a permanent pacemaker insertion. Transvalvular pressure gradients remained low at up to 4 years of follow-up (12 mmHg-21 mmHg), with no evidence of paravalvular leak. Benchtop testing demonstrated radial forces exerted at the annulus in all-size Perceval S valves to be within physiological variables, whereas compressive forces required to deform the valves were supraphysiological. CONCLUSIONS: The deployment of a sutureless valve within a surgical enlarged aortic root is a feasible solution in patients with a small aortic root.

[18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data.

OBJECTIVES: Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. METHODS: A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3-21.0 months) underwent 60 min dynamic [18F]fluorodeprenyl-D2 ([18F]F-DED), static 18 kDa translocator protein (TSPO, [18F]GE-180) and ß-amyloid ([18F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer's disease continuum (AD, n = 2), Parkinson's disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [18F]F-DED PET and the data were analyzed using equivalent quantification strategies. RESULTS: We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [18F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001; thalamus: + 15.2%, p < 0.0001). Specific [18F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and ß-amyloid PET and [18F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001; thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [18F]F-DED VT and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [18F]F-DED binding following the known physiological MAO-B expression in brain. CONCLUSIONS: [18F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.

Validation of quantitative assessment of florbetaben PET scans as an adjunct to the visual assessment across 15 software methods.

PURPOSE: Amyloid positron emission tomography (PET) with [18F]florbetaben (FBB) is an established tool for detecting Aß deposition in the brain in vivo based on visual assessment of PET scans. Quantitative measures are commonly used in the research context and allow continuous measurement of amyloid burden. The aim of this study was to demonstrate the robustness of FBB PET quantification. METHODS: This is a retrospective analysis of FBB PET images from 589 subjects. PET scans were quantified with 15 analytical methods using nine software packages (MIMneuro, Hermes BRASS, Neurocloud, Neurology Toolkit, statistical parametric mapping (SPM8), PMOD Neuro, CapAIBL, non-negative matrix factorization (NMF), AmyloidIQ) that used several metrics to estimate Aß load (SUVR, centiloid, amyloid load, and amyloid index). Six analytical methods reported centiloid (MIMneuro, standard centiloid, Neurology Toolkit, SPM8 (PET only), CapAIBL, NMF). All results were quality controlled. RESULTS: The mean sensitivity, specificity, and accuracy were 96.1 ± 1.6%, 96.9 ± 1.0%, and 96.4 ± 1.1%, respectively, for all quantitative methods tested when compared to histopathology, where available. The mean percentage of agreement between binary quantitative assessment across all 15 methods and visual majority assessment was 92.4 ± 1.5%. Assessments of reliability, correlation analyses, and comparisons across software packages showed excellent performance and consistent results between analytical methods. CONCLUSION: This study demonstrated that quantitative methods using both CE marked software and other widely available processing tools provided comparable results to visual assessments of FBB PET scans. Software quantification methods, such as centiloid analysis, can complement visual assessment of FBB PET images and could be used in the future for identification of early amyloid deposition, monitoring disease progression and treatment effectiveness.

Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome.

PURPOSE: Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. METHODS: Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value - 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). RESULTS: Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = - 0.431; p = 0.0005). CONCLUSION: [18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.

Value of 68Ga-labeled bombesin antagonist (RM2) in the detection of primary prostate cancer comparing with [18F]fluoromethylcholine PET-CT and multiparametric MRI-a phase I/II study.

OBJECTIVES: The bombesin derivative RM2 is a GRPr antagonist with strong binding affinity to prostate cancer (PCa). In this study, the impact of [68Ga]Ga-RM2 positron emission tomography-computed tomography (PET-CT) for the detection of primary PCa was compared with that of [18F]FCH PET-CT and multiparametric magnetic resonance imaging (mpMRI). METHODS: This phase I/II study was conducted in 30 biopsy-positive PCa subjects. The patients were stratified into high (10 patients), intermediate (10 patients), and low risk (10 patients) for extraglandular metastases as defined by National Comprehensive Cancer Network (NCCN) criteria (NCCN Clinical Practice Guidelines in Oncology, 2016). The prostate gland was classified in 12 anatomic segments for data analysis of the imaging modalities as well as histopathologic findings. The segment with the highest radiotracer uptake was defined as the "index lesion." All cases were scheduled to undergo prostatectomy with pelvic lymph node (LN) dissection in intermediate- and high-risk patients. Intraprostatic and pelvic nodal [68Ga]Ga-RM2 and [18F]FCH PET-CT findings were correlated with mpMRI and histopathologic results. RESULTS: Of the 312 analyzed regions, 120 regions (4 to 8 lesions per patient) showed abnormal findings in the prostate gland. In a region-based analysis, overall sensitivity and specificity of [68Ga]Ga-RM2 PET-CT in the detection of primary tumor were 74% and 90%, respectively, while it was 60% and 80% for [18F]FCH PET-CT and 72% and 89% for mpMRI. Although the overall sensitivity of [68Ga]Ga-RM2 PET-CT was higher compared to that of [18F]FCH PET-CT and mpMRI, the statistical analysis showed only significant difference between [68Ga]Ga-RM2 PET-CT and [18F]FCH PET-CT in the intermediate-risk group (p = 0.01) and [68Ga]Ga-RM2 PET-CT and mpMRT in the high-risk group (p = 0.03). In the lesion-based analysis, there was no significant difference between SUVmax of [68Ga]Ga-RM2 and [18F]FCH PET-CT in the intraprostatic malignant lesions ([68Ga]Ga-RM2: mean SUVmax: 5.98 ± 4.13, median: 4.75; [18F]FCH: mean SUVmax: 6.08 ± 2.74, median: 5.5; p = 0.13). CONCLUSIONS: [68Ga]Ga-RM2 showed promising PET tracer for the detection of intraprostatic PCa in a cohort of patients with different risk stratifications. However, significant differences were only found between [68Ga]Ga-RM2 PET-CT and [18F]FCH PET-CT in the intermediate-risk group and [68Ga]Ga-RM2 PET-CT and mpMRT in the high-risk group. In addition, GRP-R-based imaging seems to play a complementary role to choline-based imaging for full characterization of PCa extent and biopsy guidance in low- and intermediate-metastatic-risk PCa patients and has the potential to discriminate them from those at higher risks. KEY POINTS: • [68Ga]Ga-RM2 is a promising PET tracer with a high detection rate for intraprostatic PCa especially in intermediate-risk prostate cancer patients. • GRPr-based imaging seems to play a complementary role to choline-based or PSMA-based PET/CT imaging in selected low- and intermediate-risk PCa patients for better characterization and eventually biopsy guidance of prostate cancer disease.

Evaluating the Performance of an Automated Patient-Reported Outcomes Collection Platform in a Postoperative Hand Surgery Population.

PURPOSE: Reliable collection of postoperative patient-reported outcome measures (PROMs) is critical to understanding surgical outcomes and the value of care. Automated PROMs collection, triggered by the electronic medical record at the 1-year postoperative anniversary, may provide a simple way to acquire outcomes for patients who have been discharged from clinic. The purposes of this study were to (1) evaluate the percentage of responses with an automated PROMs collection platform and (2) identify whether such a system may introduce selection bias by comparing responders with nonresponders. METHODS: Adult patients (aged ≥18 years) undergoing hand and upper-extremity surgeries between August 2017 and January 2019 were included. Preoperative Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) scores were collected using tablet computer. Postoperative QuickDASH scores were collected using a single electronic survey request 1 year after surgery via an email with a personalized REDCap link. Univariate and multivariable regression analyses were performed to identify factors that differed between responders and nonresponders. RESULTS: A response rate of 27% (269 of 1010) was observed for the eligible postoperative patients. On multivariable analysis, the following were associated with greater odds of response: older age, Caucasian race (vs unknown), longer surgery duration, attending the first postoperative visit, and responding to the preoperative QuickDASH. CONCLUSIONS: The poor response rate that was observed highlights that an automated single email postoperative contact for PROMs collection is insufficient-active follow-up via reminder emails and/or telephone calls is needed. Outcome researchers and clinicians must be aware of potential selection biases, such as age and race, that may exist with automated PROMs collection. CLINICAL RELEVANCE: Single email postoperative contact to obtain postoperative PROMs is insufficient.

Risk of Total Wrist Arthrodesis Following Proximal Row Carpectomy: An Analysis of 1,070 Patients.

PURPOSE: Proximal row carpectomy (PRC) is a motion-sparing procedure with good patient-reported and clinical outcomes. Although some studies have investigated the risk of conversion to total wrist arthrodesis (TWA) after PRC, additional larger studies evaluating the specific risk factors that lead to failure are required. This study aimed to investigate the patient and procedure factors that are associated with increased risk for conversion to TWA in a large cohort of patients who underwent PRC. METHODS: The current procedural technology codes identified patients in a National Veteran's Health database undergoing a PRC over a 26-year period. Risk factors of interest comprised age, posterior interosseous nerve neurectomy, wrist arthritis pattern, bilateral surgery, smoking, comorbidities, and preoperative opioid use. The primary outcome was the rate of conversion to TWA. Cox proportional hazard regression was used to create hazard ratios of selected factors for reoperation. RESULTS: There were 1,070 PRCs performed, with a mean follow-up of 79.8 ± 59.6 months. A total of 5.3% (57/1,070) wrists underwent conversion to TWA. Younger age at the time of PRC (<50 years) significantly increased the risk of TWA (hazard ratio, 3.8; 95% confidence interval, 2.2-6.6). With every 1-year increase in age, there was a reduction of 4% (hazard ratio, 0.96; 95% confidence interval: 0.94-0.98) in the hazard of conversion to TWA. No other factors, including concomitant posterior interosseous nerve neurectomy or bilateral PRC, increased the risk of conversion to TWA. CONCLUSIONS: Proximal row carpectomy is a motion-preserving salvage procedure with a low rate of conversion to wrist arthrodesis. Younger patient age increases the risk of conversion to arthrodesis, whereas posterior interosseous nerve neurectomy, bilateral PRCs, and comorbidity status do not appear to have an impact on the risk of arthrodesis. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Minimizing Costs for Dorsal Wrist Ganglion Treatment: A Cost-Minimization Analysis.

PURPOSE: Dorsal wrist ganglions are treated commonly with aspiration, or open or arthroscopic excision in operating room (OR) or procedure room (PR) settings. As it remains unclear which treatment strategy is most cost-effective in yielding cyst resolution, our purpose was to perform a formal cost-minimization analysis from the societal perspective in this context. METHODS: A microsimulation decision analytic model evaluating 5 treatment strategies for dorsal wrist ganglions was developed, ending in either resolution or a single failed open revision surgical excision. Strategies included immediate open excision in the OR, immediate open excision in the PR, immediate arthroscopic excision in the OR, or 1 or 2 aspirations before each of the surgical options. Recurrence and complications rates were pooled from the literature for each treatment type. One-way sensitivity and threshold analyses were performed. RESULTS: The most cost-minimal strategy was 2 aspiration attempts before open surgical excision in the PR setting ($1,603 ± 1,595 per resolved case), followed by 2 aspirations before open excision in the OR ($1,969 ± 2,165 per resolved case). Immediate arthroscopic excision was the costliest strategy ($6,539 ± 264 per resolved case). Single aspiration preoperatively was more cost-minimal than any form of immediate surgery ($2,918 ± 306 and $4,188 ± 306 per resolved case performed in the PR and OR, respectively). CONCLUSIONS: From the societal perspective, performing 2 aspirations before surgical excision in the PR setting was the most cost-minimal treatment strategy, although in reference to surgeons who do not perform this procedure in the PR setting, open excision in the OR was nearly as cost-effective. As patient preferences may preclude routinely performing 2 aspirations, performing at least 1 aspiration before surgical excision improves the cost-effectiveness of dorsal wrist ganglions treatment. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic Decision Analysis II.

Quantification of [18 F]florbetaben amyloid-PET imaging in a mixed memory clinic population: The ABIDE project.

INTRODUCTION: We investigated amyloid-burden quantification in a mixed memory clinic population. METHODS: [18 F]Florbetaben amyloid-PET (positron emission tomography) scans of 348 patients were visually read and quantified using the Centiloid (CL) method. General linear models were used to assess CL differences across syndromic and etiological diagnosis. Linear mixed models were fitted to assess the predictive value of visual read (VR) and CL on longitudinal Mini-Mental Status Examination (MMSE). RESULTS: CL was associated with syndromic (F = 4.42, p = 0.014) and etiological diagnosis (F = -12.66, p < 0.001), with Alzheimer's disease (AD) patients showing the highest amyloid burden (62.9 ± 27.5), followed by dementia with Lewy bodies (DLB) (25.3 ± 35.5) and cardiovascular disease (CVD) (16.7 ± 24.5), and finally frontotemporal lobe degeneration (FTLD) (5.0 ± 17.22, t = -12.66, p < 0.001). CL remained predictive of etiological diagnosis (t =  -2.41, p = 0.017) within the VR+ population (N = 157). VR was not a significant predictor of MMSE (t = -1.53, p = 0.13) for the SCD population (N = 90), whereas CL was (t = -3.30, p = 0.001). DISCUSSION: The extent of amyloid pathology through quantification holds clinical value, potentially in the context of differential diagnosis as well as prognosis.

A more precise diagnosis by means of amyloid PET contributes to delayed institutionalization, lower mortality, and reduced care costs in a tertiary memory clinic setting.

INTRODUCTION: We aim to study the effect of a more precise diagnosis, by means of amyloid positron emission tomography (PET), on institutionalization, mortality, and health-care costs. METHODS: Between October 27, 2014 and December 31, 2016, we offered amyloid PET to all patients as part of their diagnostic work-up. Patients who accepted to undergo amyloid PET (n = 449) were propensity score matched with patients without amyloid PET (n = 571, i.e., no PET). Matched groups (both n = 444) were compared on rate of institutionalization, mortality, and health-care costs in the years after diagnosis. RESULTS: Amyloid PET patients had a lower risk of institutionalization (10% [n = 45] vs. 21% [n = 92]; hazard ratio [HR] = 0.48 [0.33-0.70]) and mortality rate (11% [n = 49] vs. 18% [n = 81]; HR = 0.51 [0.36-0.73]) and lower health-care costs in the years after diagnosis compared to matched no-PET patients (ß = -4573.49 [-6524.76 to -2523.74], P-value < 0.001). DISCUSSION: A more precise diagnosis in tertiary memory clinic patients positively influenced the endpoints of institutionalization, death, and health-care costs.