Mean Follow-up Interval Research Articles

Enhanced S-Cone Syndrome: Spectrum of Clinical, Imaging, Electrophysiologic, and Genetic Findings in a Retrospective Case Series of 56 Patients

PurposeTo describe the detailed phenotype, long-term clinical course, clinical variability, and genotype of patients with enhanced S-cone syndrome (ESCS).DesignRetrospective case series.ParticipantsFifty-six patients with ESCS.MethodsClinical history, examination, imaging, and electrophysiologic findings of 56 patients (age range, 1–75 years) diagnosed with ESCS were reviewed. Diagnosis was established by molecular confirmation of disease-causing variants in the NR2E3 gene (n = 38) or by diagnostic full-field electroretinography findings (n = 18).Main Outcome MeasuresAge at onset of visual symptoms, best-corrected visual acuity (BCVA), quantitative age-related electrophysiologic decline, and imaging findings.ResultsMean age at onset of visual symptoms was 4.0 years, and median age at presentation was 20.5 years, with mean follow-up interval being 6.1 years. Six patients were assessed once. Disease-causing variants in NR2E3 were identified in 38 patients. Mean BCVA of the better-seeing eye was 0.32 logarithm of the minimum angle of resolution (logMAR) at baseline and 0.39 logMAR at follow-up. In most eyes (76% [76/100]), BCVA remained stable, with a mean BCVA change of 0.07 logMAR during follow-up. Nyctalopia was the most common initial symptom, reported in 92.9% of patients (52/56). Clinical findings were highly variable and included foveomacular schisis (41.1% [26/56]), yellow-white dots (57.1% [32/56]), nummular pigmentation (85.7% [48/56]), torpedo-like lesions (10.7% [6/56]), and circumferential subretinal fibrosis (7.1% [4/56]). Macular and peripheral patterns of autofluorescence were classified as (1) minimal change, (2) hypoautofluorescent (mild diffuse, moderate speckled, moderate diffuse, or advanced), or (3) hyperautofluorescent flecks. One patient showed undetectable electroretinography findings; quantification of main electroretinography components in all other patients revealed amplitude and peak time variability but with pathognomonic electroretinography features. The main electroretinography components showed evidence of age-related worsening over 6.7 decades, at a rate indistinguishable from that seen in unaffected control participants. Eighteen sequence variants in NR2E3 were identified, including 4 novel missense changes.ConclusionsEnhanced S-cone syndrome has a highly variable phenotype with relative clinical and imaging stability over time. Most electroretinography findings have pathognomonic features, but quantitative assessment reveals variability and a normal mean rate of age-related decline, consistent with largely nonprogressive peripheral retinal dysfunction.

Neurological soft signs and cognition in the late course of chronic schizophrenia: a longitudinal study

Neurological soft signs (NSS) are minor (‘soft’) neurological abnormalities in sensory and motor performances, which are frequently reported in patients with schizophrenia at any stage of their illness. It has been demonstrated that NSS vary in the clinical course of the disorder: longitudinally NSS decrease in parallel with remission of psychopathological symptoms, an effect which mainly applies to patients with a remitting course. These findings are primarily based on patients with a first episode of the disorder, while the course of NSS in patients with chronic schizophrenia and persisting symptoms is rather unknown. Therefore, we investigated NSS twice in 21 patients with chronic schizophrenia (initial mean duration of illness: 23 ± 11 years) with a mean follow-up interval of 7 years. NSS were evaluated by the Heidelberg Scale, established instruments were used to rate neuropsychological performance and psychopathological symptoms. NSS showed significant increases on the subscales “motor coordination” and “integrative functions”, while positive and negative symptoms, including apathy, showed only minor, non-significant changes. Verbal memory, verbal fluency, and cognitive flexibility along with severity of global cognitive deficits demonstrated a significant deterioration. Regression analyses identified executive dysfunction (cognitive flexibility and verbal fluency) at baseline as significant predictors of NSS increase at follow-up. Our findings indicate that NSS deteriorate in the long-term course of chronic schizophrenia. This effect may be accounted for by a decrease of executive functions and logical memory, which can be attributed to premature brain aging.

Post-traumatic maxillofacial reconstruction with vascularized flaps and digital techniques: 10-year experience

The aim of this study was to present a treatment protocol for the individual repair of post-traumatic maxillofacial bone defects with vascularized flaps assisted by digital techniques. This study reviewed 20 patients with post-traumatic maxillofacial bone defects who underwent reconstruction with composite vascularized bone flaps assisted by digital techniques between April 2009 and July 2019. Preoperative computed tomography (CT) data were imported into ProPlan CMF software to complete virtual fracture reduction and reconstruction. Surgical navigation, three-dimensionally (3D) printed surgical plates, and prefabricated titanium mesh/plates were used to guide the actual surgery. All patients underwent open reduction and internal fixation and reconstruction surgery in one stage. CT data obtained at 1 week postoperative were imported into Geomagic Control software to evaluate the accuracy of the virtual surgical plan. The mean follow-up interval was 24 months (range 6–96 months). Donor and recipient site morbidity and second-stage procedures to rehabilitate the dentition and cosmetic organs were recorded. The flap success rate was 100%. Nine patients had deep circumflex iliac artery flaps and eleven patients had fibula flaps. The accuracy of computer-assisted surgery was 4.4±0.8mm. There were no postoperative complications. This study is novel in presenting a treatment protocol for individual computer-assisted reconstruction for post-traumatic maxillofacial bone defects with vascularized flaps.

Stereotactic body radiotherapy (SBRT) for the treatment of bone metastases in oligometastasised prostate cancer

Local radiation therapy of metastases in prostate cancer patients has become increasingly important in recent years. In order to improve the evaluation of the outcome, we have studied oligometastatic prostate cancer patients who were treated with stereotactic radiation therapy. 24 patients with a total of 30 bone metastases were included in the study. We examined the response to SBRT (biochemical and imaging), as well as progression-free survival and time to start of antihormonal therapy (aHT). The mean follow-up interval after completion of SBRT was 32.7 months (1.4 - 84 months). The SBRT was well tolerated, without acute or late adverse effects. In 16 patients, the PSA value decreased from a mean of 4.58 ng/mL (0.05 - 50.25 ng/mL) before SBRT to 1.19 ng/mL (0.01 - 8.85 ng/mL) after completion of SBRT. The mean biochemical progression-free survival of these patients was 17.6 months (0.7 - 85.0 months). Six patients received aHT, either before or during SBRT. In ten patients, the aHT was initiated after a mean interval of 20.6 months (1.8 - 85.0 months) after completion of the SBRT. Another six patients were not given any aHT during the whole period of observation. In 18 of 30 metastases, there was a decrease in PSMA expression within the area of SBRT in the PSMA-PET - in accordance with a partial functional response. In five patients, PSMA hyperexpression was unchanged; in 7 patients there was no PSMA imaging for follow up. In 17 patients, distant metastasis progression was diagnosed by imaging after a mean of 16.2 months (1.6 - 40.6 months). Three patients had a local recurrence in the prostatic fossa. SBRT of bone metastases in oligometastatic prostate carcinoma patients is an effective and well tolerated therapy and can help to achieve high local control in the area of the metastases as well as delay the start or the escalation of systemic therapy. Nevertheless, the high rate of progression of distant metastases shows how important correct patient selection is and that combination with aHT may be necessary.

Functional and radiological outcome of distal radius fractures stabilized by volar-locking plate with a minimum follow-up of 1year.

Distal radius fractures (DRF) are the most common fractures of the upper extremities and incidence is expected to continue rising as life expectancy increases. Palmar locking plate stabilizing has since become the standard treatment for dorsally displaced DRF. Main aim of this study was to investigate correlation between radiological and clinical outcome in patients stabilized by palmar locking plate with a minimum follow-up of one year. A total of 524 patients with DRF, stabilized using palmar angular stable locking plate fixation were included in the study. Of these, 117 patients had to be excluded and another 177 were not accessible. The study group thus compromised 230 patients who returned for the follow-up investigation and were followed-up clinically and radiologically with a mean follow-up interval of 20months. Outcome was evaluated using pain, range of motion (ROM) and grip strength parameters. In addition, self-assessment by patients was registered on the QuickDASH, PRWE and Mayo Score. The immediate postoperative and final checkup radiographs were scrutinized for alignment and intra-articular step-off. Bivariant correlation analysis showed a significant correlation between ulnar variance and QuickDASH (r = 0.18, p = 0.01), grip strength (r = -0.18, p = 0.04) and Mayo Score (r = -0.23, p = 0.001). No significant differences could be found between an unacceptable (> 2mm) and acceptable (< 2mm) ulnar variance in respect of pain, ROM, grip strength and patient-reported outcome measurements. Age, gender, additional fracture to the ulnar styloid, or type of postoperative immobilization showed no significant or clinical important impact on the final patient-reported outcome. No significant differences in incidence of complications, ROM or loss of reduction could be found in any patients over or under 65years of age. Stabilization of DRF by palmar angular stable locking plate is a safe form of treatment and results in a good clinical and radiological outcome with low complication rate. Ulnar variance showed a significant correlation to grip strength, QuickDASH and Mayo Score, but an unacceptable ulnar variance (> 2mm) was not associated with a worse clinical important outcome. Age (< 65/> 65years), gender and type of immobilization had no impact on the complication rate or in the final functional or radiological outcome.

Dissociation of Pubertal Development Abnormality and Gonadal Dysfunction in Childhood Cancer Survivors

Purpose: To determine the relationship between pubertal development and postpubertal gonadal function in childhood cancer survivors. Methods: Childhood cancer survivors (≥10 years of age) who received follow-up care in a pediatric oncology group in an academic medical center during the period from January 1, 1985, to July 1, 2010 were included in this case series. Their pubertal development and gonadal function were evaluated. Results: The cohort consists of 39 males (age 10-21 years) and 35 females (age 10-29 years) with a variety of cancer diagnosis and treatments. The average age at diagnosis was ∼7.5 years. The average age at the time of the study was 16 and 16.7 years in males and females, respectively, representing a mean follow-up interval of ∼9 years. Despite the fact that 60% of survivors received cyclophosphamide equivalents and 16.2% received cranial radiation or brain tumor resection, the majority of survivors (68%) presented with both normal puberty and normal gonadal functions at the time of follow-up. In 27% of survivors, puberty development did not predict gonadal function in early adulthood: 20% of survivors had normal puberty, but abnormal gonadal function; 7% of survivors had abnormal puberty, but gonadal function remained normal as young adults. Conclusions: Most childhood cancer survivors had normal puberty and gonadal function despite a variety of cancer treatment modalities. However, normal puberty did not predict normal gonadal function later in life in many survivors. Therefore, close follow-up with gonadal function in adolescent and early adulthood years is essential.

Long-term outcomes of surgical procedures for Marfan syndrome: aortic dissection versus aneurysm.

BackgroundMultiple of subsequent procedures may necessary in Marfan syndrome (MFS) patients after initial surgery. The aim of this study was to investigate the full spectrum of secondary distal vascular or valvular interventions encountered after initial surgery.MethodsRetrospective analysis of 201 consecutive MFS patients between January 2000 and March 2019 who underwent 274 distal aortic reinterventions and 5 mitral valve replacements.ResultsOf the enrolled 201 MFS patients (73 female, mean age 37.0±12.8 years), the surgical indication for 93 patients was aortic root aneurysm, and for another 108 patients was dissection. The mean follow-up interval was 8.4±5.5 years. Total arch replacement (TAR) was performed in 68.5% of MFS patients presenting with type A aortic dissection (TAAD) and in 2.2% of patients with aneurysm. Secondary TAR became necessary for 3.4% of patients who failed to receive TAR at initial surgery in aneurysm group during follow-up, while for 33.3% of patients in dissection group (P<0.001). Freedom from distal aortic reoperation in dissection group were 65.4%±5.2%, 49.6%±6.4%, and 38.3%±7.7% and in aneurysm group were 90.5%±3.5%, 84.2%±4.8%, and 84.2%±4.8% at 5, 10, and 15 years, respectively (P<0.001). Survival in dissection group were 94.4%±2.4%, 83.4%±5.7%, 68.4%±10.8% and in aneurysm group were 100%, 97.7%±2.3%, 97.7%±2.3% at 5, 10, and 15 years, respectively (P=0.001). Freedom from mitral valve reoperation in dissection group were 98.8%±1.2%, 98.8%±1.2%, 88.9%±9.4% at 5, 10, and 15 years, respectively. Freedom from mitral valve reoperation in aneurysm group were 97.2%±1.9%, 94.6%±3.2%, 94.6%±3.2% at 5, 10, and 15 years, respectively (P=0.775).ConclusionsTAAD at initial surgery was an independent predictor of distal aortic reoperation. Limited repair was feasible for MFS patients presenting with aneurysm at initial surgery, extended repair might be better for TAAD for its higher risk of distal reintervention. Concomitant mitral valve procedures may depend on mitral regurgitation grades.

Partial trapeziectomy and pyrocarbon interpositional arthroplasty for trapeziometacarpal osteoarthritis: minimum 8-year follow-up.

We undertook a retrospective study to evaluate minimal 8-year outcomes of 46 trapeziometacarpal joints (46 patients) treated with pyrocarbon implant arthroplasty after partial trapeziectomy for trapeziometacarpal joint osteoarthritis in two different hand surgery units. The mean follow-up interval was 9.5 years (average 113 months with a range 97-144 months). The study showed that pyrocarbon interpositional arthroplasty provided pain relief and high patient satisfaction. All patients experienced a reduction in the DASH score, with an average change of 30 points. The visual analogue scale score, the Kapandji score, and key pinch also showed remarkable improvement. The PyroDisk implant exhibited good longevity, with good implant survival. A review of the literature revealed that the functional outcomes after implant surgery are not superior to more common techniques, such as trapeziectomy with or without ligamentoplasty. Therefore, this is a reliable surgery but may not have added benefits over simpler surgical treatments. This implant could have a role, perhaps in a select group of young patients, as a time-procuring procedure. Level of evidence: IV.

A nomogram to predict the progression-free survival of clival chordoma.

Chordoma shows poor patient prognosis because of its high recurrence rate. Even though many clinical factors and biomarkers are reported to be associated with prognosis, no prediction model has been applied clinically. Thus, the authors aim to derive and validate a prognostic nomogram to predict progression-free survival (PFS) of chordoma. A total of 201 patients were randomly divided into a derivation group (151 cases) and a validation group (50 cases). The expression levels of biomarkers were quantified using tissue microarray analysis. A nomogram was established via univariate and multivariate Cox regression analysis in the derivation group. The predictive performance of the nomogram was then tested in the validation group. The mean follow-up interval was 57 months (range 26-107 months). One clinical factor and 3 biomarkers were confirmed to be associated with PFS, including degree of resection, E-cadherin, Ki-67, and VEGFA. The nomogram with these prognostic factors had areas under the receiver operating characteristic curve of 0.87 and 0.95 in the derivation group at 3 years and 5 years, respectively, compared with 0.87 and 0.84 in the validation group. Calibration and score-stratified survival curve were good in the derivation group and validation group, respectively. The established nomogram performs well for predicting the PFS of chordoma and for risk stratification, which could facilitate prognostic evaluation and follow-up.

Is Isolated Mobile Component Exchange an Option in the Management of Intraprosthetic Dislocation of a Dual Mobility Cup?

Intraprosthetic dislocation is a specific complication of dual mobility cups, although it occurs less frequently with the latest generations of implants. Intraprosthetic dislocation is related to long-term polyethylene wear of the mobile component chamfer and retentive area, leading to a snap-out of the femoral head. With the increased use of dual mobility cups, even in younger and active patients, the management of intraprosthetic dislocation should be defined according to its type. However, no previous studies, except for case reports, have described the strategy to manage long-term wear-related intraprosthetic dislocation, particularly when a dual mobility cup is not loose. This study aimed to (1) determine the prevalence of intraprosthetic dislocation in this patient population and the macroscopic findings at the time of surgical revision and (2) evaluate whether isolated mobile component exchange could be an option to manage intraprosthetic dislocation occurring with a well-fixed dual mobility cup metal shell. From January 1991 to December 2009, a continuous series of 5274 THAs with dual mobility cups (4546 patients; 2773 women; mean [range] age 58 years [22-87]; bilateral THA = 728) were prospectively enrolled in our institutional total joint registry. A cementless, hemispherical dual mobility cup was systematically implanted, regardless of the patient's age or indication for THA. At the latest follow-up examination, the registry was queried to isolate each occurrence of intraprosthetic dislocation, which was retrospectively analyzed regarding the patient's demographics, indication for THA, radiographs, intraoperative findings (polyethylene wear and lesion patterns on the mobile component, periarticular metallosis, and implant damage because of intraprosthetic impingement of the femoral neck), management of intraprosthetic dislocation (isolated exchange of the mobile component or revision of the dual mobility cup), and outcome. At a mean (range) follow-up duration of 14 years (3-26), 3% of intraprosthetic dislocations (169 of 5274) were reported, with a mean (range) time from THA of 18 years (13-22). Intraprosthetic dislocation occurred predominantly in younger men (mean [range] age at THA, 42 years [22-64] versus 61 years [46-87]; p < 0.001, and sex ratio (male to female, 1:32 [96 male and 73 female] versus 0.62 [1677 male and 2700 female]; p < 0.001) in patients with intraprosthetic dislocation and those without, respectively, but was not influenced by the indication for THA (105 patients with intraprosthetic dislocation who underwent THA for primary hip osteoarthritis and 64 with other diagnoses versus 3146 patients without who underwent THA for primary hip osteoarthritis and 1959 for other diagnoses (p = 0.9)). In all patients with intraprosthetic dislocation, a macroscopic analysis of the explanted mobile component revealed circumferential polyethylene wear and damage to the chamfer and retentive area, with subsequent loss of retaining power for the femoral head. Nine percent of intraprosthetic dislocations (16 of 169 patients with intraprosthetic dislocations) were associated with aseptic loosening of the dual mobility cup and were managed with acetabular revision without recurrence at a mean (range) follow-up duration of 7.5 years (5-11). Ninety-one percent of intraprosthetic dislocations (153 of 169) were pure, related to wear of the mobile component chamfer and retentive area without aseptic loosening of the dual mobility cup, and managed with isolated mobile component exchange. Intraprosthetic dislocation recurred in 6% (nine of 153) at a mean (range) follow-up interval of 3 years (2-4.5). Additionally, severe premature polyethylene wear of the mobile component with loosening of the dual mobility cup occurred in 12% of patients (19 of 153) at a mean (range) follow-up duration of 1.5 years (0.5-3). A failure rate of 18% (28 of 153 patients undergoing isolated mobile component exchange) was reported within 5 years after isolated mobile component exchange to manage intraprosthetic dislocation occurring with a well-fixed dual mobility cup metal shell. The two modes of failure were early recurrence of intraprosthetic dislocation or severe premature metallosis-related polyethylene wear of the mobile component with loosening of the dual mobility cup. Acetabular revision with synovectomy should remain the standard procedure to manage intraprosthetic dislocation, particularly if periarticular metallosis is present. The exception is intraprosthetic dislocation occurring in elderly or frail patients, for whom a conventional acetabular revision procedure would be associated with an unjustified surgical or anesthetic risk. Level II, prognostic study.

Neuropsychiatric symptoms in Parkinson's disease: association with caregiver distress and disease severity.

The condition of caregivers is important to the quality of care received by people with Parkinson's disease (PD), especially at the late disease stages. This study addresses the distress placed on caregivers by participants' neuropsychiatric symptoms at different stages of PD in Taiwan. This prospective study enrolled 108 people with PD. All participants were examined with the Unified Parkinson's Disease Rating Scale (UPDRS), Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), Cognitive Abilities Screening Instrument (CASI), and Clinical Dementia Rating (CDR) scale. Caregiver distress was measured using the Neuropsychiatric Inventory Caregiver Distress Scale (NPI-D). Statistical analysis was used to explore the PD-related factors that contribute to caregiver distress. The mean follow-up interval in the 108 PD participants were 24.0 ± 10.2 months with no participant lost to follow-up due to death. NPI-distress (the sum of NPI caregiver distress scale across the 12 domains of the NPI) was positively correlated with NPI-sum (the total score across the 12 domains of the NPI) (r = 0.787, p < 0.001), CDR (r = 0.403, p < 0.001), UPRDS (r = 0.276, p = 0.004), and disease duration (r = 0.246, p = 0.002), but negatively correlated with CASI (r = -0.237, p = 0.043) and MMSE (r = -0.281, p < 0.001). Multiple linear regression analysis showed that only NPI-sum and disease duration were independently correlated with NPI-distress. The disease duration and NPI-sum are independent predictors of caregiver distress in Taiwanese populations with PD. Early detection and reduction of neuropsychiatric symptoms in people with PD can help decrease caregiver distress.

3018 Long Term Symptomatic Outcomes of Treatment of Uterine Fibroids in a Multidisciplinary Clinic

Study Objective To determine the utilization of medical, interventional radiologic, and gynecologic surgical treatments at a multidisciplinary fibroid clinic, also to assess pre- and post-intervention changes in fibroid symptoms, pelvic floor symptoms, and quality of life over a multi-year follow-up period. Design A retrospective survey study from 2013-2017. Setting Academic University Hospital. Patients or Participants 516 pre-menopausal women with pelvic MRI evidence of uterine fibroids seen at a multidisciplinary fibroid clinic from 2013-2017. Interventions Demographic and clinical information were collected including baseline Uterine Fibroid Symptoms – Quality of Life (UFS-QOL) and Pelvic Floor Distress Index (PFDI) questionnaires. All patients were sent a follow-up electronic survey at a single time point in 2018 assessing secondary treatments, fertility and re-administering UFS-QOL and PFDI questionnaires. Measurements and Main Results Our cohort of 516 patients utilized various treatments including hysterectomy (N=73, 17.1%), non-hysteroscopic myomectomy (N=68, 15.9%), and uterine fibroid embolization (N=117, 27.5%). Patients who underwent hysterectomy had worse baseline UFS-QOL and PFDI scores. 25.8% of patients responded to the follow-up survey with a mean follow-up interval of 28.6 months. Significant improvement was seen in UFS (-57.30% ± 66.90% vs -22.84% ± 55.50%, p=0.003) and PFDI (-61.20% ± 42.40% vs -11.82% ± 93.21%, p=0.012) scores for patients undergoing any intervention compared to expectant/medical management. There was no significant difference in UFS or PFDI improvement between interventional groups. Conclusion Patients undergoing any intervention reported better symptom improvement than patients undergoing expectant management or medical therapy. Symptomatic improvement based on UFS-QOL and PFDI scores were comparable between patients undergoing interventional radiologic procedures, myomectomy, and hysterectomy interventions.

Two- to five-year follow-up of 78 patients after treatment with the Flow Redirection Endoluminal Device

Flow-diverter stents are well-established for the treatment of cerebral aneurysms. Flow Redirection Endoluminal Device differs from other flow-diverter stents by its dual-layer design and has proved equality to other devices in numerous short-term surveys. However, follow-up data covering substantially more than one year are still limited for this device. We present our long-term experience with Flow Redirection Endoluminal Device. Seventy-eight patients harboring distal internal carotid artery (91%) or vertebrobasilar (9%) cerebral aneurysms treated with Flow Redirection Endoluminal Device with or without adjunctive coiling met the inclusion criteria. All cases were evaluated for aneurysm occlusion (according to Modified Raymond Roy Classification, MRRC), for flow-diverter stents patency and configuration and for procedure- and device-related morbidity and mortality. Mean follow-up interval was 36.9 ± 9.5 months (<30 months: n = 18; 31-42 months: n = 31; >42 months: n = 24). Total and subtotal aneurysm occlusion after six months was assessed in 92.0% (MRRC1 = 77.3%, MRRC2 = 14.7%, MRRC3a =2.7%, MRRC3b = 4.1%) and increased to 95.9% (MRRC1 = 90.5%, MRRC2 = 5.4%, MRRC3a = 2.7%). There was one case of aneurysm growth requiring early re-treatment. Procedure-related morbidity was observed in three cases (3.8%; one transient hemiparesis, one suspected foreign-body reaction, and one micro-wire perforation). There was no procedure- or device-related mortality. In-stent stenosis due to intimal hyperplasia was observed in two cases and fish-mouthing in three cases. Our long-term data covering two to five years after flow diversion confirm that Flow Redirection Endoluminal Device is a safe and effective device for the treatment of cerebral aneurysms with progressive high aneurysm occlusion rates; recurrence rates were very low. Overall device-related morbidity was low and was not observed later than six months after intervention.

Plasma pS129-α-Synuclein Is a Surrogate Biofluid Marker of Motor Severity and Progression in Parkinson's Disease.

Phosphorylated α-synuclein accounts for more than 90% of α-synuclein found in Lewy bodies of Parkinson’s disease (PD). We aimed to examine whether plasma Ser129-phosphorylated α-synuclein (pS129-α-synuclein) is a surrogate marker of PD progression. This prospective study enrolled 170 participants (122 PD patients, 68 controls). We measured plasma levels of total and pS129-α-synuclein using immunomagnetic reduction-based immunoassay. PD patients received evaluations of motor and cognition at baseline and at a mean follow-up interval of three years. Changes in the Movement Disorder Society revision of the Unified Parkinson’s Disease Rating Scale motor score (MDS-UPDRS part III) and Mini-Mental State Examination (MMSE) score were used to assess motor and cognition progression. Our results showed that plasma levels of total and pS129-α-synuclein were significantly higher in PD patients than controls (total: 1302.3 ± 886.6 fg/mL vs. 77.8 ± 36.6 fg/mL, p < 0.001; pS129-α-synuclein: 12.9 ± 8.7 fg/mL vs. 0.8 ± 0.6 fg/mL, p < 0.001), as was the pS129-α-synuclein/total α-synuclein ratio (2.8 ± 1.1% vs. 1.1 ± 0.6%, p = 0.01). Among PD patients, pS129-α-synuclein levels were higher with advanced motor stage (p < 0.001) and correlated with MDS-UPDRS part III scores (r = 0.27, 95% CI: 0.09–0.43, p = 0.004). However, we found no remarkable difference between PD patients with and without dementia (p = 0.75). After a mean follow-up of 3.5 ± 2.1 years, PD patients with baseline pS129-α-synuclein > 8.5 fg/mL were at higher risk of motor symptom progression of at least 3 points in the MDS-UPDRS part III scores than those with pS129-α-synuclein < 8.5 fg/mL (p = 0.03, log rank test). In conclusion, our data suggest that plasma pS129-α-synuclein levels correlate with motor severity and progression, but not cognitive decline, in patients with PD.

P5009The major bleeding event is the stronger predictor of long term mortality rather than the coronary event in the secondary prevention of ischemic heart disease in Japan

Abstract Background/Introduction Secondary prevention for ischemic heart disease (IHD) is important part in health care. To improve the risk factor control with general practitioners, we decided to set up a unique referral system to connect the hospital and outpatient clinics. Purpose Long term prognosis of IHD patients is unknown. The aims of this study are introducing our unique audit referral system and showing the long term prognosis of IHD patients with optimal second prevention therapy. Methods IHD patient registry was established in 2009 to connect cardiologists in the core hospitals and more than 200 general practitioners in Shizuoka city. To audit the treatment of general practitioners, we adopted a circulation type cooperative form. Target values of risk factors are as follows; low-density-lipoprotein cholesterol (LDL-C) concentration less than 100 mg/dl, HbA1c in diabetic patients less than 7%, systolic blood pressure (SBP) less than 130mmHg, and diastolic blood pressure (DBP) less than 80mmHg. General practitioners are required to introduce registered patients at least once a year even there is no event. Mean follow-up interval was 2001±794 days. Results We could follow 1240 patients who were registered from May 2009 to December 2013 and followed by at least one visit to the hospital in the prescribed manner until September 2018. Mean age was 77.3±10.6 years old, and 39.6% of them had old myocardial infarction. Latest risk factor controls are as follows; LDL-C 88.0±21.3mg/dl, HbA1c control in diabetic patients 7.0±1.1%, SBP and DBP 133.7±16.5 and 75.0±11.8mmHg respectively. Cumulative incidence of all-cause death was 10.8%, cardiac death was 1.5%, and coronary event (combination of cardiac death, myocardial infarction, angina pectoris which need hospitalization, and any lesion revascularization) was 15.8%. Cumulative incidence of major bleeding was 2.6%. The patients were divided into three groups without overlapping; major bleeding group (n=34), coronary event group (n=195), and event-free group (n=1049). The nonparametric test showed significant differences between three groups concerning age (p=0.026), the rate of using antithrombotic drugs (p&lt;0.001) and mortality (p=0.017). Kaplan-Meier method concerning all-cause death showed a significant difference between event-free group and major bleeding group (log rank p=0.002), and coronary event group and major bleeding group (p=0.026), while no statistical difference between event-free group and coronary event group. Cumulative survival rate Conclusions Our unique referral system revealed long term events in the stable IHD patients in Japan. The major bleeding event is a strong predictor of long term mortality in IHD patients rather than the coronary event.

29Prognostic safety of automatic cancellation of rest myocardial perfusion scan by machine learning: a report from multicenter REFINE SPECT registry of new generation SPECT

Abstract Background We aimed to develop a machine learning (ML) computer score derived from stress imaging and clinical data, which indicates if the rest scan could be automatically and safely canceled in the routine stress/rest myocardial perfusion SPECT (MPS). Methods A total of 20414 stress/rest cases from the REFINE SPECT registry collected from 5 sites in 3 countries with Tc-99m-based MPS images, clinical data, and clinical follow-up were included in the study. All images were automatically processed at our Medical Center. The automatically generated myocardial contours were checked by experienced technologists. In total, 93 variables (26 clinical, 17 stress-test, and 50 stress-imaging variables) were used to build a LogitBoost model for prediction of adverse events (AE), including coronary revascularization, death, myocardial infarction, and unstable angina. 10-fold cross-validation was performed to separate test from validation data for the assessment of ML. The overall ML predictive performance was compared to quantitative (stress total perfusion deficit [TPD]) by the area under the receiver operating characteristic curves (AUC). ML cut-off (ML1) to simulate the decision of cancellation of the rest scan was set to result in the same % of normal scans as these determined by the normal clinical reader diagnosis on a 4-point scale in the whole population, or the same % of scans with visual summed stress scores (SSS) = 0 in the subpopulation with available SSS. A second ML cutoff (ML2) was established to achieve a 1% annual risk of AE. The annual risk of AE of the normal ML score was compared with normal clinical diagnosis and with the finding of SSS = 0. Results The mean follow-up interval was 4.7±1.5 years. Overall, 3542 AE were observed (3.7% annual risk). The AUC for AE was higher for ML (0.780±0.005) than for stress TPD (0.698±0.006) (p&lt;0.001). Normal clinical diagnosis was reported in 60% cases. In 70% (14242 scans) with available segmental scores, 53% had SSS=0. ML1 and ML2 thresholds were compared with normal visual diagnosis and with SSS = 0 for AE (Figure). ML1 achieved a lower annual risk (1.5%) than normal clinical diagnosis (2.1%) or SSS = 0 (1.6% versus 2.3%) (p&lt;0.001). The more conservative ML2 threshold with a 1% annual risk of AE resulted in a 40% canceling rate. Figure 1 Conclusion ML could be used to automatically cancel the rest MPS scan with the same proportion as using normal visual MPS reading, but with significantly lower AE rate in stress-only scans. Acknowledgement/Funding R01HL089765 from the National Heart, Lung, and Blood Institute/National Institutes of Health (NHLBI/NIH)

Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals.

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT): A Morphologic and Molecular Study of 26 Cases Confirms Recurrent NCOA1-3 Rearrangement.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm, of uncertain biological potential, that was recently reported to exhibit recurrent gene fusions involving NCOA2-3. The purpose of this study was to, using a larger sample size, better characterize the histopathologic and molecular diversity of UTROSCT. Twenty-six cases of UTROSCT from 5 institutions were selected for further study. Fluorescence in situ hybridization for NCOA1, NCOA2, NCOA3, ESR1 and GREB1, and targeted RNA sequencing was performed on 17 and 8 UTROSCTs, respectively. Eight cases underwent massively parallel sequencing to detect single nucleotide variants (SNV), copy number variations, and structural variants using a targeted hybrid-capture based assay. NCOA1-3 rearrangement was identified in 81.8% (18/22) of cases. The most common fusion was ESR1-NCOA3, occurring in 40.9% (9/22). GREB1-NCOA1 (n=4), ESR1-NCOA2 (n=3), and GREB1-NCOA2 (n=1) rearrangements were also identified. No recurrent SNVs were identified and no tumor had SNVs in FOXL2, DICER1, STK11, or AKT1, which can be seen in ovarian sex cord-stromal tumors. Copy number variations were infrequent. Clinical follow-up was available for 11 cases with a mean follow-up interval of 94.4 (range, 1 to 319) months. Only one case had a recurrence 66 months after the initial diagnosis and this was the single case with a GREB1-NCOA2 fusion. This study reports the morphologic spectrum of UTROSCT and confirms the recently reported recurrent NCOA2-3 gene fusions, in addition to identifying novel rearrangements involving NCOA1 in these tumors.

Blood NfL

To examine whether plasma neurofilament light chain (NfL) levels were associated with motor and cognitive progression in Parkinson disease (PD). This prospective follow-up study enrolled 178 participants, including 116 with PD, 22 with multiple system atrophy (MSA), and 40 healthy controls. We measured plasma NfL levels with electrochemiluminescence immunoassay. Patients with PD received evaluations of motor and cognition at baseline and at a mean follow-up interval of 3 years. Changes in the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score and Mini-Mental State Examination score were used to assess motor and cognition progression. Plasma NfL levels were significantly higher in the MSA group than in the PD and healthy groups (35.8 ± 6.2, 17.6 ± 2.8, and 10.6 ± 2.3 pg/mL, respectively, p < 0.001). In the PD group, NfL levels were significantly elevated in patients with advanced Hoehn-Yahr stage and patients with dementia (p < 0.001). NfL levels were modestly correlated with UPDRS part III scores (r = 0.42, 95% confidence interval 0.46-0.56, p < 0.001). After a mean follow-up of 3.4 ± 1.2 years, a Cox regression analysis adjusted for age, sex, disease duration, and baseline motor or cognitive status showed that higher baseline NfL levels were associated with higher risks for either motor or cognition progression (p = 0.029 and p = 0.015, respectively). Plasma NfL levels correlated with disease severity and progression in terms of both motor and cognitive functions in PD. This study provides Class III evidence that plasma NfL level distinguishes PD from MSA and is a surrogate biomarker for PD progression.

A comparison study assessing neuropsychological outcome of patients with post-operative pediatric cerebellar mutism syndrome and matched controls after proton radiation therapy.

Post-operative pediatric cerebellar mutism syndrome (CMS), characterized by mutism, ataxia/hypotonia, and emotional lability, can result in long-term deficits following resection of posterior fossa (PF) tumors. This longitudinal study compared neuropsychological outcomes of pediatric patients with post-operative CMS to a matched control patient group without CMS. Fifty-eight PF tumor patients received post-surgical proton radiation therapy (PRT) and testing at baseline and at ≥ 1-year post-PRT over a 10-year period. Of these, 18 (31%) had post-operative CMS with baseline and follow-up neuropsychological test data. Those participants were matched to 18 controls by tumor location, age, gender, and handedness; no significant group differences were found at baseline for clinical/demographic variables. Total mean age at baseline was 7.26years (SD = 4.42); mean follow-up interval was 3.26years (SD = 2.24). Areas assessed: overall intelligence, expressive and receptive vocabulary, visuomotor integration, fine motor speed, inhibition, emotional control, depression, and anxiety. Patients were 52% male; 86% medulloblastoma/14% ependymoma; 86% craniospinal irradiation/14% focal radiation; and 86% chemotherapy. No group differences were found between most mean baseline scores; expressive vocabulary and fine motor speed were significantly lower in the post-operative CMS group (p< 0.05). Mean change scores revealed no significant differences for the sample; scores were within the normal range except fine motor skills were impaired for both groups. Longitudinal neuropsychological outcomes for post-operative pediatric CMS patients did not differ significantly from matched controls without this condition. Patients were in the normal range in all areas except fine motor speed, which was impaired for both groups independent of CMS diagnosis.