Individual Patient Analysis Research Articles

Development of machine learning models for fractional flow reserve prediction in angiographically intermediate coronary lesions.

Fractional flow reserve (FFR) represents the gold standard in guiding the decision to proceed or not with coronary revascularization of angiographically intermediate coronary lesion (AICL). Optical coherence tomography (OCT) allows to carefully characterize coronary plaque morphology and lumen dimensions. We sought to develop machine learning (ML) models based on clinical, angiographic and OCT variables for predicting FFR. Data from a multicenter, international, pooled analysis of individual patient's level data from published studies assessing FFR and OCT on the same target AICL were collected through a dedicated database to train (n = 351) and validate (n = 151) six two-class supervised ML models employing 25 clinical, angiographic and OCT variables. A total of 502 coronary lesions in 489 patients were included. The AUC of the six ML models ranged from 0.71 to 0.78, whereas the measured F1 score was from 0.70 to 0.75. The ML algorithms showed moderate sensitivity (range: 0.68-0.77) and specificity (range: 0.59-0.69) in detecting patients with a positive or negative FFR. In the sensitivity analysis, using 0.75 as FFR cut-off, we found a higher AUC (0.78-0.86) and a similar F1 score (range: 0.63-0.76). Specifically, the six ML models showed a higher specificity (0.71-0.84), with a similar sensitivity (0.58-0.80) with respect to 0.80 cut-off. ML algorithms derived from clinical, angiographic, and OCT parameters can identify patients with a positive or negative FFR.

Geographical variation in patient characteristics and outcomes in heart failure with mildly reduced and preserved ejection fraction.

Compared to heart failure (HF) with reduced ejection fraction, HF with preserved ejection fraction (HFpEF), and HF with mildly reduced ejection fraction (HFmrEF) are increasing in prevalence, yet little is known about the geographic variation in patient characteristics, treatments and outcomes among these two HF phenotypes. The aim of this study was to investigate geographic differences in HFpEF and HFmrEF. We conducted an individual patient analysis of five clinical trials enrolling patients with HFpEF or HFmrEF from North America (NA), Latin America (LA), Western Europe (WE), Central/Eastern Europe and Russia (CEER), and Asia-Pacific (AP). We compared regions using descriptive statistics and multivariable regression models. Among the 19 959 patients included, 4066 (23.1%) had HFmrEF and 15 353 (76.9%) HFpEF. Regardless of HF phenotype, patients from WE were oldest, and those in CEER youngest. LA had the largest portion of females and NA most black patients. Obesity and diabetes were most prevalent in NA and hypertension and coronary heart disease most common in CEER. Self-reported health status varied strikingly and was the worst in NA and best in AP. Among patients with HFmrEF, rates of the primary composite endpoint (cardiovascular death or HF hospitalization) were: NA 12.56 per 100 patient-years (/100py), AP 11.67/100py, CEER 10.12/100py, LA 8.90/100py, and WE 8.43/100py, driven by differences in the rate of HF hospitalization. The corresponding values in HFpEF were 11.47/100py, 7.80/100py, 5.47/100py, 5.92/100py, and 7.80/100py, respectively. There is substantial geographic variation in patient characteristics, treatment and outcomes among patients with HFpEF and HFmrEF. These findings have implications for interpretation and generalizability of trial results, design and conduct of future trials, and optimization of care for these patients.

Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.

In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant. In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48weeks (median period of 84weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients. Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy. Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.

Prognostic Value of Complete Resection of the High-Frequency Oscillation Area in Intracranial EEG: A Systematic Review and Meta-Analysis.

High-frequency oscillations (HFOs; ripples 80-250 Hz; fast ripples [FRs] 250-500 Hz) recorded with intracranial electrodes generated excitement and debate about their potential to localize epileptogenic foci. We performed a systematic review and meta-analysis on the prognostic value of complete resection of the HFOs-area (crHFOs-area) for epilepsy surgical outcome in intracranial EEG (iEEG) accessing multiple subgroups. We searched PubMed, Embase, and Web of Science for original research from inception to October 27, 2022. We defined favorable surgical outcome (FSO) as Engel class I, International League Against Epilepsy class 1, or seizure-free status. The prognostic value of crHFOs-area for FSO was assessed by (1) the pooled FSO proportion after crHFOs-area; (2) FSO for crHFOs-area vs without crHFOs-area; and (3) the predictive performance. We defined high combined prognostic value as FSO proportion >80% + FSO crHFOs-area >without crHFOs-area + area under the curve (AUC) >0.75 and examined this for the clinical subgroups (study design, age, diagnostic type, HFOs-identification method, HFOs-rate thresholding, and iEEG state). Temporal lobe epilepsy (TLE) was compared with extra-TLE through dichotomous variable analysis. Individual patient analysis was performed for sex, affected hemisphere, MRI findings, surgery location, and pathology. Of 1,387 studies screened, 31 studies (703 patients) met our eligibility criteria. Twenty-seven studies (602 patients) analyzed FRs and 20 studies (424 patients) ripples. Pooled FSO proportion after crHFOs-area was 81% (95% CI 76%-86%) for FRs and 82% (73%-89%) for ripples. Patients with crHFOs-area achieved more often FSO than those without crHFOs-area (FRs odds ratio [OR] 6.38, 4.03-10.09, p < 0.001; ripples 4.04, 2.32-7.04, p < 0.001). The pooled AUCs were 0.81 (0.77-0.84) for FRs and 0.76 (0.72-0.79) for ripples. Combined prognostic value was high in 10 subgroups: retrospective, children, long-term iEEG, threshold (FRs and ripples) and automated detection and interictal (FRs). FSO after complete resection of FRs-area (crFRs-area) was achieved less often in people with TLE than extra-TLE (OR 0.37, 0.15-0.89, p = 0.006). Individual patient analyses showed that crFRs-area was seen more in patients with FSO with than without MRI lesions (p = 0.02 after multiple correction). Complete resection of the brain area with HFOs is associated with good postsurgical outcome. Its prognostic value holds, especially for FRs, for various subgroups. The use of HFOs for extra-TLE patients requires further evidence.

Abstract PO2-04-12: From Clinical Trials to Clinical Practice; Real World Clinical Outcomes of Patients Treated with Ribociclib in Combination with Aromatase Inhibitors or Fulvestrant for HR-Positive, HER2- Negative Metastatic Breast Cancer

Abstract Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors have revolutionized the treatment landscape of hormone receptor-positive (HR+), human epidermal growth factor receptor-2 (HER2)-negative metastatic breast cancer (MBC), with an impressive efficacy and safety profile. Here we report real-world clinical outcomes and toxicity data in patients treated at a tertiary care cancer center. Methods: The study is a retrospective analysis of individual patients’ data. All consecutive patients with HR+ and HER2-negative MBC, treated at our institution with ribociclib plus aromatase inhibitors (AI) or fulvestrant, between June 2017 and May 2020 were reviewed. Data were collected from patients’ electronic medical records. Progression free survival (PFS) was defined as the time from treatment initiation with CDK4/6i until the first documented progression, death from any cause or last follow-up, whichever occurred first. The Overall survival (OS) was defined as the time from treatment initiation with CDK4/6i until the date of death from any cause, or last follow-up. Results: A total of 305 patients, median age 49 (22-87) years were enrolled. Although bone metastasis was reported in 241 (79.0%) patients, bone-only metastasis was identified in 64 (20.9%). Visceral metastasis in the liver and lungs were reported in 22.0% and 25.9 % of patients, respectively. CDK4/6i combined with AI were used in first-line setting in 195 (63.9%) patients and with fulvestrant as a second line (20.7%) or beyond (15.4%). Dose reduction was required in 44 (14.14%) patients, mostly because of neutropenia (n=38, 12.5%) and abnormal liver enzymes (n=12, 3.9%), while 11 (3.6%) discontinued treatment, mostly due cardiac toxicities. Nevertheless, there were no deaths due to toxicity. Patients were followed up for a median of 31.1 months. Overall response rate (ORR) was 51.4% and median PFS, irrespective of the line of therapy, was 19.3 (17.6-23.3) months. PFS was longer in first-line setting; 23.1 (19.7-NR) months compared to 13.9 (10.2-17.6) months in second-line or beyond, p&amp;lt; 0 .0001, and when combined with AI compared to fulvestrant; 28.6 (17.8-23.1) months versus 9.1 (4.4-NR) months, p=0.0001, and in those with bone-only metastasis; 23.1 (19.5-NR) months versus 17.3 (12.2-18.9) months for patients with visceral metastasis, p=0.0008. The median OS was not reached. Conclusions: Despite enrolling sicker patients, and outside the stringent clinical trials settings, our treatment outcomes, in real world settings, are comparable to those reported in major clinical trials, including MONALEESA-2, MONALEESA-3 and MONALEESA-7. Citation Format: Baha' Sharaf, Faris Tamimi, Sarah Edaily, Osama Salama, Hazem Abdulelah, Anas Zayed, Mahmoud Abunasser, Hala Abu-Fares, Hikmat Abdel-Razeq. From Clinical Trials to Clinical Practice; Real World Clinical Outcomes of Patients Treated with Ribociclib in Combination with Aromatase Inhibitors or Fulvestrant for HR-Positive, HER2- Negative Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-12.

Effectiveness and tolerability of brivaracetam in patients with epilepsy stratified by comorbidities and etiology in the real world: 12-month subgroup data from the international EXPERIENCE pooled analysis

ObjectiveTo assess the effectiveness and tolerability of brivaracetam (BRV) in adults with epilepsy by specific comorbidities and epilepsy etiologies.MethodsEXPERIENCE/EPD332 was a pooled analysis of individual patient records from several non-interventional studies of patients with epilepsy initiating BRV in clinical practice. Outcomes included ≥ 50% reduction from baseline in seizure frequency, seizure freedom (no seizures within prior 3 months), continuous seizure freedom (no seizures since baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Analyses were performed for all adult patients (≥ 16 years of age) and stratified by comorbidity and by etiology at baseline (patients with cognitive/learning disability [CLD], psychiatric comorbidity, post-stroke epilepsy, brain tumor−related epilepsy [BTRE], and traumatic brain injury−related epilepsy [TBIE]).ResultsAt 12 months, ≥ 50% seizure reduction was achieved in 35.6% (n = 264), 38.7% (n = 310), 41.7% (n = 24), 34.1% (n = 41), and 50.0% (n = 28) of patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, respectively; and continuous seizure freedom was achieved in 5.7% (n = 318), 13.7% (n = 424), 29.4% (n = 34), 11.4% (n = 44), and 13.8% (n = 29), respectively. During the study follow-up, in patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE, 37.1% (n = 403), 30.7% (n = 605), 33.3% (n = 51), 39.7% (n = 68), and 27.1% (n = 49) of patients discontinued BRV, respectively; and TEAEs since prior visit at 12 months were reported in 11.3% (n = 283), 10.0% (n = 410), 16.7% (n = 36), 12.5% (n = 48), and 3.0% (n = 33), respectively.ConclusionsBRV as prescribed in the real world is effective and well tolerated among patients with CLD, psychiatric comorbidity, post-stroke epilepsy, BTRE, and TBIE.

Transient immune activation without loss of intraepidermal innervation and associated Schwann cells in patients with complex regional pain syndrome

BackgroundComplex regional pain syndrome (CRPS) develops after injury and is characterized by disproportionate pain, oedema, and functional loss. CRPS has clinical signs of neuropathy as well as neurogenic inflammation. Here, we asked whether skin biopsies could be used to differentiate the contribution of these two systems to ultimately guide therapy. To this end, the cutaneous sensory system including nerve fibres and the recently described nociceptive Schwann cells as well as the cutaneous immune system were analysed.MethodsWe systematically deep-phenotyped CRPS patients and immunolabelled glabrous skin biopsies from the affected ipsilateral and non-affected contralateral finger of 19 acute (< 12 months) and 6 chronic (> 12 months after trauma) CRPS patients as well as 25 sex- and age-matched healthy controls (HC). Murine foot pads harvested one week after sham or chronic constriction injury were immunolabelled to assess intraepidermal Schwann cells.ResultsIntraepidermal Schwann cells were detected in human skin of the finger—but their density was much lower compared to mice. Acute and chronic CRPS patients suffered from moderate to severe CRPS symptoms and corresponding pain. Most patients had CRPS type I in the warm category. Their cutaneous neuroglial complex was completely unaffected despite sensory plus signs, e.g. allodynia and hyperalgesia. Cutaneous innate sentinel immune cells, e.g. mast cells and Langerhans cells, infiltrated or proliferated ipsilaterally independently of each other—but only in acute CRPS. No additional adaptive immune cells, e.g. T cells and plasma cells, infiltrated the skin.ConclusionsDiagnostic skin punch biopsies could be used to diagnose individual pathophysiology in a very heterogenous disease like acute CRPS to guide tailored treatment in the future. Since numbers of inflammatory cells and pain did not necessarily correlate, more in-depth analysis of individual patients is necessary.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6months. However, in routine care, it is often extended to 12months, despite lacking robust supporting data. GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. For glioblastoma patients, extending post-radiation temozolomide from 6 to 12months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Predicting preterm birth using explainable machine learning in a prospective cohort of nulliparous and multiparous pregnant women.

Preterm birth (PTB) presents a complex challenge in pregnancy, often leading to significant perinatal and long-term morbidities. "While machine learning (ML) algorithms have shown promise in PTB prediction, the lack of interpretability in existing models hinders their clinical utility. This study aimed to predict PTB in a pregnant population using ML models, identify the key risk factors associated with PTB through the SHapley Additive exPlanations (SHAP) algorithm, and provide comprehensive explanations for these predictions to assist clinicians in providing appropriate care. This study analyzed a dataset of 3509 pregnant women in the United Arab Emirates and selected 35 risk factors associated with PTB based on the existing medical and artificial intelligence literature. Six ML algorithms were tested, wherein the XGBoost model exhibited the best performance, with an area under the operator receiving curves of 0.735 and 0.723 for parous and nulliparous women, respectively. The SHAP feature attribution framework was employed to identify the most significant risk factors linked to PTB. Additionally, individual patient analysis was performed using the SHAP and the local interpretable model-agnostic explanation algorithms (LIME). The overall incidence of PTB was 11.23% (11 and 12.1% in parous and nulliparous women, respectively). The main risk factors associated with PTB in parous women are previous PTB, previous cesarean section, preeclampsia during pregnancy, and maternal age. In nulliparous women, body mass index at delivery, maternal age, and the presence of amniotic infection were the most relevant risk factors. The trained ML prediction model developed in this study holds promise as a valuable screening tool for predicting PTB within this specific population. Furthermore, SHAP and LIME analyses can assist clinicians in understanding the individualized impact of each risk factor on their patients and provide appropriate care to reduce morbidity and mortality related to PTB.

The changing landscape of cardiac co-morbidities and in-hospital cardiac complications mediating Covid-19 mortality between 2020 and 2021

BackgroundCardiac co-morbidities and in-hospital cardiac complications significantly contribute to COVID-19 mortality. However, their influence on mortality between 2021 and 2020 may differ due to the availability of vaccines, different viral strains, and therapeutic advancements. MethodsWe performed a retrospective chart review and individual patient analysis of all COVID-19 associated in-patient deaths in 2020 (n = 346) and 2021(n = 527) in a large Minneapolis health system. Cause of death was adjudicated by at least two health care providers, including one cardiologist. ResultsPatients who died in 2021 were younger, of similar race/ethnicity, and body mass index compared to 2020. In 2021, 24 % of the cohort was full or partially vaccinated, while none were vaccinated in 2020. Patients who died in 2021 had significantly fewer cardiovascular co-morbidities and major adverse cardiovascular events prior to COVID-19 infection, resulting in significantly fewer in-hospital cardiac adverse events compared to patients who died in 2020, including myocardial infarction, stroke, and atrial fibrillation. In contrast, patients in 2021 had significantly higher rates of venous thromboembolic events. ConclusionPatients who died from COVID-19 in 2021 had significantly fewer cardiovascular co-morbidities and in-hospital cardiovascular complications compared to patients who died in 2020. Sixteen percent of patients stipulated as dying from COVID-19 actually die from other causes.

Postoperative Seizure Prophylaxis in Meningioma Resection: A Systematic Review and Meta-Analysis.

Seizures in the early postoperative period may impair patient recovery and increase the risk of complications. The aim of this study is to determine whether there is any advantage in postoperative seizure prophylaxis following meningioma resection. This systematic review was conducted in accordance with PRISMA guidelines. PUBMED, Web of Science, Embase, Science Direct, and Cochrane were searched for papers until April 2023. Among nine studies, a total of 3249 patients were evaluated, of which 984 patients received antiepileptic drugs (AEDs). No significant difference was observed in the frequency of seizure events between patients who were treated with antiepileptic drugs (AEDs) and those who were not. (RR 1.22, 95% CI 0.66 to 2.40; I2 = 57%). Postoperative seizures occurred in 5% (95% CI: 1% to 9%) within the early time period (<7 days), and 9% (95% CI: 1% to 17%) in the late time period (>7 days), with significant heterogeneity between the studies (I2 = 91% and 97%, respectively). In seizure-naive patients, the rate of postoperative seizures was 2% (95% CI: 0% to 6%) in the early period and increased to 6% (95% CI: 0% to 15%) in the late period. High heterogeneity led to the use of random-effects models in all analyses. The current evidence does not provide sufficient support for the effectiveness of prophylactic AED medications in preventing postoperative seizures in patients undergoing meningioma resection. This underscores the importance of considering diagnostic criteria and conducting individual patient analysis to guide clinical decision-making in this context.

Effectiveness and Tolerability of 12-Month Brivaracetam in the Real World: EXPERIENCE, an International Pooled Analysis of Individual Patient Records.

Real-world evidence studies of brivaracetam (BRV) have been restricted in scope, location, and patient numbers. The objective of this pooled analysis was to assess effectiveness and tolerability of brivaracetam (BRV) in routine practice in a large international population. EXPERIENCE/EPD332 was a pooled analysis of individual patient records from multiple independent non-interventional studies of patients with epilepsy initiating BRV in Australia, Europe, and the United States. Eligible study cohorts were identified via a literature review and engagement with country lead investigators, clinical experts, and local UCB Pharma scientific/medical teams. Included patients initiated BRV no earlier than January 2016 and no later than December 2019, and had ≥6 months of follow-up data. The databases for each cohort were reformatted and standardised to ensure information collected was consistent. Outcomes included ≥50% reduction from baseline in seizure frequency, seizure freedom (no seizures within 3 months before timepoint), continuous seizure freedom (no seizures from baseline), BRV discontinuation, and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were considered non-responders/not seizure free. Analyses were performed for all adult patients (≥16 years), and for subgroups by seizure type recorded at baseline; by number of prior antiseizure medications (ASMs) at index; by use of BRV as monotherapy versus polytherapy at index; for patients who switched from levetiracetam to BRV versus patients who switched from other ASMs to BRV; and for patients with focal-onset seizures and a BRV dose of ≤200mg/day used as add-on at index. Analysis populations included the full analysis set (FAS; all patients who received at least one BRV dose and had seizure type and age documented at baseline) and the modified FAS (all FAS patients who had at least one seizure recorded during baseline). The FAS was used for all outcomes other than ≥50% seizure reduction. All outcomes were summarised using descriptive statistics. Analyses included 1644 adults. At baseline, 72.0% were 16-49 years of age and 92.2% had focal-onset seizures. Patients had a median (Q1, Q3) of 5.0 (2.0, 8.0) prior antiseizure medications at index. At 3, 6, and 12 months, respectively, ≥50% seizure reduction was achieved by 32.1% (n=619), 36.7% (n=867), and 36.9% (n=822) of patients; seizure freedom rates were 22.4% (n=923), 17.9% (n=1165), and 14.9% (n=1111); and continuous seizure freedom rates were 22.4% (n=923), 15.7% (n=1165), and 11.7% (n=1111). During the whole study follow-up, 551/1639 (33.6%) patients discontinued BRV. TEAEs since prior visit were reported in 25.6% (n=1542), 14.2% (n=1376), and 9.3% (n=1232) of patients at 3, 6, and 12 months, respectively. This pooled analysis using data from a variety of real-world settings suggests BRV is effective and well tolerated in routine clinical practice in a highly drug-resistant patient population.

Diagnostic accuracy of the latest-generation digital PET/CT scanner for detection of metastatic lymph nodes in head and neck cancer.

The aim of this retrospective analysis was to assess the diagnostic accuracy of the latest-generation digital positron emission tomography/computed tomography (PET/CT) scanner in the detection of cervical lymph node metastasis in patients undergoing staging work-up for head and neck cancer. A total of 55 consecutive patients with head and neck cancer at our institution who had a PET/CT after installation of the latest-generation PET/CT (Siemens Biograph Vision) who subsequently underwent surgical neck dissection were included. The nodal station location and number of reported PET/CT-positive metastatic lymph nodes were compared to a gold standard of final surgical pathology after neck dissection. In total, 188 neck levels and 1,373 lymph nodes were resected; 56 neck levels (118 nodes) in 31 (56%) patients contained nodal metastases on surgical pathology. On a nodal level-by-level analysis, the overall sensitivity for the detection of lymph node metastases on the latest-generation PET/CT scanner was 96.4% and the specificity was 86.4%. The sensitivity and specificity for the neck side analysis were 94.0% and 63.7%, and for the individual patient analysis were 100% and 71%, respectively. In this single-institution study, latest-generation PET/CT had a high sensitivity and moderate to high specificity for detecting cervical node metastasis in head and neck cancer. Compared to data from older PET/CT scanners, the sensitivity of the latest-generation PET/CT was slightly higher, while the specificity was similar or slightly lower. Physicians involved in the management of head and neck cancer should be aware of possible changes in the overall diagnostic accuracy when changing to a latest-generation PET/CT scanner.

Clarifying the clinical landscape of pediatric spinal arteriovenous shunts: an institutional experience and individual patient-data meta-analysis

BackgroundPediatric spinal arteriovenous shunts (SAVS) are rare lesions with heterogeneous pathogenesis and clinical manifestations.ObjectiveTo evaluate the clinical characteristics, angioarchitecture, and technical/clinical outcomes in SAVS through a large single-center cohort analysis...

The Heterogeneity of Ovomucoid-Specific IgE Idiotype Is Associated With Egg Allergy Symptom Severity.

Immunoglobulin E (IgE)-mediated egg allergy presents as one of the most common food allergies. The level of specific IgE (sIgE) antibody is widely used as an important in vitro diagnostic indicator. However, sIgE antibody levels are often inconsistent with the clinical manifestations of patients. The heterogeneity of egg-specific IgE idiotypes (sIgE-IDs) may help reflect clinical egg allergy severity. Eight peptides were synthesized, corresponding to the linear epitopes of ovomucoid (OVM). The sIgE-IDs of egg-allergic patients were detected by enzyme-linked immunosorbent assay. Fresh peripheral blood was collected from patients with different heterogeneity strength of sIgE-ID, and egg extract was used as a stimulus to the basophil activation test (BAT). RBL-2H3 cells were sensitized with serum with different strength of sIgE-ID heterogeneity and the release rate of β-hexosaminidase was calculated. Among 75 patients with egg allergy, 24% had sIgE for all epitopes and 85% had sIgE for at least one epitope. Analysis of individual patients revealed differences in epitope recognition patterns among the patients, that is, heterogeneity in sIgE-ID. More importantly, the number of IgE-positive peptides had a strong correlation with allergic symptoms in egg-allergic patients (r = 0.706). BAT and RBL-2H3 cell degranulation confirmed that higher sIgE-ID heterogeneity strength was more effective in inducing effector cell responses. Our results suggest that the greater the heterogeneity strength of OVM-sIgE-ID, the more severe the allergic symptoms.

Significant Mortality Associated With COVID-19 and Comorbid Cerebrovascular Disease: A Quantitative Systematic Review.

We report the first quantitative systematic review of cerebrovascular disease in coronavirus disease 2019 (COVID-19) to provide occurrence rates and associated mortality. Through a comprehensive search of PubMed we identified 8 cohort studies, 5 case series, and 2 case reports of acute cerebrovascular disease in patients with confirmed COVID-19 diagnosis. Our first meta-analysis utilizing the identified publications focused on comorbid cerebrovascular disease in recovered and deceased patients with COVID-19. We performed 3 additional meta-analyses of proportions to produce point estimates of the mortality and incidence of acute cerebrovascular disease in COVID-19 patients. Patient's with COVID-19 who died were 12.6 times more likely to have a history of cerebrovascular disease. We estimated an occurrence rate of 2.6% (95% confidence interval, 1.2-5.4%) for acute cerebrovascular disease among consecutively admitted patients with COVID-19. While for those with severe COVID-19' we estimated an occurrence rate of 6.5% (95% confidence interval, 4.4-9.6%). Our analysis estimated a rate of 35.5% for in-hospital mortality among COVID-19 patients with concomitant acute cerebrovascular disease. This was consistent with a mortality rate of 34.0% which we obtained through an individual patient analysis of 47 patients derived from all available case reports and case series. COVID-19 patients with either acute or chronic cerebrovascular disease have a high mortality rate with higher occurrence of cerebrovascular disease in patients with severe COVID-19.

Lysosomal glycogen accumulation in Pompe disease results in disturbed cytoplasmic glycogen metabolism.

Pompe disease is an inherited metabolic myopathy caused by deficiency of acid alpha-glucosidase (GAA), resulting in lysosomal glycogen accumulation. Residual GAA enzyme activity affects disease onset and severity, although other factors, including dysregulation of cytoplasmic glycogen metabolism, are suspected to modulate the disease course. In this study, performed in mice and patient biopsies, we found elevated protein levels of enzymes involved in glucose uptake and cytoplasmic glycogen synthesis in skeletal muscle from mice with Pompe disease, including glycogenin (GYG1), glycogen synthase (GYS1), glucose transporter 4 (GLUT4), glycogen branching enzyme 1 (GBE1), and UDP-glucose pyrophosphorylase (UGP2). Expression levels were elevated before the loss of muscle mass and function. For first time, quantitative mass spectrometry in skeletal muscle biopsies from five adult patients with Pompe disease showed increased expression of GBE1 protein relative to healthy controls at the group level. Paired analysis of individual patients who responded well to treatment with enzyme replacement therapy (ERT) showed reduction of GYS1, GYG1, and GBE1 in all patients after start of ERT compared tobaseline. These results indicate that metabolic changes precede muscle wasting in Pompe disease, and imply a positive feedforward loop in Pompe disease, in which lysosomal glycogen accumulation promotes cytoplasmic glycogen synthesis and glucose uptake, resulting in aggravation of the disease phenotype.

Left atrial volume, function and B-lines at rest and during vasodilator stress echocardiography

Abstract Background Left atrial volume index (LAVi), left atrial reservoir function assessed with global peak amplitude longitudinal strain (PALS), and B-lines at lung ultrasound are supplementary markers of left ventricular filling pressures. Aim To assess the relationship between LAVi, PALS and B-lines at rest and peak vasodilator stress. Methods A comprehensive dipyridamole stress echo was completed in 266 patients (187 male, 71%, age 65±10 years) with chronic coronary syndromes. LAVi was measured with the biplane disk summation method. PALS was measured from a single vendor with 2-dimensional speckle tracking echocardiography and expressed in % values as the mean of the 12 atrial segments from 4- and 2-chamber values. B-lines were assessed with the simplified 4-site scan in the third intercostal space, with global score from 0 to 40, and considered significant with global score ≥2 units. Results During dipyridamole, LAVi decreased (rest= 26±14 ml/m2 vs stress= 24±12 ml/m2, p&amp;lt;0.001), PALS increased (rest= 33±8 vs stress= 38±10%, p&amp;lt;0.001), and B-lines were more frequent (rest= 0.4, median interquartile range 0–30, vs stress= 0.7, median interquartile range 0–30, units, p&amp;lt;0.001). There was a significant, linear, inverse correlation between LAVi and PALS both at rest (r=−0.301, p&amp;lt;0.001) and at peak stress (r=−0.279, p&amp;lt;0.001, see figure). At group analysis, peak B-lines were directly correlated with peak LAVi (r=0.151, p=0.017) and inversely correlated with peak PALS (r=−0.234, p&amp;lt;0.001). At individual patient analysis, 4/93 patients (4.3%) showed stress B-lines (black dots in figure) with normal LAVi (&amp;lt;34 ml/m2) and preserved PALS (&amp;gt;42%). Conclusion Vasodilator stress echocardiography with combined assessment of left atrial volume, function and pulmonary congestion is feasible with high success rate in patients with chronic coronary syndromes. Pulmonary congestion is more frequent with dilated left atrium with reduced atrial contractile reserve, but it may occur in a minority of patients with normal LAVi and normal PALS. Funding Acknowledgement Type of funding sources: None.

MM-192 Young Patients With Multiple Myeloma Diagnosed Before 50 Years of Age: Single-Center Experience

Multiple myeloma is a disease of older adults, and there are conflicting data about the presentation, treatment, and prognosis in younger age groups. The present study is designed to analyze the clinical and hematological profile and outcomes in young adults with multiple myeloma. The study is a retrospective analysis of individual patients' data. All consecutive patients with multiple myeloma aged 50 years or younger and treated in our institution between September 2007 and December 2020 were reviewed. Data were collected from patients' electronic medical records. A total of 175 patients were reviewed, 115 (65.7%) were male, 47 (26.8%) were smokers, and the median age was 45 (range: 24-50). At diagnosis, 73.1% of the patients presented at International Staging System (ISS) stage I-II, lytic bone lesions presented in 81.7% of the cohort, and anemia presented in 46.9%. The median M component is 3.20, 28 had no serum M component, and 74 had no serum or urine M protein. IgG Kappa 73 (41.7) and Free Kappa 40 (22.8) represent the majority of the protein isotype. The median bone marrow involvement is 60%, 14.3% (25/175) did cytogenic testing, and the most common abnormality is 4:14. VTD is the most commonly used induction regimen, 109 (62%) underwent ASCT, and 42 had relapse. The outcome is as follows: CR, 56 (32); DP, 26 (14.8); PR, 43 (24.6); SD, 5 (2.8); VGPR, 35 (20); <PR, 8 (4.6). After a median follow-up of 73 months, 61.1% of patients were still alive. Ninety-four patients of the population (53.7%) had experienced disease progression or/and death, and 62.3% of patients underwent autologous stem cell transplantation with a median overall survival (OS) of 118 months versus 24 months for those who did not. The OS for patients with ASCT was 75.2% versus 37.9% for those without (P<0.0001). There is a need for more research focusing on multiple myeloma in young patients regarding epidemiological landscape, disease biology, and clinical management.

Reappraising the variability of effects of antipsychotic medication in schizophrenia: a meta-analysis.

It is common experience for practising psychiatrists that individuals with schizophrenia vary markedly in their symptomatic response to antipsychotic medication. What is not clear, however, is whether this variation reflects variability of medication-specific effects (also called "treatment effect heterogeneity"), as opposed to variability of non-specific effects such as natural symptom fluctuation or placebo response. Previous meta-analyses found no evidence of treatment effect heterogeneity, suggesting that a "one size fits all" approach may be appropriate and that efforts at developing personalized treatment strategies for schizophrenia are unlikely to succeed. Recent advances indicate, however, that earlier approaches may have been unable to accurately quantify treatment effect heterogeneity due to their neglect of a key parameter: the correlation between placebo response and medication-specific effects. In the present paper, we address this shortcoming by using individual patient data and study-level data to estimate that correlation and quantitatively characterize antipsychotic treatment effect heterogeneity in schizophrenia. Individual patient data (on 384 individuals who were administered antipsychotic treatment and 88 who received placebo) were obtained from the Yale University Open Data Access (YODA) database. Study-level data were obtained from a meta-analysis of 66 clinical trials including 17,202 patients. Both individual patient and study-level analyses yielded a negative correlation between placebo response and treatment effect for the total score on the Positive and Negative Syndrome Scale (PANSS) (ρ=-0.32, p=0.002 and ρ=-0.39, p<0.001, respectively). Using the most conservative of these estimates, a meta-analysis of treatment effect heterogeneity provided evidence of a marked variability in antipsychotic-specific effects between individuals with schizophrenia, with the top quartile of patients experiencing beneficial treatment effects of 17.7 points or more on the PANSS total score, while the bottom quartile presented a detrimental effect of treatment relative to placebo. This evidence of clinically meaningful treatment effect heterogeneity suggests that efforts to personalize antipsychotic treatment of schizophrenia have potential for success.