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ICAM-1 Hypomethylation Predicts Poor Prognosis in Patients With Hepatitis B Virus-Related Acute-on-Chronic Liver Failure.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with a high short-term mortality rate. Therefore, early and accurate prognostic prediction is crucial for precise clinical management. This study aims to investigate the expression patterns of intercellular adhesion molecule-1 (ICAM-1) and its predictive value for the short-term prognosis of patients with HBV-ACLF. The Methylight method was used to quantitatively detect ICAM-1 promoter methylation level in peripheral blood mononuclear cells (PMBCs) of 286 participants. Meanwhile, the mRNA and plasma expression levels of ICAM-1 were determined using RT-qPCR and ELISA, respectively. The ICAM-1 promoter methylation levels in PBMCs of HBV-ACLF patients were significantly lower than those in chronic hepatitis B (CHB) patients and healthy controls (HCs), whereas the mRNA and plasma expression levels of ICAM-1 were markedly elevated. The ICAM-1 methylation levels in HBV-ACLF patients correlated with specific clinical parameters. Among HBV-ACLF patients, ICAM-1 methylation levels were significantly lower in the non-survivor groups at both 28 and 90 days. The study further revealed that ICAM-1 methylation level serves as an independent influencing factor for the prognosis of HBV-ACLF patients at 28 and 90 days. Based on ROC curve and Kaplan-Meier curves, ICAM-1 methylation levels demonstrated excellent performance in predicting 28- and 90-day mortality in patients with HBV-ACLF. In conclusion, patients with HBV-ACLF exhibit hypomethylation of the ICAM-1 promoter. The combination of ICAM-1 promoter methylation level and MELD score can effectively enhance the predictive ability for the short-term prognosis of HBV-ACLF patients.

Humans

Immediate prognosis in recurrent myocardial infarction.

Of 880 patients admitted consecutively to a coronary-care unit with acute myocardial infarction, 200 had had a previous infarction. The mortality-rate in the first twenty-eight days after infarction was higher in the group with recurrent infarction (26 per cent) than in the group with first infarctions (16.9 per cent). When the patients were matched for sex and age this difference in mortality-rate was only statistically significant in men aged less than seventy. In patients with previous infarctions the short-term prognosis was worse in those with two or more previous infarctions, in those in whom infarction had occurred less than three months before, and in those with a previous infarction in the anteroseptal wall.

Age Factors

ANXA3 hypomethylation as a prognostic biomarker in hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is associated with a poor prognosis. This research aimed to characterize the expression pattern and clinical value of Annexin A3 (ANXA3) in HBV-ACLF patients. METHODS: First of all, ACLF-related datasets were downloaded from the Gene Expression Omnibus (GEO) database to carry out bioinformatics analyses. RT-qPCR, ELISA, and Methylight were used to measure ANXA3 gene expression and promoter methylation levels. A validation cohort was leveraged to further validate the results. RESULTS: Transcriptome analysis showed that ANXA3 was among the most differentially expressed genes when comparing dead patients with HBV-ACLF to those with survivors. The mRNA and serum levels of ANXA3 were elevated, and methylation levels were decreased in HBV-ACLF patients. The PMR value of ANXA3 in patients with HBV-ACLF was negatively correlated with inflammation-related cytokines IL-6, TNF-&#x3b1;, and IL-1&#x3b2;, as well as quantitative clinical parameters AST, TBIL, PT, INR, NEUT%, and MELD score, and positively correlated with PTA (all p&#x2009;<&#x2009;0.05). In HBV-ACLF patients, ANXA3 was considered to be an independent influence factor for the 90-day mortality. It was also found that ANXA3, especially hypomethylation, was associated with 28- and 90-day overall survival in patients with HBV-ACLF based on receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and Kaplan-Meier curves. CONCLUSIONS: ANXA3 hypomethylation has a prominent predictive value for short-term mortality in patients with HBV-ACLF and may serve as a promising biomarker of HBV-ACLF prognosis.

Humans

The pathology of invasive breast cancer. A syllabus derived from findings of the National Surgical Adjuvant Breast Project (protocol no. 4).

The inter-relationships of 32 pathologic and 7 clinical parameters encountered in the study of 1000 examples of invasive breast carcinoma have been presented. In some instances the biological significance of these associations is at present unclear. In others it is to be noted that there is no information provided as to the rank of their significance. Nevertheless, the associations that were encountered not only help further characterize the various forms of breast cancer but also provide information regarding the possible biological significance of some of their features. Although it is not our intention to minimize the possible significance of the inter-relationships of pathologic parameters, most emphasis in the summarizing statements which follow has been placed upon those correlations which may relate to prognosis. In this regard reference has been made to short-term treatment failure, vis a vis local recurrence and/or metastases, which may not necessarily accurately reflect patient survival, although generally such a relationship exists. Information in this regard as well as to the rank of the significance of these pathologic features shall be forthcoming when sufficient time has elapsed since the inception of this study to allow for such conclusions, i.e. survival or long-term treatment failure rates. Lastly, it becomes evident that the guidelines followed in the examination of these specimens appear to represent at least the minimum requirements necessary for a meaningful pathologic evaluation of breast carcinoma.

Adenocarcinoma, Mucinous

Prognosis of SMON patients.

The following points have become clear on prognosis of SMON through the analysis of 981 cases collected. 1) The prognosis of the old whose ages were 60 year old or over is not favorable, when compared with that of the young. However, there is no prognostic difference between male and female. 2) The cummulative death rate of SMON which was calculated by the life table method is approx twice as much as the generally expected value. 3) Approximately 80% of the patients showed some sort of improvement 7 to 12 months after the onset of the disease. The rate for 13 months or over if nearly the same. 4) The abdominal symptoms found at the time of the onset of the disease decreased markedly in the course of the disease. 5) Among neurological symptoms, the prognosis of motor disorders is more favorable. The complete recovery of sensory disturbances was extremely rare, but approx 60% showed more or less favorable in the course of the illness. Approximately 40% of the cases with visual disturbances completely recovered or showed favorable improvement, whereas 9% of them became worse. As for the prognosis of visual impairment, it is more serious than other symptoms. 6) The patients who had been administered clioquinol over long period displayed a higher rate of severe or moderate motor, sensory and visual disturbances, compared with the group with short-term administration of clioquinol. The death rate was also higher in the former group. 7) The rate of relapse as a whole was 16.7% and 68% of them was seen within 18 months after the onset. There is no difference in relapse according to sex. There was seen a high rate of relapse in the group of longterm administration of clioquinol. 8) A 10.5% of total cases were either unable to walk or in need of assistance in walking, whereas the rate of patients who cannot get dressed or who cannot defecate unassisted was lower. 9) Approximately 65% returned to the job in 12 months or more after the onset. The employment rate was not different according to sex, whereas it was lower along with the age advances. 10) Approximately 20% were not received medical treatment. The rate of non-treated patients is higher in the younger patients. The rate of hospitalized patients was higher in the older patients.

Adult

Risk prediction in patients with heart failure with preserved ejection fraction: the LIFE-Preserved model.

BACKGROUND AND AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) constitutes a heterogeneous disease with varying prognosis. Given the rising incidence of HFpEF, accurate risk prediction for these patients is needed to identify high-risk individuals, who may benefit the most from preventive treatments. The LIFE-Preserved model was developed and validated for the prediction of individual short-term and lifetime risk for HF hospitalization or cardiovascular (CV) death in patients with HFpEF. METHODS: LIFE-Preserved was derived in 20 332 patients aged 40-90 years with a left ventricular ejection fraction &#x2265; 50% from the Swedish HF Registry. Cause- and sex-specific Cox models were derived to predict the risk of HF hospitalization or CV death using 14 routinely available predictors. Use of age as the timescale allowed for predictions beyond the maximum follow-up duration in the derivation data, adjusted for competing risks. External validation was performed in two trials (EMPEROR-Preserved and TOPCAT-Americas) and three registries (NHS England Secure Data Environment, Veterans Affairs, and HF-Particles). Model performance was assessed by discrimination and calibration. RESULTS: During a median follow-up of 1.8 years (interquartile range .6-4.2, maximum 19 years), 9341 first HF hospitalizations or CV deaths (46%) were observed in Swedish HF Registry. External validation included data from 28 062 patients with HFpEF [9930 (35%) first HF hospitalizations or CV deaths]. Pooled C-statistics were .714 (95% confidence interval .652-.775) in trials and .658 (95% confidence interval .599-.717 in registries, with adequate calibration in all external validation sources. Performance was similar in men and women. An interactive calculator of the LIFE-Preserved model has been made available here. CONCLUSIONS: The LIFE-Preserved model enables prediction of short-term and lifetime risk of HF hospitalization or CV death in patients with HFpEF. The model could serve as a tool to identify high-risk HFpEF patients, guiding clinical management and shared decision-making.

Humans

Aneurysmectomy in the aged.

The records of 206 aneurysmectomy patients over the age of 70 years were reviewed. Increased three- and five-year mortality was seen with a variety of risk factors--cerebral vascular disease, cardiac disease, diastolic hypertension, renal disease, and cigarette smoking--but 30-day mortality was not affected. Age was not a significant risk factor. It is recommended that patients with aneurysms less than 7.5 cm be observed if multiple risk factors are present. Almost all patients with aneurysms greater than 7.5 cm should have resection to prevent death from rupture, although this will be short-term palliation in patients with multiple risk factors.

Age Factors

Cancer of the cardia.

The records of 157 patients with cardioesophageal carcinoma were reviewed. It is evident that although the prognosis of patients with squamous carcinoma is better than that of patients with adenocarcinoma, neither lesion is compatible with substantial long-term survival. Palliative resection of squamous carcinoma provides satisfactory short-term relief of symptoms. Palliative resection of adenocarcinoma, however, does not afford a similar response. Alternative modes of therapy are suggested.

Adenocarcinoma

[Study of the long-term psychological consequences of heart valve prostheses].

The present follow-up period of cardiac surgery allows assessment of the long-term consequences of valvular prostheses, the short-term consequences having already been the object of many studies. 50 patients of both sexes, operated on for aortic or mitral valve disease between 1973 and 1974 were interviewed to assess their degree of psychological adaptation with regard to their cardiac status and the principal factors of adaptation. The position of the prosthetic valve (aortic or mitral) seemed to be of little importance and the prognosis depended rather on sex, age at operation, previous personality, intelligence quotient, postoperative psychiatric complications and the interval between diagnosis of the disease and operation.

Adaptation, Psychological

Dysphoric response to neuroleptic treatment in schizophrenia: its relationship to autonomic arousal and prognosis.

Longitudinal pharmacotherapeutic data from 58 schizophrenic patients suggest that the emergence of a dysphoric state, characterized by a combination of anxiety, depression, and accusatoriness, early in the course of neuroleptic treatment augurs poor therapeutic outcome and is associated with an unfavorable prognostic classification and a tendency for autonomic arousal to increase with treatment from a drug-free base line somewhat higher than normal. These associations particularly characterized the nonparanoid schizophrenics with nuclear prognostic classification and poor short-term as well as long-term therapeutic outcome; they did not apply to the paranoids. The dysphoric response was unrelated to base-line dysphoria or to the extrapyramidal reactions to neuroleptic medication, and seemed to reflect some basic biological differences between the poor prognosis nonparanoid, the good prognosis nonparanoid, and the paranoid schizophrenics.

Adult

The presence or absence of standard modifiable cardiovascular risk factors in patients with myocardial infarction impacts long-term but not 30-day mortality: a UK Biobank prospective cohort study.

AIMS: Prior studies reported higher early mortality after acute myocardial infarction (MI) in patients without standard modifiable cardiovascular risk factors (SMuRFs), warranting further validation. We aimed to evaluate whether SMuRF-absence is associated with increased 30-day cardiovascular mortality following MI. METHODS AND RESULTS: We conducted a population-based cohort study using UK Biobank data (n = 487 177). Incident MI cases occurring between 2006 and 2022 were identified through linkage to hospital and death registries. Standard modifiable cardiovascular risk factors (diabetes, hypertension, hypercholesterolaemia, current smoker) were defined at baseline and continuously assessed until MI onset. Thirty-day mortality following MI was estimated using Cox proportional hazards models, adjusted for sociodemographic, clinical, and cardiogenomic variables, were used to estimate 30-day mortality risks. Logistic regression model was used to estimate mortality risk at 10 years post-MI. Among 15 463 patients experiencing an MI (1034 without SMuRFs), SMuRF-absence was not significantly associated with 30-day mortality (HR: 0.82, 95% CI: 0.65-1.04, P = 0.103). Propensity score-matched analyses supported these findings (HR: 0.95, 95% CI: 0.69-1.29, P = 0.729). Further analyses stratified by distinct time intervals (2006-2022) revealed no significant modification of this association by advancements in acute MI management. Interaction analyses indicated no significant effect modification by sex, age, socioeconomic status, or period of MI occurrence. However, extended analysis to 10 years revealed that SMuRF absence was significantly associated with lower long-term mortality (OR: 0.61, 95% CI: 0.49-0.75, P < 0.01). CONCLUSION: In this population-based cohort, SMuRF status significantly impacted long-term but not short-term mortality following MI, indicating early survival is predominantly driven by acute-phase factors rather than baseline cardiovascular risk profiles.

Humans

Value of thyroid-stimulating-antibody determinations in predicting short-term thyrotoxic relapse in Graves' disease.

Thirty consecutive patients with hyperthyroid Graves' disease received a 6-month course of antithyroid drugs. Sixteen patients relapsed within 6 months of the withdrawal of antithyroid therapy. All patients with high levels of thyroid-stimulating antibodies (TSAb) at the time of drug withdrawal relapsed within 2 months of discontinuing the antithyroid treatment while all patients with low or undetectable TSAb activity at the time of drug withdrawal remained in remission. It was not possible to predict the disease course in patients who had intermediate levels of TSAb when antithyroid therapy was stopped.

Adult

Some aspects of tuberculoid leprosy and chemotherapeutic trials.

The author describes the progress made in our knowledge of tuberculoid leprosy since the original case of Jadassohn in 1898. The numerical importance of T patients in different parts of the world is reviewed and their role in the transmission of the disease discussed. An analysis is made of the subgroups into which T leprosy is divided according to the clinical symptoms, bacteriology, histopathology and immunology in the Madrid classification as well as in the Souza-Lima-Souza Campos and Ridley-Jopling studies. The author concludes that a majority of T patients are immunologically stable and belong to two well defined groups, the first called T annular in the Souza-Lima-Souza Campos study and TT in the Ridley-Jopling classification and the second called T reactional by S.L.-S.C. and BT by R.J. Taking into account the high proportion of T cases in most epidemiological situations, their generally accepted good prognosis under treatment and the present availability of several drugs of proved efficacy, the author suggests to carry out in T leprosy under controlled conditions a trial of a number of therapeutic regimens of not more than 12 months duration. Follow-up periods will make possible medium and long-term evaluation of results after 3 and 5 years respectively of the initiation of the chemotherapeutic regimens. The practical implications of effective and well tolerated short-term therapy in T leprosy is stressed. Its widespread use in field programmes will represent among other advantages a considerable economy in personnel and drugs costs. The use of a single protocol is recommended. The one worked out by THELEP for therapeutic trials in lepromatous leprosy could be adopted with a few changes made necessary because of the morphological and bacteriological differences between L and T leprosy. It is suggested that, if the results of the trial are successful, similar regimens could be tried in indeterminate leprosy.

Clinical Trials as Topic

[Therapeutic effect of vitamin A acid (retinoic acid) in various forms of palmar/plantar hyperkeratoses: experimental studies on 68 patients].

Up to date, the treatment of palmar/plantar hyperkeratoses presents a therapeutic problem. The known therapeutic procedures result in short-term improvement only, if any at all. In these investigations involving 68 patients suffering from palmar/plantar hyperkeratoses of different etiology, small doses of vitamin A acid (retinoic acid) topically applied, produced a striking improvement in hypertrophic lichen planus of palms or soles: the regression was complete and in most cases permanent. The skin texture of patients with genetic keratoses and callosities became normal within a few weeks: but this condition remained free of symptoms only as long as vitamin A acid was used as a maintenance dose once or twice weekly. In hyperkeratotic exzema, pityriasis rubra pilaris, and in verrucae plantaris vitamin A acid topically applied was found to be unsuitable for treatment. The possible side effects of this treatment are mentioned. Several possibilities regarding the way of action of vitamin A acid are discussed.

Administration, Topical

Pathologic findings from the national surgical adjuvant breast project (protocol no. 4). II. The significance of regional node histology other than sinus histiocytosis in invasive mammary cancer.

The morphologic appearances of regional lymph nodes in radical mastectomy specimens obtained from 303 women entered into a prospective study of invasive breast cancer were categorized into patterns that have been considered to reflect immunologic function. An attempt was made to correlate these with 31 other histological and 8 clinical features, including short-term treatment failure (3 months to 4 years, average 24 months). No significant relationship to the latter was encountered. However, a lymphocyte predominance pattern was significantly associated with a stellate tumor border, absent cell reaction within the dominant tumor, absent sinus histocytosis of lymph nodes, combination tumor types, and a patient age of 55 years or more. A similar relationship between age of patient and sinus histiocytosis was found with the germinal center predominance pattern. In addition, this histologic appearance was associated with circumscribed tumors, severe cell reaction, and the infiltrating ductal carcinoma NOS and medullary types. Nodes with an unstimulated appearance were also found to be related to an absent cell reaction but marked sinus histiocytosis and a patient age of 45-54 years. Possible reasons for the differences between these findings and those of others relating prognostic value to such assessment of nodal histology is discussed, as are the findings of studies relevant to the identity of immunologic function with the morphologic appearance of nodal structure. The findings from this study fail to indicate any value of such nodal assessments as prognostic discriminants for breast cancer. Although longer periods of observation might alter this conclusion, such an event is regarded as unlikely.

Adenocarcinoma, Mucinous

Thrombus Metabolism-Based Molecular Subtyping for Prognostic Risk Stratification in Acute Ischemic Stroke: A Preliminary Study.

AIMS: To preliminarily characterize metabolic molecular subtypes of cerebral thromboemboli and evaluate their clinical significance in anterior circulation acute ischemic stroke due to large vessel occlusion (AIS-LVO). METHODS: Untargeted metabolomics was performed on thromboemboli retrieved from 36 patients with anterior circulation AIS-LVO using ultra-performance coupled liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Unsupervised hierarchical clustering was employed to identify distinct metabolic molecular subtypes, and their associations with stroke etiology, radiographic severity, and functional outcomes were analyzed. RESULTS: Two distinct thrombus metabolic molecular subtypes (C1 and C2) were identified based on 12 metabolites significantly associated with both short-term (7-day &#x2206;NIHSS) and long-term (90-day mRS) functional outcomes. The C1 subtype, predominantly cardioembolic, exhibited enhanced lipid metabolism, whereas the C2 subtype, primarily atherothrombotic, demonstrated increased folate metabolism. Patients with C1 thromboemboli presented more severe admission ischemic lesions (as indicated by ASPECTS) and experienced poorer short-term and long-term outcomes. A six-metabolite signature derived from LASSO regression was identified for exploratory discrimination of thrombus metabolic subtypes, etiological subtypes, and 90-day outcomes. CONCLUSION: This preliminary exploratory study identifies two metabolically distinct thrombus molecular subtypes with clinical implications in anterior circulation AIS-LVO, providing a novel basis for risk stratification and personalized secondary prevention and warrants further investigation.

Humans

Intratumoral B cell and interferon signatures in newly diagnosed glioblastoma are associated with longer survival in patients treated with SurVaxM.

Glioblastoma (GBM) has proved difficult to treat, and there is dire need for more effective therapies. In a single arm phase IIa trial (NCT02455557), treatment of newly diagnosed GBM patients with the peptide vaccine SurVaxM resulted in promising median progression-free and overall survival. To investigate molecular features that associate with GBM responsiveness to SurVaxM, retrospective whole exome and RNA sequencing was performed on patient tumors (n&#x2009;=&#x2009;34) collected prior to standard of care treatment plus SurVaxM. Differential gene expression and mutational profiles were characterized between patients with short-term (OS&#x2009;<&#x2009;18&#xa0;months) or long-term (OS&#x2009;&#x2265;&#x2009;18&#xa0;months) overall survival. Greater expression of interferon, complement, and humoral immunity signatures were associated with long-term survival. Deconvolution of transcriptomes identified enrichment of intratumoral memory B cell populations in long-term survivors that were validated by CD20 staining in matched samples. A five-gene expression signature and a B cell specific signature predicted survival within the SurVaxM-treated cohort, however, these signatures were not associated with improved outcomes in a similarly treated population obtained from The Cancer Genome Atlas (TCGA) that did not receive immunotherapeutic intervention. Although prospective validation is ongoing, the findings in this discovery cohort specify molecular features of GBM associated with better overall survival and potential responsiveness to immunotherapy with SurVaxM.

Humans

Anti-tumour effects of combined lenvatinib and EGFR Inhibition in advanced differentiated thyroid cancer cells.

PURPOSE: Differentiated thyroid cancer (DTC) typically has a favourable prognosis, while advanced forms of these tumours exhibit aggressive behaviour, leading to decreased survival. Lenvatinib has demonstrated effectiveness in managing advanced DTC. However, its long-term efficacy is compromised by resistance mechanisms, which remain unexplored, limiting its clinical utility. METHODS: In vitro studies were conducted using three advanced DTC cell lines of the papillary subtype: K1 (BRAF p.V600E), BCPAP (BRAF p.V600E) and TPC-1 (RET/PTC1). IC50 for Lenvatinib and Gefitinib were defined, and their effects on cell viability, colony formation, gene expression, and pathway activation were assessed individually and in combination. Comparative genomic hybridisation was performed to uncover intrinsic resistance mechanisms. RESULTS: Lenvatinib IC50 was higher in K1 and BCPAP than in TPC-1, indicating greater TPC-1 susceptibility, as confirmed by viability assays. Gefitinib showed similar IC50 values across all cell lines. The Lenvatinib plus Gefitinib combination (Combo) significantly reduced K1 and BCPAP viability when comparing with monotherapies, with no significant effects in TPC-1. Clonogenic assays mirrored these results and revealed higher recovery in K1 and BCPAP after Combo withdrawal. Combo treatment increased EGFR expression and induced ERK1/2 and AKT phosphorylation&#x2019;s dysregulation in all cell lines. CONCLUSIONS: This study showed that RET/PTC1 cells are more responsive to Lenvatinib than BRAF-mutated cells, and that EGFR targeting with Gefitinib enhanced Lenvatinib&#x2019;s inhibitory effect in BRAF-mutated cells. Dysregulation of EGFR and Lenvatinib target gene&#x2019;s expression, as well as of MAPK and PI3K signalling may indicate short-term adaptive resistance. These findings provide insight into Lenvatinib resistance mechanisms in thyroid cancer and highlight the need for further research to overcome refractoriness.

Humans