Clinical Subtypes Research Articles

EPH225 Characteristics of Patients with Transthyretin Amyloidosis and Methodological Approaches for Establishing Clinical Subtype in the Netherlands

EPH225 Characteristics of Patients with Transthyretin Amyloidosis and Methodological Approaches for Establishing Clinical Subtype in the Netherlands

Increase in Vascular Endothelial Growth Factor (VEGF) Expression and the Pathogenesis of iMCD-TAFRO.

TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (F/R), renal failure (R), and organomegaly (O)) is a heterogeneous clinical subtype of idiopathic multicentric Castleman disease (iMCD) associated with a significantly poorer prognosis than other subtypes of iMCD. TAFRO symptomatology can also be seen in pathological contexts outside of iMCD, but it is unclear if those cases should be considered representative of a different disease entity or simply a severe presentation of other infectious, malignant, and rheumatological diseases. While interleukin-6 (IL-6) is an established driver of iMCD-TAFRO pathogenesis in a subset of patients, the etiology is unknown. Recent case reports and literature reviews on TAFRO patients suggest that vascular endothelial growth factor (VEGF), and the interplay of VEGF and IL-6 in concert, rather than IL-6 as a single cytokine, may be drivers for iMCD-TAFRO pathophysiology, especially renal injury. In this review, we discuss the possible role of VEGF in the pathophysiology and clinical manifestations of iMCD-TAFRO. In particular, VEGF may be involved in iMCD-TAFRO pathology through its ability to activate RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways. Further elucidating a role for the VEGF-IL-6 axis and additional disease drivers may shed light on therapeutic options for the treatment of TAFRO patients who do not respond to, or otherwise relapse following, treatment with IL-6 targeting drugs. This review investigates the potential role of VEGF in the pathophysiology of iMCD-TAFRO and the potential for targeting related signaling pathways in the future.

TMEM147: A Promising Cancer Biomarker Associated with Immune Cell Infiltration and Prognosis in LIHC-Insights from a Comprehensive Pan-Cancer Genomic Analysis.

Previous studies have demonstrated the regulatory roles of Transmembrane protein 147 (TMEM147) in various diseases, including cancer. However, systematic pan-cancer analyses investigating the role of TMEM147 in diagnosis, prognosis, and immunological prediction are lacking. An analysis of data from The Cancer Genome Atlas (TCGA) revealed differential TMEM147 expression across various types of cancer as well as within immune and molecular cancer subtypes. Moreover, high TMEM147 expression was associated with poor disease-specific survival (DSS), overall survival (OS), and progression-free interval (PFI) across cancers, suggesting its potential as a prognostic biomarker. Our study further revealed a significant correlation between TMEM147 expression and T helper cell and Tcm cell infiltration in most cancer types. In the case of liver hepatocellular carcinoma (LIHC), the effect of TMEM147 on prognosis varied among different clinical subtypes. Additionally, functional enrichment analysis revealed an association between TMEM147 and metabolic pathways. Finally, experiments on the MIHA cell line and four LIHC cell lines confirmed the role of TMEM147 in promoting liver cancer cell proliferation, further confirming the clinical value of TMEM147 in liver cancer diagnosis. Our findings suggest that TMEM147 may serve as a diagnostic and prognostic biomarker across cancers while also playing a significant role in LIHC.

Correlation between common driver gene variations and clinicopathological typing in lung adenocarcinoma

Objective: To correlate the common driver gene variations in primary lung adenocarcinoma with their clinical characteristics and histopathological subtypes. Methods: There were 4 995 cases of primary lung adenocarcinoma diagnosed at Weifang People's Hospital of Shandong Province from January 2015 to December 2021 which were retrospectively analyzed. Among them 1 983 cases were evaluated for their histopathological subtype; 3 012 were analyzed for the correlation of their histopathological subtypes and corresponding driver gene variations, including invasive non-mucinous adenocarcinoma (INMA) and invasive mucinous adenocarcinoma (IMA), and morphologically, poorly-differentiated, moderately-differentiated and well-differentiated adenocarcinomas. Next-generation sequencing was used to detect variations in EGFR, KRAS, ALK, RET, ROS1, MET, HER2, or BRAF driver genes. Results: There were 2 384 males and 2 611 females. EGFR and ALK variations were more commonly found in female patients aged 60 years or older, with EGFR mutation rate in clinical stage Ⅰ (25.80%) significantly higher than in other stages (P<0.05). KRAS mutations were more commonly detected in male smokers aged 60 years or older, HER2 mutations were more commonly in patients younger than 60 years, and RET mutations were more commonly in non-smokers (all P<0.05). No correlation was found between ROS1, MET, and BRAF gene variations and their clinical characteristics (P>0.05). For the histopathological subtypes, among the 1 899 cases of acinar adenocarcinoma, EGFR mutation rate was the highest (67.30%) compared to the other genes. Exon 21 L858R and exon 19 del were the main mutation sites in IMA and INMA, with a higher mutation rate at exon 20 T790M (11.63%) in micropapillary adenocarcinoma. In IMA, KRAS had the highest overall mutation rate (43.80%), with statistically significant difference in mutation rates of exon 2 G12D and exon 2 G12V in acinar adenocarcinoma, solid, and IMA (P<0.05). KRAS mutation at various sites were higher in poorly differentiated groups compared to moderately- and well-differentiated groups (P<0.05). HER2 mutations were more commonly observed in acinar adenocarcinoma, papillary, and micropapillary adenocarcinoma of INMA. BRAF mutation was higher in micropapillary adenocarcinoma compared with other types (P<0.05). Conclusions: Variations in EGFR, ALK, KRAS, HER2, and RET in primary lung adenocarcinoma are associated with patients' age, smoking history, and clinical stage, and driver gene mutations vary among different histopathological subtypes. EGFR mutations are predominant in INMA, while KRAS mutations are predominant in IMA.

Programmed death-ligand 1 expression in carcinoma of unknown primary

We examined the expression of programmed death-ligand 1 (PD-L1) in carcinoma of unknown primary (CUP) and its potential implications. Tissue microarrays were constructed for 72 CUP cases (histologic subtypes: 22 adenocarcinoma, 15 poorly differentiated carcinoma, 19 squamous cell carcinoma, and 14 undifferentiated carcinoma; clinical subtype: favorable type 17 [23.6%], unfavorable type 55 [76.4%]), with immunohistochemical staining performed for PD-L1 (22C3, SP142, SP263, and 28 − 8), CK7, and CK20 to determine the association between staining results and clinicopathological parameters. In CUP, the PD-L1 positivity rate was 5.6–48.6% (tumor cells [TC] or tumor proportion score [TPS]: 5.6–36.1%, immune cell score [IC]: 8.3–48.6%, combined positive score [CPS]: 16.7%) using different cutoff values for 22C3 (TPS ≥ 1%, CPS ≥ 10), SP142 (TC ≥ 50%, IC ≥ 10%), SP263, and 28 − 8 (TC and IC ≥ 1%). PD-L1 SP142 TC and PD-L1 SP263 IC showed the lowest (5.6%) and highest (48.6%) positivity rates, respectively. The PD-L1 positivity rate did not significantly differ based on the histologic subtype, clinical subtype, or CK7/CK20 across clones. Considering TC κ ≥ 1%, TC κ ≥ 50%, IC κ ≥ 1%, and IC κ ≥ 10%, the PD-L1 positivity rate was TC = 4.2–36.1% and IC = 9.7–48.6%; the overall agreement between antibodies ranged from 69.4 to 93.1%, showing fair or better agreement (κ ≥ 0.21). In CUP, PD-L1 positivity varied depending on antibodies and scoring systems, with no difference observed according to histologic or clinical subtypes.

Dose/Exposure Relationship of Exercise and Distant Recurrence in Primary Breast Cancer.

Postdiagnosis exercise is associated with lower breast cancer (BC) mortality but its link with risk of recurrence is less clear. We investigated the impact and dose-response relationship of exercise and recurrence in patients with primary BC. Multicenter prospective cohort analysis among 10,359 patients with primary BC from 26 centers in France between 2012 and 2018 enrolled in the CANcer TOxicities study, with follow-up through October 2021. Exercise exposure was assessed using the Global Physical Activity Questionnaire-16, quantified in standardized metabolic equivalent of task-hours per week (MET-h/wk). We examined the dose/exposure response of pretreatment exercise on distant recurrence-free interval (DRFI) for all patients and stratified by clinical subtype and menopausal status using inverse probability treatment weighted multivariable Cox models to estimate hazard ratios (HRs). For the overall cohort, the relationship between exercise and DRFI was nonlinear: increasing exercise ≥ 5 MET-h/wk was associated with an inverse linear reduction in DRFI events up to approximately 25 MET-h/wk; increasing exercise over this threshold did not provide any additional DRFI benefit. Compared with <5 MET-h/wk, the adjusted HR for DRFI was 0.82 (95% CI, 0.61 to 1.00) for ≥ 5 MET-h/wk. Stratification by subtype revealed the hormone receptor-/human epidermal growth factor receptor 2- (HR-/HER2-; HR, 0.59 [95% CI, 0.38 to 0.92]) and HR-/HER2+ (HR, 0.37 [95% CI, 0.14 to 0.96]) subtypes were preferentially responsive to exercise. The benefit of exercise was observed especially in the premenopausal population. Postdiagnosis/pretreatment exercise is associated with lower risk of DRFI events in a nonlinear fashion in primary BC; exercise has different impact on DRFI as a function of subtype and menopausal status.

Clinical presentations and diagnostic application of proposed biomarkers in psychiatric-onset prodromal dementia with Lewy bodies.

Research criteria for the diagnosis of prodromal dementia with Lewy bodies (DLB) include three clinical subtypes: mild cognitive impairment with Lewy bodies (MCI-LB), delirium-onset prodromal DLB, and psychiatric-onset prodromal DLB. Late-onset psychiatric manifestations are at a higher risk of developing dementia, but its relation to prodromal DLB remains unclear. In addition to the risk of severe antipsychotic hypersensitivity reactions, accurate discrimination from non-DLB cases is important due to the potential differences in management and prognosis. This article aims to review a rapidly evolving psychiatric topic and outline clinical pictures of psychiatric-onset prodromal DLB, including the proposed biomarker findings of MCI-LB: polysomnography-confirmed rapid eye movement sleep behaviour disorder, cardiac [123I]metaiodobenzylguanidine scintigraphy, and striatal dopamine transporter imaging. We first reviewed clinical pictures of patients with autopsy-confirmed DLB. Regarding clinical reports, we focused on the patients who predominantly presented with psychiatric manifestations and subsequently developed DLB. Thereafter, we reviewed clinical studies regarding the diagnostic applications of the proposed biomarkers to patients with late-onset psychiatric disorders. Clinical presentations were mainly late-onset depression and psychosis; however, other clinical manifestations were also reported. Psychotropic medications before a DLB diagnosis may cause extrapyramidal signs, and potentially influences the proposed biomarker findings. These risks complicate clinical manifestation interpretation during the management of psychiatric symptoms. Longitudinal follow-up studies with standardised evaluations until conversion to DLB are needed to investigate the temporal trajectories of core features and proposed biomarker findings. In patients with late-onset psychiatric disorders, identification of patients with psychiatric-onset prodromal DLB provides the opportunity to better understanding the distinct prognostic subgroup that is at great risk of incident dementia. Advances in the establishment of direct biomarkers for the detection of pathological α-synuclein may encourage reorganising the phenotypic variability of prodromal DLB.

Integrating multi-omics approaches in deciphering atopic dermatitis pathogenesis and future therapeutic directions.

Atopic dermatitis (AD), a complex and heterogeneous chronic inflammatory skin disorder, manifests in a spectrum of clinical subtypes. The application of genomics has elucidated the role of genetic variations in predisposing individuals to AD. Transcriptomics, analyzing gene expression alterations, sheds light on the molecular underpinnings of AD. Proteomics explores the involvement of proteins in AD pathophysiology, while epigenomics examines the impact of environmental factors on gene expression. Lipidomics, which investigates lipid profiles, enhances our understanding of skin barrier functionalities and their perturbations in AD. This review synthesizes insights from these omics approaches, highlighting their collective importance in unraveling the intricate pathogenesis of AD. The review culminates by projecting future trajectories in AD research, particularly the promise of multi-omics in forging personalized medicine and novel therapeutic interventions. Such an integrated multi-omics strategy is poised to transform AD comprehension and management, steering towards more precise and efficacious treatment modalities.

Identifying New Subtypes of Multiple System Atrophy Using Cluster Analysis.

Multiple system atrophy (MSA) is a disease with diverse symptoms and the commonly used classifications, MSA-P and MSA-C, do not cover all the different symptoms seen in MSA patients. Additionally, these classifications do not provide information about how the disease progresses over time or the expected outcome for patients. To explore clinical subtypes of MSA with a natural disease course through a data-driven approach to assist in the diagnosis and treatment of MSA. We followed 122 cases of MSA collected from 3 hospitals for 3 years. Demographic characteristics, age of onset, clinical signs, scale assessment scores, and auxiliary examination were collected. Age at onset; time from onset to assisted ambulation; and UMSARS I, II, and IV, COMPASS-31, ICARS, and UPDRS III scores were selected as clustering elements. K-means, partitioning around medoids, and self-organizing maps were used to analyze the clusters. The results of all three clustering methods supported the classification of three MSA subtypes: The aggressive progression subtype (MSA-AP), characterized by mid-to-late onset, rapid progression and severe clinical symptoms; the typical subtype (MSA-T), characterized by mid-to-late onset, moderate progression and moderate severity of clinical symptoms; and the early-onset slow progression subtype (MSA-ESP), characterized by early-to-mid onset, slow progression and mild clinical symptoms. We divided MSA into three subtypes and summarized the characteristics of each subtype. According to the clustering results, MSA patients were divided into three completely different types according to the severity of symptoms, the speed of disease progression, and the age of onset.

Cognitive Impairments in Drug-Naive Patients With First-Episode Negative Symptom–Dominant Psychosis

Available antipsychotic medications are predominantly used to treat positive symptoms, such as hallucinations and delusions, in patients with first-episode psychosis (FEP). However, treating negative and cognitive symptoms, which are closely related to functional outcomes, remains a challenge. To explore the cognitive characteristics of patients with negative symptom-dominant (NSD) psychosis. This large-scale cross-sectional study of patients with FEP was led by the Shanghai Mental Health Center in China from 2016 to 2021, with participants recruited from 10 psychiatric tertiary hospitals. A comprehensive cognitive assessment was performed among 788 patients with FEP who were drug-naive. Symptom profiles were determined using the Positive and Negative Symptoms Scale (PANSS), and NSD was defined as a PANSS score for negative symptoms higher than that for positive and general symptoms. Positive symptom-dominant (PSD) and general symptom-dominant (GSD) psychosis were defined similarly. Data were analyzed in 2023. Psychotic symptoms were categorized into 3 groups: NSD, PSD, and GSD. Neurocognitive performance, assessed using the Chinese version of the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery. This study included 788 individuals with FEP (median age, 22 [IQR, 17-28] years; 399 men [50.6%]). Patients with NSD exhibited more-pronounced cognitive impairment than did those with PSD or GSD. Specifically, cognitive differences between the NSD and PSD group, as well as between the NSD and GSD group, were most notable in the processing speed and attention domains (Trail Making [F = 4.410; P = .01], Symbol Coding [F = 4.957; P = .007], Verbal Learning [F = 3.198; P = .04], and Continuous Performance [F = 3.057; P = .05]). Patients with PSD and GSD showed no significant cognitive differences. Cognitive impairment was positively associated with the severity of negative symptoms. Most of the cognitive function tests used were able to differentiate patients with NSD from those with PSD and GSD, with significant differences observed across a range of tests, from Brief Visuospatial Memory Test-Revised (χ2 = 3.968; P = .05) to Brief Assessment of Cognition in Schizophrenia symbol coding (χ2 = 9.765; P = .002). The findings of this cross-sectional study of patients with FEP suggest the presence of a clinical subtype characterized by a predominance of negative symptoms and cognitive impairment.

Plasma mutational burden in PIK3CA and TP53 independently predicts early progression in patients with HR+/HER2- metastatic breast cancer (MBC) enrolled in the GEICAM/2014-12 FLIPPER trial.

1029 Background: There is an unmet need for molecular diagnostics to predict therapy outcomes using blood-based biomarker monitoring to guide treatments in HR+/HER2- MBC patients. Here, we report initial results of serial ctDNA analyses in a trial of Fulvestrant (F) + CDK4/6 inhibitor (CDK4/6i) Palbociclib (Pa) vs. F + Placebo (Pl). Endocrine therapy + CDK4/6i are currently the cornerstones of treatment for HR+/HER2- MBC. However, between 10–30% of patients suffer primary resistance. Thus, early identification of HR+/HER2- MBC patients that progress during CDK4/6i treatment is required. Methods: The GEICAM FLIPPER trial (NCT02690480) is a multicenter, double-blind, randomized, phase II study comparing F+Pa vs F+Pl in postmenopausal women with HR+/HER2- MBC. Sequential plasma was collected from 187 patients at baseline, 12, 24, 36, and 48 weeks on treatment and at progression. In total, 903 samples were analyzed using the Plasma-SeqSensei BC IVD kit (Sysmex Inostics) that identifies and quantifies ctDNA mutations in six BC-related genes. The mutant allele frequency (MAF) of PIK3CA and TP53 variants was assessed in baseline samples (median value as cutoff). These variants, identified as the most prevalent, were used as surrogate markers for mutational burden. The Kaplan-Meier method was used to estimate median (m) PFS and overall survival (OS). Hazard ratio (HR) and odds ratio (OR) were calculated with 95% confidence interval (CI) using Cox proportional hazards regression model and logistic regression respectively, unadjusted or adjusted by age, site of disease, disease presentation at study entry and clinical subtype. Results: Previously we showed that F+Pa improved 1-year PFS (83.5% vs. 71.9%, p=0.064) and mPFS (31.8 vs. 22.0 months, p=0.001) vs F+Pl. Here, ctDNA analyses revealed that having ≥1 mutation in PIK3CA + TP53 was prognostic of early (≤12 months) progression (OR 2.37; 95% CI 1.1-5.12, p=0.0274) independent of treatment arm. Furthermore, having ≥2 mutations was associated with treatment resistance (not achieving objective response; OR 3.55; 95% CI 1.28-9.87, p=0.0151). Additionally, worse mPFS and mOS were seen in patients with ≥2 mutations in PIK3CA + TP53 (PFS: HR 3.6; 95% CI 2.25-5.76, p&lt;0.0001; OS: HR 2.92; 95% CI 1.66-5.12, p=0.002) and in patients with high MAF (PFS: HR 2.43; 95% CI 1.6-3.68, p&lt;0.0001; OS: HR 2.83; 95% CI 1.75-4.58, p&lt;0.0001). Finally, having ≥2 mutations in PIK3CA + TP53 was predictive of early progression (OR 22.32; 95% CI 4.12-120.9, p&lt;0.0001) and worse mOS (61.8 vs. 34.79 months) in the F+Pl arm (HR 5.91; 95% CI 2.65-13.16, p&lt;0.0001) but not in the F+Pa arm. Conclusions: Baseline plasma mutational burden in both PIK3CA and TP53 genes was significantly associated with Fulvestrant +/- Palbociclib treatment outcome in HR+/HER2- MBC and appeared to be predictive of Palbociclib benefit. Clinical trial information: NCT02690480 .

Effectiveness of limited plasma exchange in Guillain-Barré syndrome

Objective: The aim of this study is to compare the efficacy of limited plasma exchange against supportive and standard treatments in treatment of Guillain-Barré syndrome (GBS). Method: A total of 90 GBS patients admitted to Yangon General Hospital, Yangon, Myanmar were recruited over 1.5-year-period from January 2017 to June 2018 and they were divided into 3 groups according to the treatment they received (convenience sampling method): supportive (n=36), limited plasma exchange (LPE) (n=35) and standard (therapeutic plasma exchange - TPE or IVIg) (n=19)). Their clinical features, electrophysiological subtypes and severity were compared at baseline, and outcome (change in GBS disability score (GDS) at 30 days after entry) was assessed and compared. Results: Baseline characteristics such as gender, GBS subtypes and respiratory involvement were comparable, but standard treatment group had older patients, and LPE group had shorter latency to nadir and more cases with antecedent diarrhea, which are poor outcome predictors. At 30 days from entry, mean GDS improvement was 0.9 + 0.6 in supportive, 1.4 + 0.6 in LPE and 1.2 + 0.8 in standard treatment groups respectively. The difference between LPE and supportive treatment was statistically significant (p 0.002) but there was no difference between LPE and standard treatment (p = 0.512). Regarding untoward effects, apart from one transient hypotension and 2 anemic cases, no other serious adverse effects were noted from LPE therapy. Conclusion: LPE may be superior to supportive treatment and may not be inferior to standard treatment. Therefore, LPE may be an alternative effective treatment for GBS patients who are not accessible to standard treatments especially in low income countries with limited resources.

Clinicopathologic features of patients with breast cancer in a single tertiary hospital in the Philippines.

e23313 Background: Breast cancer incidence in the Philippines is among the highest in Asia - the WHO reported it to be as high as 33,079 in 2022. Data provided by the Philippine Cancer Society and Department of Health Rizal Cancer Registry in 2009 included 1,615 breast cancer patients and noted a significant increase in breast cancer incidence from the year 1980 to 2002 in 7 cities in Metro Manila. This retrospective study aims to describe and analyze clinicopathologic and treatment data of Filipino breast cancer patients in a tertiary hospital. This study represents the largest pooled data in the Philippines on breast cancer demographics. Methods: Patients diagnosed with invasive breast cancer in St. Luke’s Medical Center (SLMC) from 2009 to 2020 were included. Patients diagnosed with other breast histopathologic results [i.e. ductal and lobular carcinoma in situ without invasive component] and double primaries were excluded. The study was approved by the Ethics Review Committee (Reference No.: SL-19157). Results: A total of 5,462 breast cancer patients were included. Majority of the patients were late perimenopausal (50-59 yo, 30.06%), menopausal (60-69 yo, 23.03%), and premenopausal (below 44 yo, 19.28%,) at the time of diagnosis. Patients were diagnosed with stage II (N = 1,816, 47.24%), followed by stage I (N = 943, 24%), and stage III (N = 662, 17%). Sixty four percent (N = 1,498) were node negative while 46% (N = 1,300) were node positive. Among patients with de novo metastasis, 14.6% metastasized to the bone while visceral sites include chest wall (17.4%), lung (16.6%), liver (11.5%) and brain (7.45%). Luminal her2- (48.9%) was the most common clinical subtype followed by non-luminal her2+ (15.6%) and triple negative (6.7%). Definitive surgery was the mainstay of treatment – 94% (N = 4116) underwent modified radical mastectomy (MRM) while 5% (N = 223) underwent breast conserving surgery (BCS). Eight hundred patients (19%) received neoadjuvant treatment (hormonal and/or systemic chemotherapy) while 2,246 patients (54%) received adjuvant treatment. Total number of breast cancer patients who underwent adjuvant radiation was 1,399 (25.6%). Conclusions: Compared to middle-high income countries, data suggests that MRM is the preferred surgical technique over BCS. Majority of patients in the study are luminal her2-. However, only 54% received adjuvant treatment. Another observation is the low rate of neoadjuvant treatment by the study population. Further research on the risk factors or reasons for not receiving treatment as well as the outcomes of these patient cohorts is needed to shed light on these cancer care gaps.

Unbiased clustering and molecular characterisation of novel metabolic phenotypes in a heart failure cohort

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DIASyM cluster Heart Failure is a heterogeneous clinical syndrome characterized by the inability to pump enough blood and thus provide enough oxygen to the human body. The current classification of heart failure is based on the left ventricular ejection faction (LVEF). Although the classification clearly defines heart failure subtypes and stages, and clinical guidelines are available for their management, it is preferable to prevent the disorder or take control over it from its onset. Evidence suggests strong molecular connections between human metabolism and heart failure. Exploiting the unique and diverse molecular characteristics that drive heart failure could be an effective strategy for patient stratification, to identify new therapeutic targets and to personalize treatments. The current research attempts to identify clinically relevant metabolic subgroups of individuals with the help of a similarity network-based approach, based on targeted proteomics data of a heart failure cohort. With Olink targeted proteomics technology, six protein abundance panels (547 distinct proteins) from 3063 subjects (1103 females) were obtained. Using nonlinear combination methods, the created networks were integrated into a single similarity network and then used for clustering with unbiased network-based approaches. The results have distinguished the subgroups with worse outcome prediction, supported by significantly different clinical profiles. Surprisingly, the significant clinical parameters have shown the dominance of not only classical metabolic signatures (diabetes) but also parameters related to kidney and liver function. The differential protein abundance profiles were then compared among clusters to derive novel insights into clinical subtypes, and have highlighted a significant contribution of inflammatory proteins to the unbiased subtyping rationale. The study attempted to improve previous patient stratification efforts, by having a large sample size with a broader variety of molecular variables. These results will pave the way to precision medicine, and will allow indirectly to integrate and/or adjust the analysis by adding clinically relevant social parameters such as lifestyle, parents’ anamnesis, demographics that are often left out due to their lower contribution at the pre-processing steps in comparison to more objective laboratory parameters. Previous studies have already clustered the heart failure population, based on various clinical and biochemical parameters. However, the clustering was guided by well-established metabolic parameters and thus, the results can be highly biased. The current project allows an unbiased, data-driven approach that holds more potential to identify novel and clinically relevant metabolic subgroups and to define new molecular targets.

Anomalies of Midbrain/Hindbrain Development and Related Disabilities: Pontocerebellar Hypoplasia, Congenital Disorders of Glycosylation, and Cerebellar Hemisphere Hypoplasia

AbstractRecent progress in developmental biology, molecular genetics, and neuroimaging has enabled a more profound comprehension of developmental disorders affecting the embryonic midbrain and hindbrain, which manifest clinically. The purpose of this review is to describe anomalies of the midbrain/hindbrain such as pontocerebellar hypoplasia (PCH), congenital disorders of glycosylation (CDG), cerebellar hemisphere hypoplasia. PCH is a group of disorders that is both clinically and genetically diverse. These disorders are identified by the hypoplasia and degeneration of the cerebellum and ventral pons. A total of 18 distinct clinical subtypes of PCH, each linked to pathogenic variants in 19 different genes, have been documented, like mutations in TSEN54 (coding a subunit of tRNA splicing endonucleases complex) and TBC1D23 which display moderate-to-severe intellectual disability (ID) and microcephaly. CDG represent a set of inherited conditions marked by impaired glycosylation of proteins and lipids. The most prevalent subtype among CDG is PMM2-CDG, inherited in a recessive manner, causing reduced activity of phosphomannomutase. Its phenotype varies from mild to severe, involving the central nervous system and affecting many other organs as well. Patients who are severely affected also exhibit visceral symptoms alongside severe ID and other neurological manifestations. Cerebellar hypoplasia (CH) is characterized by a cerebellum of diminished volume while maintaining its shape. CH exhibits a diverse range of neuroradiologic features, etiologies, clinical characteristics, and neurodevelopmental involvement. Cerebello–oculo–facio–genital syndrome is linked to a recessive MAB21L1 mutation. Jubert's syndrome, associated with a rare autosomal recessive mutation, is identified on magnetic resonance imaging by cerebellar worm hypoplasia and midbrain malformations. The rhombencephalosynapsis, characterized by vermian agenesis or hypogenesis with the fusion of the cerebellar hemispheres, emerges during embryogenesis. It can manifest alone or in conjunction with other and/or extracerebral abnormalities.

Associations of clinical subtypes and bile acid levels of intrahepatic cholestasis of pregnancy with pregnancy outcomes

Intrahepatic cholestasis of pregnancy (ICP) can lead to many adverse pregnancy outcomes, and the influencing factors remain unclear at present. This study retrospectively analyzed clinical data from 1815 pregnant women with ICP and evaluated the relationship between ICP subtypes, gestational age at onset, and pregnancy outcomes. The results of this study show that during pregnancy, the levels of biochemical indicators (TBA, DBIL and ALT) in the serum of pregnant women initially diagnosed with subtypes of ICP were noted to constantly change, and the subtype of ICP and its severity also changed. The incidence of adverse pregnancy outcomes [meconium-stained amniotic fluid (MSAF), NICU transfer, Apgar score ≤ 7 at 1 min, and preterm birth] in patients with ICP1 (icteric type) was significantly higher than for patients with ICP2, ICP3 or ICP4. The preterm birth rate of early-onset ICP was higher than that of late-onset ICP in ICP1 and ICP3 subtypes. In conclusion, the outcome of pregnancy in women with ICP is closely related to the serum TBA level and ICP subtype, which should be recognized in the clinic.

Characterization of acute-on-chronic liver diseases: A multicenter prospective cohort study.

Acute-on-chronic liver disease (AoCLD) accounts for the majority of patients hospitalized in the Department of Hepatology or Infectious Diseases. To explore the characterization of AoCLD to provide theoretical guidance for the accurate diagnosis and prognosis of AoCLD. Patients with AoCLD from the Chinese Acute-on-Chronic Liver Failure (ACLF) study cohort were included in this study. The clinical characteristics and outcomes, and the 90-d survival rate associated with each clinical type of AoCLD were analyzed, using the Kaplan-Meier method and the log-rank test. A total of 3375 patients with AoCLD were enrolled, including 1679 (49.7%) patients with liver cirrhosis acute decompensation (LC-AD), 850 (25.2%) patients with ACLF, 577 (17.1%) patients with chronic hepatitis acute exacerbation (CHAE), and 269 (8.0%) patients with liver cirrhosis active phase (LC-A). The most common cause of chronic liver disease (CLD) was HBV infection (71.4%). The most common precipitants of AoCLD was bacterial infection (22.8%). The 90-d mortality rates of each clinical subtype of AoCLD were 43.4% (232/535) for type-C ACLF, 36.0% (36/100) for type-B ACLF, 27.0% (58/215) for type-A ACLF, 9.0% (151/1679) for LC-AD, 3.0% (8/269) for LC-A, and 1.2% (7/577) for CHAE. HBV infection is the main cause of CLD, and bacterial infection is the main precipitant of AoCLD. The most common clinical type of AoCLD is LC-AD. Early diagnosis and timely intervention are needed to reduce the mortality of patients with LC-AD or ACLF.

GR.3 Distinct longitudinal brain atrophy trajectories in parkinson’s disease clinical subtypes: insight towards precision medicine

Background: Parkinson’s disease (PD) varies widely across individuals in terms of clinical manifestations and course of progression. We aimed to compare patterns of brain atrophy between PD clinical subtypes using longitudinally acquired brain MRIs. Methods: We used T1-weighted MRIs from Parkinson’s Progression Markers Initiative (PPMI) on 134 PD individuals and 60 healthy controls with at least two MRIs. Patients were classified into three clinical subtypes at de novo stage using validated subtyping criteria based on major motor and non-motor classifiers (early cognitive impairment, RBD, dysautonomia): mild-motor predominant (n=74), intermediate (n=44), and diffuse-malignant (n=16). Deformation-based morphometry (DBM) maps were calculated and mixed effect models were used to examine the interaction between PD subtypes and rate of atrophy across brain regions over time, controlling for sex and age at baseline. Results: Individuals with ‘diffuse malignant’ PD showed a significantly higher rate of atrophy across multiple brain regions, including lateral nucleus of the forebrain, precuneus, paracentral lobule, inferior temporal gyrus, fusiform gyrus, and lateral hemisphere of the cerebellum (FDR corrected p&lt;0.05). Conclusions: We demonstrated an accelerated atrophy pattern within several brain regions in ‘diffuse malignant’ PD subtype. These findings suggest the presence of a more diffuse multidomain neurodegenerative process in a subgroup of people with PD, favoring the existence of diverse underlying pathophysiologies.

Treatment outcomes of pediatrics acute myeloid leukemia (AML) and associated factors in the country’s tertiary referral hospital, Ethiopia

BackgroundPediatric Acute Myeloid Leukemia (AML) is a major cause of morbidity and mortality in children with cancer in Africa and other developing continents. Systemic chemotherapy and effective supportive care have significantly contributed to increased survival rates of pediatric AML in developed countries reaching approximately 70%. There is a paucity of contextual data regarding overall and event-free survival outcomes in children with acute myeloid leukemia in developing countries and most centers in Africa provide palliative care. The objective of this study was to assess the overall survival, event-free survival, and associated factors in pediatric AML patients treated in Ethiopia.MethodsThis retrospective study was conducted on Pediatric AML patients treated at Tikur Anbessa Hospital between January 1, 2015, and May 30, 2022. The socio-demographic profile of patients, the clinical characteristics, the biochemical and morphological subtypes of AML were analyzed using SPSS version 25. The Kaplan–Meier survival curve was used to estimate the probabilities of overall and event-free survival. Statistical significance was set at p < 0.05.ResultsA total of 92 children with AML were included in this study. The median age at diagnosis was 7 years (interquartile range: 5–10 years) with a slight male predominance. The median duration of symptoms was one month. Neutropenic fever (56, 86.2%) was the most common complication during treatment. About 29.3% of the patients succumbed to early death. The corresponding 1-year and 3-year OS probabilities were 28.2% and 23% respectively. The median event-free survival time for all pediatric AML patients was one-month (95% CI: 0.77–1.23). The determinants of poorer survival outcomes were FAB subtype, type of protocol used, and signs of CNS involvement (p < 0.05).ConclusionThe survival rates of children from AML were low in the study setting. More than 25% of AML patients succumbed to early death, and febrile neutropenia was the most common complication. Effective supportive and therapeutic measures should be taken to manage febrile neutropenia and to prevent early death in AML patients.

First-time catheter ablation outcomes for atrial fibrillation are dependent on low-voltage areas rather than paroxysmal vs. persistent classifications: a REAL-AF study

Abstract Background Left atrial low-voltage areas (LA LVA) measured at time of catheter ablation for atrial fibrillation (AF) have been increasingly recognized as an indicator of atrial fibrosis [1]. However, little is known whether first-time catheter ablation outcomes differ between paroxysmal AF (PAF) and persistent AF (PerAF) in patients with higher LA LVA, which may indicate a more advanced substrate independent of clinical subtype. Purpose To evaluate whether outcomes of first-time catheter ablation for AF are dependent on LA LVA rather than PAF vs. PerAF types in a multicenter registry of patients. Methods The Real-world Experience of Catheter Ablation for the Treatment of Symptomatic PAF and PerAF Using Novel Contact Force Technologies registry (REAL-AF) is a prospective, observational multicenter registry of patients undergoing catheter ablation. We evaluated 4181 patients undergoing first-time catheter ablation for both PAF and PerAF to determine AF recurrence within 12 months. Contact maps were created using a 5-spline high-density catheter. LA LVA was calculated using these contact maps based on a bipolar voltage of &amp;lt;0.50 mV. LA LVA was categorized into low (&amp;lt;5%) vs. high (≥5%) based on preliminary data. Risk of recurrence was analyzed using Cox proportional hazard models. Results Patients with LA LVA ≥5% who underwent first-time catheter ablation for AF (both PAF and PerAF) experienced a higher risk of AF recurrence within 12 months (Hazard ratio (HR): 1.95, p&amp;lt;0.001), see Figure 1. Overall, 82.0% of patients were free of AF in the LA LVA &amp;lt;5% group compared to 69.1% in the LA LVA ≥5% group. This association remained significant in a subpopulation of patients presenting in normal sinus rhythm (N = 2463) at time of ablation (HR: 1.90, p&amp;lt;0.001). 12-month ablation outcomes between PAF and PerAF in patients with LA LVA ≥5% (N = 1590) were not statistically significant (71.0% vs 67.3% respectively, HR: 1.15, p=0.30), see Figure 2. Finally, in the LA LVA &amp;lt;5% group (N = 2591), patients with PerAF had a 1.42 times higher risk for AF recurrence within 12 months after catheter ablation (p=0.04). Conclusion This is the largest real-world registry to date demonstrating that LA LVA ≥5% is associated with a higher risk of AF recurrence within 12 months in patients undergoing first-time catheter ablation for AF. Among patients with LA LVA ≥5%, AF recurrence was not associated with AF type. These findings motivate further studies into using LA LVA as a prognostic tool for patients undergoing first-time catheter ablation for AF and using non-invasive methods to assess this in order to stratify patients further.