Pathological Subgroups Research Articles

Somatic Molecular Heterogeneity in Bilateral Macronodular Adrenocortical Disease (BMAD) Differs Among the Pathological Subgroups.

Bilateral macronodular adrenocortical disease (BMAD) is an uncommon cause of Cushing's syndrome leading to bilateral macronodules. Isolated BMAD has been classified into three molecular groups: patients with ARMC5 alteration, KDM1A alteration, and patients without known genetic cause. The aim of this study was to identify by NGS, in a cohort of 26 patients with BMAD, the somatic alterations acquired in different nodules after macrodissection from patients with germline ARMC5 or KDM1A alterations and to analyze potential somatic alterations in a panel of five other genes involved in adrenal pathology (GNAS, PDE8B, PDE11A, PRKAR1A, and PRKACA). Twenty-three patients (7 ARMC5, 3 KDM1A, and 13 BMAD with unknown genetic cause) were analyzable. Somatic ARMC5 or KDM1A events were exclusively observed in patients with germline ARMC5 and KDM1A alterations, respectively. Six out of 7 ARMC5 patients have a high heterogeneity in identified somatic events, whereas one ARMC5 and all KDM1A patients show a loss of heterozygosity (LOH) in all nodules. Except for passenger alterations of GNAS, no genetic alteration susceptible to causing the disease was detected in the BMAD with unknown genetic cause. Our study reinforces our knowledge of the somatic genetic heterogeneity of ARMC5 and the somatic homogeneity of KDM1A. It reveals the absence of purely somatic events in these two genes and provides a new tool for detecting KDM1A alterations by FISH 1p36/1q25.

Branched-chain amino acids and risk of lung cancer: insights from mendelian randomization and NHANES III.

Recent studies have observed the relationships of circulatory and dietary intake of branched-chain amino acids (BCAAs) with long-term risk of certain cancers. However, the exact causality of BCAA with lung cancer (LUCA) and its pathological subtypes remains obscure. The aim of this study is to investigate the association between BCAA metabolism and risk of LUCA. Here we conducted Mendelian randomization (MR) and observational epidemiological analyses to investigate the association between BCAA and risk of LUCA. With single nucleotide polymorphism (SNP)-phenotype association data extracted from genome-wide association studies (GWAS), we performed univariate and multivariate MR analyses to infer the causal effect of circulatory BCAA concentrations on LUCA. We further investigated the effects of several potential mediators and quantified the mediation effects. Population-level analyses were performed in the National Health and Nutrition Examination Survey (NHANES) III. Our results demonstrated that genetically predicted circulatory valine concentrations causally increased the risk of overall LUCA [odds ratio (OR) =1.324, 95% confidence interval (CI): 1.058-1.658, P=0.01]. For pathological subgroups, elevated levels of leucine, isoleucine, valine, and total BCAA were founded to be significantly associated with a higher risk of squamous cell lung cancer (LUSC); however, they did not significantly affect lung adenocarcinoma (LUAD). Moreover, body mass index (BMI) mediated approximately 3.91% (95% CI: 1.22-7.18%) of the total effect of leucine on LUSC. In the NHANES III population, dietary total BCAA intake was significantly associated with BMI ≥30 kg/m2, while no non-linear relationships were observed. This study provides genetic evidence for the histology-specific causality of BCAA on LUCA and implies the mediation role of BMI in this relationship. Further studies are needed to confirm these findings and elucidate the underlying mechanisms.

Two cases of atrial myxoma with calcification and ossification as the main features

BackgroundCardiac myxomas are the most common type of primary cardiac tumors in adults, but they can have variable features that make them difficult to diagnose. We report two cases of atrial myxoma with calcification or ossification, which are rare pathological subgroups of myxoma.Case presentationA 47-year-old woman and a 35-year-old man presented to our hospital with different symptoms. Both patients had a history of chronic diseases. Transthoracic and transesophageal echocardiography revealed a mass in the left or right atrium, respectively, with strong echogenicity and echogenic shadows. The masses were suspected to be malignant tumors with calcification or ossification. Contrast transthoracic echocardiography(cTEE) showed low blood supply within the lesions. The patients underwent surgical resection of the atrial mass, and the pathology confirmed myxoma with partial ossification or massive calcification.ConclusionWe report two rare cases of atrial myxoma with calcification or ossification and analyze their ultrasonographic features. Transthoracic echocardiography and cTEE can provide valuable information for the diagnosis and management of such mass. However, distinguishing calcification and ossification in myxoma from calcification in malignant tumors is challenging. More studies are needed to understand the pathogenesis and imaging characteristics of these myxoma variants.

Evaluation of digit ratio (2D:4D) in breast cancer patients

Breast cancer is a hormone-dependent cancer. Hormonal exposure begins in the intrauterine period and continues in later years of life. 2D:4D ratio is accepted as an indicator of this exposure. The aim of this study was to investigate whether there is a difference in 2D:4D ratio between pathological subgroups of breast cancer and healthy control group. In this study, 204 participants, 154 breast cancer patients and 50 healthy control volunteers with similar age distribution, were included. Both hands of all participants were scanned using a digital scanner. The second and fourth finger lengths were measured using a digital measuring ruler with an accuracy of 0.05 mm. The 2D:4D ratio was calculated as the length of the second finger divided by the length of the fourth finger. A total of 204 patients (55 triple negative, 52 luminal B, 33 luminal A, 14 HER2-overexpessing and 50 healthy control volunteers) were subjected to finger scanning. There was no statistically significant difference in mean age between the groups. The right hand 2D:4D ratio was significantly lower in the Luminal A group compared to the other groups (p < 0.048). Although prenatal hormonal exposure is accepted as a risk factor for breast cancer, no study has evaluated patients in pathological subgroups. The 2D:4D ratio may be associated with breast cancer especially in the luminal A group in which hormone receptors are strongly positive and which has a better prognosis compared to the other groups.

A deep learning-based algorithm for automatic detection of perilunate dislocation in frontal wrist radiographs

This study proposes a Deep Learning algorithm to automatically detect perilunate dislocation in anteroposterior wrist radiographs. A total of 374 annotated radiographs, 345 normal and 29 pathological, of skeletally mature adolescents and adults aged ≥16 years were used to train, validate and test two YOLOv8 deep neural models. The training set included 245 normal and 15 pathological radiographs; the pathological training set was supplemented by 240 radiographs obtained by data augmentation. The test set comprised 30 normal and 10 pathological radiographs. The first model was used for detecting the carpal region, and the second for segmenting a region between Gilula’s 2nd and 3rd arcs. The output of the segmentation model, trained multiple times with varying random initial parameter values and augmentations, was then assigned a probability of being normal or pathological through ensemble averaging. In the study dataset, the algorithm achieved an overall F1-score of 0.880: 0.928 in the normal subgroup, with 1.0 precision, and 0.833 in the pathological subgroup, with 1.0 recall (or sensitivity), demonstrating that diagnosis of perilunate dislocation can be improved by automatic analysis of anteroposterior radiographs. Level of evidence: III.

#735 The clinicopathologic prognostic factors to estimate ESRD in patients with FSGS from national wide cohort of renal biopsy

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is one of the leading causes of glomerulonephritis in Korea. FSGS can be caused by heterogenous aetiologies with subdivided by primary, secondary, and genetical forms. The proposed clinicopathologic classification is dependent on amount of proteinuria, laboratory findings of possible secondary causes, and genetic profiles, however, that may not provide definite subtypes of FSGS. Therefore, it is important to search for prognostic markers of any form of FSGS. Method We enrolled a total of 20,404 adult patients who underwent native renal biopsy from 1979 to 2018 in 18 hospitals in Korea. Clinical, demographic, and laboratory data were collected in conjunction with pathologic findings. Among diagnosis of FSGS by pathologists of each hospital, we selected patients with definite segmental sclerosis by light microscopic examination including ≥10 glomeruli and without electron dense deposits by electron microscopic examination. We excluded patients with other forms of pathologic diagnosis except FSGS, with diabetes mellitus, or with follow-up period &amp;lt; 6 months after renal biopsy. We evaluated prognostic factors to estimate the risk of ESRD which event was found from ESRD registry of the Korean Society of Nephrology or the data from each hospital. Results Among 511 selected FSGS patients, 314 (61.4%) men were included. Mean age was 45.0 ± 17.9 years at biopsy. The laboratory finding of serum creatinine, estimated GFR, and urine protein to creatinine ratio (UPCR) was 1.38 ± 0.85 mg/dl, 71.8 ± 36.6 ml/min/1.73 m2, and 4.32 ±4.84 g/g creatinine, respectively (there were no missing data). GFR &amp;lt;60 ml/min/1.73 m2 was found in 41.5 % of patients and UPCR ≥ 3.0 g/g creatinine in 41.1 % of patients. During 117.5 ± 100.1 months of follow-up period, there were 97 (19.0%) patients with incident ESRD. Clinical prognostic factors to incident ESRD were estimated GFR, diastolic blood pressure, and year of renal biopsy. Pathologic prognostic factors were glomerular size, amount of global sclerosis and segmental sclerosis, severity of increase in glomerular matrix, interstitial fibrosis, interstitial inflammation, and tubular atrophy, and presence of artherosclerosis of intrarenal vessels. Adjusted with clinicopathologic factors related to incident ESRD, Cox's proportional hazard models revealed only pathologic findings of amount of glomerular global sclerosis and segmental sclerosis and presence of tubular atrophy were the independent prognostic factors (Model with 3.5 % of missing cases and -2 log likelihood ratio is 956.9, p &amp;lt; 0.001). GFR and UPCR showed significant relationship with incidence of ESRD, however, the significance was gone in the model adjusted with pathologic findings. AUC by ROC to estimate the event of ESRD by percentage of global sclerosis (GS) was 0.601 (range; 0.538-0.663, p = 0.002) and, by percentage of segmental sclerosis (SS), 0.679 (range; 0.616-0.743, p &amp;lt; 0.001). We grouped patients with three pathology categorical variables of a criterion of GS 30.9%, SS 10.5 %, and moderate degree in severity of tubular atrophy (TA), resulted in 8 groups, and summarized into 4 groups according to the relative risk to develop ESRD (Fig. 1). UPCR was a significant risk factor to estimate ESRD only in Group 4 with the criterion of 2 g/g creatinine by the Kaplan-Meier test (p = 0.034). GFR was not a prognostic factor in any pathology subgroup. Conclusion Important prognostic factors to estimate incident ESRD were pathologic findings of global sclerosis, segmental sclerosis, and tubular atrophy in FSGS patients. Significance of UPCR and GFR as prognostic factors was varied according to pathologic findings. We need to reconsider the criterion of UPCR to initiate immunosuppressive treatment and to break down the effect of immunosuppressive treatments for FSGS according to pathologic findings at renal biopsy.

Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease

Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

Psychosexological correlates of 372 women with vulvodynia, overactive pelvic floor, postcoital cystitis, and interstitial cystitis.

Among the plethora of urogynecological conditions possibly affecting women, some of them, less explored, have significant impacts on sexological and psychological health, with a mutual influence. The aim of this study was to investigate the sexological and psychological correlates of four urogynecological pathologies in a sample of women of childbearing age: overactive pelvic floor, vulvodynia, postcoital cystitis, and interstitial cystitis. Women cured of these conditions were also included, to assess the same aspects after the remission of physical symptoms. We recruited 372 women with an average age of 33.5years through an online platform shared by a popular forum for women with urogynecological pathologies between March and May 2021. The participants filled out a socio-anamnestic questionnaire and a set of psychometric tests. Participant data were collected by use of the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, Toronto Alexithymia Scale-20, Female Sexual Function Index, and Orgasmometer-F, and the SPSS (Statistical Package for Social Sciences) v.26 was used for data analysis. Overactive pelvic floor was reported by 66.4% of the women, vulvodynia by 55%, postcoital cystitis by 58.8%, and interstitial cystitis by 8.3%, and these conditions were often comorbid with each other, with 9.4% and 7% of women reporting having suffered psychological and sexual abuse, respectively. The presence of past abuse was correlated with overactive pelvic floor (P < .05), vulvodynia (P <.01), and major depression (P < .01). Significantly more depression occurred in women with vulvodynia than in the other subgroups (P < .05), except for women with only an overactive pelvic floor. There was no difference between the subgroups in the occurrence of alexithymia, sexual function, and orgasm (P < .05). Interestingly, the prevalence of sexual dysfunction increased in cured women. The lack of significant differences, except for depression, between the pathological subgroups suggests a similar clinical and psychological relevance of the four pathologies studied. The persistence of sexual dysfunctions in cured women may be related to a residual dysfunctional relational modality with the partner. The evaluation of both psychological and sexological variables in a group of less-explored urogynecological conditions represents a strength of this study, while a lack of a face-to-face assessment could represent a limitation. The results of the present study should promote psychosexological interventions in women with these diseases, both during the pathological state and after remission.

Frequency of epilepsy and pathological EEG findings in a Norwegian sample of children with fetal alcohol spectrum disorder: Impact on cognition and adaptive functioning.

Fetal alcohol spectrum disorder (FASD) comprises a combination of developmental, cognitive, and behavioral disabilities that occur in children exposed to alcohol prenatally. A higher prevalence of epilepsy and pathological electroencephalographic (EEG) features have also been reported in individuals with FASD. We examined the frequency of epilepsy, pathological EEG findings, and their implications for cognitive and adaptive functioning in children with FASD. We conducted a cross-sectional study of 148 children with FASD who underwent a multidisciplinary assessment and a 120-min EEG recording. Group comparisons and regression analyses were performed to test the associations between epilepsy and pathological EEG findings, FASD subgroups and neurocognitive test results and adaptive functioning. The frequency of epilepsy was 6%, which compares with 0.7% in Norway overall. Seventeen percent of children without epilepsy had pathological EEG findings. Attention-deficit hyperactivity disorder (ADHD) was diagnosed in 64% of the children. Children with epilepsy and/or pathological EEG findings had comparable cognitive and adaptive scores to those with normal EEG. However, children with frontal EEG pathology (without epilepsy) had significantly lower scores on the IQ indices Processing speed and Working memory than FASD children without such findings, irrespective of ADHD comorbidity. There was a greater prevalence of epilepsy among children with FASD than in the general Norwegian population. A greater frequency of EEG pathology was also evident in children without epilepsy, across all FASD subgroups. Irrespective of epilepsy, ADHD comorbidity, and FASD subgroup, children with frontal EEG pathology, despite having a normal total IQ, showed significantly slower processing speed and poorer working memory, which may indicate specific executive function deficits that could affect learning and adaptive functioning.

Associations between neuropsychiatric symptoms, pathology in neuropathological cohorts of Alzheimer’s disease, Alzheimer’s disease with Lewy bodies and Dementia with Lewy bodies

AbstractBackgroundNeuropsychiatric symptoms (NPS) are frequent in Alzheimer’s Disease dementia (ADD) but a higher NPS burden is found in dementia with Lewy bodies (DLB). Lewy body (LB) pathology frequently co‐occurs with AD pathology and may not meet neuropathological criteria for DLB (ADLB). Previous studies have shown that both ADLB and DLB cases have faster cognitive and/or functional decline compared to AD. However, the differences in NPS severity over disease course and survival in these pathologic subgroups is not well understood.MethodCases from the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) with a final neuropathologic diagnosis of DLB (±AD co‐pathology; n = 65), ADLB (n = 89), AD (without LB) (n = 140), and controls (no neuropathological diagnosis) (n = 82) were included. Total NPI‐Q (scores ranging from 0‐36) at time of enrollment and within 2.5 years of death were calculated for all groups. Statistical analysis utilizing ANCOVA (adjusting for age, sex, baseline MMSE and cognitive symptom duration) with pairwise comparisons, and Kaplan‐Meier curves were completed.ResultAge at onset of cognitive symptoms was not different between pathology groups. NPI‐Q scores at enrollment were highest in ADLB (7.33 ± 4.85), and higher (p&lt;0.001) than DLB (5.10 ± 3.37), AD (4.54 ± 3.63) and controls (1.78 ± 1.70). At final evaluation, NPI‐Q scores were highest in DLB (10.04 ± 6.28), followed by ADLB (8.0 ± 4.), and ADD (7.61 ± 5.05) when compared to controls (2.78 ± 3.97) (all p&lt;0.001). DLB and AD demonstrated significant increases in NPI‐Q severity during follow up (p &lt; 0.001). AD had longer survival time (5.8 years) compared to ADLB (4.0 years) and DLB (3.9 years). Subjects with NPS had a shorter median survival time (3.4 years) compared to subjects without NPS (6.5 years; p = 0.002).ConclusionA higher NPS burden and shorter survival is seen in both DLB and ADLB, as compared with AD. This suggests that diffuse neocortical LB pathology is not the major driver of either NPS or survival.

The role of visual rating and automated brain volumetry in early detection and differential diagnosis of Alzheimer's disease.

Medial temporal lobe atrophy (MTA) is a diagnostic marker for mild cognitive impairment (MCI) and Alzheimer's disease (AD), but the accuracy of quantitative MTA (QMTA) in diagnosing early AD is unclear. This study aimed to investigate the accuracy of QMTA and its related components (inferior lateral ventricle [ILV] and hippocampus) with MTA in the early diagnosis of MCI and AD. This study included four groups: normal (NC), MCI stable (MCIs), MCI converted to AD (MCIs), and mild AD (M-AD) groups. Magnetic resonance image analysis software was used to quantify the hippocampus, ILV, and QMTA. MTA was rated by two experienced neurologists. Receiver operating characteristic area under the curve (AUC) analysis was performed to compare their capability in differentiating AD from NC and MCI, and optimal thresholds were determined using the Youden index. QMTA distinguished M-AD from NC and MCI with higher diagnostic accuracy than MTA, hippocampus, and ILV (AUCNC = 0.976, AUCMCI = 0.836, AUCMCIs = 0.894, AUCMCIc = 0.730). The diagnostic accuracy of QMTA was superior to that of MTA, the hippocampus, and ILV in differentiating MCI from AD. The diagnostic accuracy of QMTA was found to remain the best across age, sex, and pathological subgroups analyzed. The sensitivity (92.45%) and specificity (90.64%) were higher in this study when a cutoff value of 0.635 was chosen for QMTA. QMTA may be a better choice than the MTA scale or the associated quantitative components alone in identifying AD patients and MCI individuals with higher progression risk.

The maximal contrast-enhanced range of CT for differentiating the WHO pathological subtypes and risk subgroups of thymic epithelial tumors.

To explore the value of maximal contrast-enhanced (CEmax) range using contrast-enhanced CT (CECT) imaging in differentiating the pathological subtypes and risk subgroups of thymic epithelial tumors (TETs). The pre-treatment-CECT images of 319 TET patients from May 2012 to November 2021 were analyzed retrospectively. The CEmax was defined as the maximum difference between the CT value of the solid tumor on pre-contrast and contrast-enhanced images. The mean CEmax value was calculated at three different tumor levels. There was a significant difference in the CEmax among the eight main pathological subtypes [types A, AB, B1, B2, and B3 thymoma, thymic carcinoma (TC), low-grade neuroendocrine tumor (NET) and high-grade NET] (p < 0.001). Among the eight subtypes, the CEmax values of types A, AB, and low-risk NET were higher than those of the other subtypes (all p < 0.001), and there was no difference among types B1-B3 and high-risk NET (all p > 0.05). There was no difference for CEmax values between NET and TC (p = 0.491). For the risk subgroups, the CEmax of TC (including NET) was 35.35 ± 11.41 HU, which was lower than that of low-risk thymoma (A and AB) (57.73±21.24 HU) (P < 0.001) and was higher than that of high-risk thymoma (B1-B3) (27.37±8.27 HU) (P < 0.001). The CEmax cut-off values were 38.5 HU and 30.5 HU respectively (AUC: 0.829 and 0.712; accuracy, 72.4% and 67.7%). The tumor CEmax on CECT helps differentiate the pathological subtypes and risk subgroups of TETs. In this study, an improved simplified risk grouping method was proposed based on the traditional (2004 edition) simplified risk grouping method for TETs. If Type B1 thymoma is classified as high-risk, radiologists using this improved method may improve the accuracy in differentiating risk level of TETs compared with the traditional method.

Bridging Integrator 3 (BIN3) Downregulation Predicts a Poor Prognosis in Patients with Esophagus Carcinoma: A Study based on TCGA Data.

Bridging integrator 3 (BIN3) has been reported to play a key role in certain tumors. Nevertheless, little is known about the role and clinical value of BIN3 in esophagus carcinoma (ESCA). This study aimed to investigate the pathological and prognostic role of BIN3 in ESCA patients. Genes significantly correlated with the prognosis of ESCA patients were screened and identified by comprehensive analysis of differentially expressed genes associated with overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) in ESCA. The expression of BIN3, pathological features correlation and subgroup overall survival analysis were performed using The Cancer Genome Atlas (TCGA) and GTEx databases. Moreover, the potential signaling pathways in which BIN3 was involved were analyzed by GO-KEGG enrichment analysis and gene set enrichment analysis (GSEA). Immune infiltrates correlation of BIN3 in ESCA was performed by TIMER and ssGSEA. The influence of BIN3 on epithelial-mesenchymal transition (EMT) was validated by western blot. There were two differentially expressed genes related to the prognosis of ESCA patients, which were identified from three gene clusters associated with overall survival (OS), diseasespecific survival (DSS) and progression-free interval (PFI) in ESCA patients. The BIN3 mRNA level was found to be significantly decreased in ESCA compared to normal tissues (p < 0.05). The decreased expression of BIN3 in ESCA was significantly correlated with the clinical stage (p = 0.015), T stage (p < 0.05), histological type (p < 0.001), age (p < 0.05) and gender (p < 0.05). ESCA patients with high BIN3 expression were observed to be correlated with T stage (T3 & T4), age (＜＝60), gender (male), primary therapy outcome (PD) and columnar metaplasia (No) of favorable OS. GO-KEGG enrichment analysis revealed that BIN3 was involved in endocytosis. GSEA showed that several pathways were enriched in BIN3, such as O linked glycosylation of mucins, PID HNF3B pathway, biocarta TFF pathway, WP pregnane X receptor pathway, reactome regulation of beta cell development, WP Urea cycle and associated pathways and others. BIN3 was significantly related to the infiltration level of T cells (p < 0.001), Tregs (p < 0.001), B cells (p < 0.001), NK cells (p < 0.001), and macrophage M2 (p < 0.001). In addition, BIN3 overexpression inhibited N-cadherin expression and promoted E-cadherin expression in ESCA cell lines TE-1. These results suggest that BIN3 might be a potential prognostic biomarker in ESCA. BIN3 functions as a tumor-suppressor role in ESCA, which is significantly associated with the immune infiltration of ESCA.

Overall Survival Following Neoadjuvant Chemotherapy Versus Adjuvant Chemotherapy in Clinically Node Negative T1 Triple Negative Breast Cancer.

The purpose of this study was to compare the overall survival (OS) of upfront surgery followed by adjuvant chemotherapy (ACT) versus neoadjuvant chemotherapy (NACT) followed by surgery in patients with clinical T1 clinically node negative triple negative breast cancer (TNBC). We retrospectively reviewed 48,329 women with cT1N0 TNBC from 2006 to 2016 in the National Cancer Database (NCDB).Patients were categorized into five pathologic subgroups based on ACT versus NACT and definitive pathologic stage after surgery: ACT with unchanged stage (pT0-1N0), ACT with pathologic upstage (any nodal disease, > pT1N0), NACT with pCR (ypT0-isN0), NACT with stable disease (SD) (ypT1N0), and NACT with progressive disease (PD) (any nodal disease, > ypT1N0). The primary outcome was 5 year OS. Patients with TNBC who underwent upfront surgery followed by ACT had better OS compared with those who received NACT (p < 0.001). The hazard ratio (HR) for death for NACT compared with ACT was 1.42 (95% CI 1.26-1.59, p < 0.001) on multivariate analysis. Patients who underwent upfront surgery followed by ACT and whose pathological stage was unchanged from clinical stage had similar outcomes compared with those who received NACT and attained pCR with 5 year OS of 92.7% versus 93.3% (p = 0.34). Patients with clinical T1cN0 tumors who underwent NACT with pCR had better outcomes compared with those who underwent ACT with unchanged stages. (p = 0.025). For cT1N0 TNBC patients, OS of upfront surgery followed by ACT was not inferior to those who underwent NACT. Neoadjuvant chemotherapy was associated with better outcomes in cT1c patients who attained pCR.

The Subgroup Imperative: Chest Radiograph Classifier Generalization Gaps in Patient, Setting, and Pathology Subgroups.

To externally test four chest radiograph classifiers on a large, diverse, real-world dataset with robust subgroup analysis. In this retrospective study, adult posteroanterior chest radiographs (January 2016-December 2020) and associated radiology reports from Trillium Health Partners in Ontario, Canada, were extracted and de-identified. An open-source natural language processing tool was locally validated and used to generate ground truth labels for the 197 540-image dataset based on the associated radiology report. Four classifiers generated predictions on each chest radiograph. Performance was evaluated using accuracy, positive predictive value, negative predictive value, sensitivity, specificity, F1 score, and Matthews correlation coefficient for the overall dataset and for patient, setting, and pathology subgroups. Classifiers demonstrated 68%-77% accuracy, 64%-75% sensitivity, and 82%-94% specificity on the external testing dataset. Algorithms showed decreased sensitivity for solitary findings (43%-65%), patients younger than 40 years (27%-39%), and patients in the emergency department (38%-60%) and decreased specificity on normal chest radiographs with support devices (59%-85%). Differences in sex and ancestry represented movements along an algorithm's receiver operating characteristic curve. Performance of deep learning chest radiograph classifiers was subject to patient, setting, and pathology factors, demonstrating that subgroup analysis is necessary to inform implementation and monitor ongoing performance to ensure optimal quality, safety, and equity.Keywords: Conventional Radiography, Thorax, Ethics, Supervised Learning, Convolutional Neural Network (CNN), Machine Learning Algorithms Supplemental material is available for this article. © RSNA, 2023See also the commentary by Huisman and Hannink in this issue.

Implication of MRI Risk Stratification System on the Survival Benefits of Adjuvant Chemotherapy After Neoadjuvant Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer

To investigate the implication of a Magnetic resonance imaging (MRI) risk stratification system on the selection of patients with locally advanced rectal cancer (LARC) who can benefit from adjuvant chemotherapy (ACT) after neoadjuvant chemoradiotherapy (NCRT). This retrospective study included 328 patients with LARC who underwent NCRT and surgery. The median follow-up duration was 79 months (Interquartile range, 66-94 months). Cox logistic regression analysis was used to identify MRI risk factors and develop a risk stratification system to stratify patients into groups with high and low risks. Kaplan-Meier curves of distant metastasis-free survival (DMFS) and overall survival (OS) were used to show the benefits of ACT and stratify results based on the MRI risk stratification system and postoperative pathological staging. An MRI risk stratification system was built based on four MRI risk factors, including MRI-identified T3b-T4 stage, N1-N2 stage, extramural venous invasion, and tumor deposits. 74 (22.6%) patients with 3-4 MRI risk factors were classified into the MRI high-risk group. ACT could significantly improve 5-year DMFS (19.2% versus 52.1%; p<0.001) and OS (34.6% versus 75.0%; p<0.001) for patients in the MRI high-risk group, while ACT had no survival benefit for patients in the MRI low-risk group. The benefits of ACT were not observed in patients with any pathological staging subgroups (ypT0-2N0, ypT3-4N0, and ypN+). Patients in the MRI high-risk group could benefit from ACT, regardless of postoperative pathological staging. Baseline MRI should be considered more in ACT decision-making.

Radiofrequency Echographic Multi Spectrometry (REMS) for the assessment of muscle strength

Objective: Due to the limitations of available methods for muscle strength evaluation, there is a need to develop more effective ways to quantify muscle function and performance in individuals suffering from musculoskeletal diseases. This study investigated the relationship between handgrip strength and a novel parameter derived from ultrasound scans of the forearm obtained using Radiofrequency Echographic Multi Spectrometry (REMS) technology. Estimations of muscle strength were performed in two study groups: healthy subjects and individuals affected by sarcopenia. Methods: A total of 58 Caucasian volunteers (30 healthy individuals and 28 subjects affected by sarcopenia) were recruited. A handgrip strength test was used to measure the Maximum Voluntary Contraction (MVC) of each subject’s dominant arm. Transversal echographic scans of the forearm were performed using an EchoStation device (Echolight S.p.a., Lecce, Italy) equipped with a 40 mm linear probe. A dedicated segmentation algorithm was designed and optimized for automatic identification of the ulnar and radius muscle profiles. The correlation between MVC values and REMS-based estimations of MVC (MVCREMS) was established using a linear regression approach. Results: MVCREMS showed excellent correlation with the MVC taken as ground truth. A high correlation value (r=0.95) was found in the overall population, and the corresponding values in the healthy and pathological subgroups were r=0.90 and r=0.83, respectively (p&lt;0.0001). Conclusion: This technique allows reliable estimation of muscle strength in both pathological and healthy subjects, and is a valid alternative to conventional handgrip tests for use in primary care. In the future, this technique might help to enhance the assessment, screening and prevention of musculoskeletal diseases.

Prevalence of pancreatic exocrine insufficiency after pancreatic surgery measured by 13C mixed triglyceride breath test: A prospective cohort study

BackgroundPatients undergoing pancreatic surgery are at risk of pancreatic exocrine insufficiency (PEI) and needing pancreatic enzyme replacement therapy (PERT). MethodsThis study included 254 patients undergoing pancreatic surgery for oncologic indications. A13C mixed triglyceride breath test was performed immediately preoperative and postoperative. This test analyzes the pancreatic remnant lipase activity measuring 13CO2 in breath samples after a test meal with 1.3-distearyl-(13C-Carboxyl)octanol-glycerol. Cumulative percent dose recovery after 6 h of less than 23% confirms PEI. In addition, PEI was compared between pathology subgroups. ResultsIn 197 patients undergoing pancreaticoduodenectomy, cPDR-6h decreased significantly from a median of 32.84% before to 15.80% after surgery (p < 0.0001). This decrease in exocrine function was significant in all pathology subgroups except in pancreatic neuroendocrine tumors. Exocrine function decreased most in pancreatic ductal adenocarcinoma (PDAC). In addition, the percentage of patients needing PERT because of PEI increased from 25.9% to 68.0% postoperative (p < 0.001). Overall, patients with an MPD diameter of more than 3 mm had a higher risk of developing postoperative PEI: 62.7% compared to 37.3% (p = 0.009), OR = 3.11.In contrast, the majority of the 57 patients undergoing a distal pancreatectomy did not experience any significant change in exocrine function. ConclusionsThe vast majority of patients undergoing pancreaticoduodenectomy for oncologic indications experience a significant drop in exocrine function, are at high risk of developing pancreatic exocrine insufficiency and consequently need to be treated with pancreatic enzyme replacement therapy. Therefore, systematic screening for pancreatic exocrine insufficiency is needed after pancreaticoduodenectomy.

O002 Expression of MLN64 (lymph node metastasis 64) gene transcript in clinical gastric cancer and relationship with the ERBB4

Abstract Introduction MLN64 (Lymph Node Metastasis 64, or STARD3 (StAR Related Lipid Transfer Domain Containing 3)) has a role in the progression of certain cancers including breast and prostate cancers and connected to the pattern of ERBB2 (Her2). The present study explored the expression of MLN64 in clinical gastric cancer in connection with the ERBB family. Methods A gastric cancer cohort (n=322) was tested for the expression profile of MLN64 along with the ERBB family members. Comparisons were made between clinical, pathological subgroups and the clinical outcome together with ERBB expression status. Results Gastric tumours expressed significantly raised levels of MLN64 than normal tissues (p=0.0012) and showed a stepwise increase with increased tumour grade and TNM staging. However, there was no significant difference between node negative and node positive tumours. MLN64 alone had a weak value in evaluating the overall (OS) and disease free (DFS) survival. Amongst the four ERBB family members, MLN64 had a significant correlation with ERBB4 (Her4) (p=0.004). Stratification of patients by ERBB4 expression status indicates that in patients with low ERBB4 tumours, MLN64 presents a significant factor in assessing both disease free (DFS) p=0.027) and overall survival (OS) (p=0.048). Similarly, MLN64 expression identified a subpopulation of node positive patients with a most adverse clinical outcome (p=0.009 for DFS and p=0.048 for OS). Conclusion MLN64 expression is an indicator for the disease progression and clinical outcome in gastric cancer. Together with the expression pattern of ERBB4, it makes a prognostic factor for the patients.

Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes

Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau-positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (142 FTLD cases and 92 controls), generated using the Illumina 450K or EPIC microarrays. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differentially methylated loci across FTLD subgroups/subtypes. In addition, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5’UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. In addition, in the three independent co-methylation networks, OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development.