Higher Hazard Ratio Research Articles

Class III Obesity Is Associated with Worse Overall Survival in Previously Untreated Younger Patients with Acute Myeloid Leukemia Enrolled on SWOG 1203

Mohamed Sorror and Mary-Elizabeth Percival contributed equally to this project. Introduction: There has been inconsistent evidence supporting the association between obesity and outcomes in patients with newly diagnosed acute myeloid leukemia (AML). Prior studies have studied obesity as defined by body mass index (BMI) ≥ 30. However, this general definition of obesity can be further subdivided into class I obesity (BMI 30 to <35), class II obesity (BMI 35 to <40) and class 3 obesity (BMI ≥40). Given the high prevalence of obesity in the United States (41.9%; with class III obesity 9.2%), distinctions in degree of obesity may be associated with outcomes for patients with AML (Stierman et al, 2021). We were interested in studying outcomes in patients with AML stratified by class I, class II and class III obesity after induction chemotherapy and allogeneic hematopoietic cell transplant (HCT). Identification of at-risk patient populations could aid in design of future interventions. Methods: We retrospectively reviewed a group of 738 previously untreated subjects with AML randomized to daunorubicin and cytarabine (DA), idarubicin and cytarabine (IA), and IA with vorinostat as part of clinical trial SWOG 1203, conducted by the SWOG Cancer Research Network between 2012 and 2015. Subjects with adverse risk cytogenetics were recommended to receive HCT in their first complete remission (CR1); subjects with intermediate risk cytogenetics were selected for HCT in CR1 per local institutional standards. Nine patients who did not receive protocol therapy or had missing BMI were excluded (final cohort 729 patients). Early death was defined as death within 56 days of induction chemotherapy. Multivariable time-dependent Cox regression model and Fisher's exact test were used for analysis of overall survival (OS). HCT in first complete remission (CR1) was included as a time-dependent covariate. Results: The median age was 49 years (range, 18 to 60), 51% were male, 90% had de novo disease, and 88% had a performance status (PS) of 0-1 (Table 1). Among these patients, 1% (n=9) were underweight, 25% (n=182) were normal weight, 31% (n=225) were overweight, 20% (n=145) had class I obesity, 11% (n= 82) had class II obesity and 12% (n= 86) had class III obesity. There was no difference in the rate of achieving composite CR (CR with or without count recovery) between different weight categories (p=0.17). There was no clear trend in early death rate by weight (underweight: 11%; normal weight: 4%; overweight: 6%;class I obesity: 7%; class II obesity: 4%; class III obesity: 17%), though class III obesity had a significantly higher early death rate as compared to all the other groups combined (p=0.004). In multivariable Cox regression analyses, class III obesity was significantly associated with worse OS when compared to normal weight (hazard ratio (HR) 2.56, 95% confidence interval (CI) 1.68-3.90; p<0.001); though not statistically significant, we identified a trend towards worse OS for patients with class I (HR 1.40, 95% CI 0.95-2.06; p=0.09) and class II obesity (HR 1.48, 95% CI 0.95-2.31; p=0.09) (Figure 1). Other co-variates with a significant association with OS included age (HR 1.03, 95% CI 1.01-1.04; p<0.001), intermediate cytogenetic risk (HR 2.45, 95% CI 1.33-4.51; p=0.004), and adverse cytogenetic risk (HR 5.86, CI 3.10-11.06; p<0.001). HCT during CR1 was not found to be significantly associated with OS (HR 0.88, CI 0.67-1.15; p=0.3). No significant difference was identified in time to HCT based on BMI category. In patients who underwent HCT during CR1, class III obesity (HR 2.32, 95% CI 1.22-4.43; p=0.01) and older age (HR 1.02, 95% CI 1.00-1.04; p=0.01) were significantly associated with worse OS; in contrast no significant association was identified between OS and class I obesity (HR 1.30, 95% CI 0.77-2.20;p=0.32), while a higher HR and a trend existed for class II obesity (HR 1.76, 95% CI 0.97-3.17; p=0.06). Conclusions: Our retrospective analysis suggests that among newly diagnosed younger patients with AML, those with class III obesity are at increased risk of early death and shorter overall survival. Future directions include assessing lean body mass in addition to BMI in patients with newly diagnosed AML, as sarcopenic obesity is known to portend poor outcomes. Identifying this at-risk patient population may help guide future investigation of early weight management interventions in patients with newly diagnosed AML.

Can Whole Genome and Whole Transcriptome Sequencing Replace Standard Procedures in CLL Diagnostics?

Background: The advantages of genome-wide sequencing approaches over conventional methods in CLL diagnostics are a matter of debate and exact guidelines for the application of next-generation sequencing in a diagnostic context are currently missing. Aim: Compare the accuracy of whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) in determining the presence of point mutations, IGHV mutational status (IGHVms), and chromosomal aberrations to conventional procedures in a clinical setting. Patients and Methods: The cohort comprised 317 CLL patients. Diagnosis was established following WHO guidelines. WGS (100x, 2x151bp) and WTS (5x10 7 reads, 2x101bp) data were generated on NovaSeq instruments. For routine diagnostics, sequencing was carried out by Sanger or targeted panel sequencing (1500x, 2x101bp). Chromosome banding analysis (CBA) and FISH were available for 231 patients. WGS data were analyzed for chromosomal aberrations and copy number alterations using Manta and GATK. IGHVms was determined by Sanger sequencing and/or fragment analysis for 248 patients. Analysis of IGHVms was carried out using IgCaller (WGS) and MiXCR (WTS). Results: Comparing copy number variants (CNV) and balanced structural variants (SV) between CBA and WGS revealed a high concordance. In detail, 297 CNV were detected by both techniques while 32 and 52 were detected only by CBA (small subclones) or by WGS, respectively. 33 balanced SV were detected by both while 8 and 3 were detected only by CBA and WGS, respectively. A complex karyotype (≥ 3 abnormalities) was observed by both techniques in 55 cases, while 5 and 10 cases were categorized as complex by CBA only or WGS only, respectively. Survival analysis of cases with 3 to 5 chromosomal aberrations predicted by routine or WGS revealed similar hazard ratios that were positively correlated with the number of aberrations. For comparing SNV calls from routine and WGS, we investigated genes with validated mutations in at least ten patients in routine diagnostics. This criterion was met by ATM, MYD88, NOTCH1, SF3B1, and TP53. We observed high concordance between routine and WGS data ( ATM 99.4%, MYD88 100%, NOTCH1 97.8%, SF3B1 100%, TP53 99.1%). Five mutations were detected in routine only and three in WGS only (routine only/WGS only: ATM 1/0, MYD88 0/0, NOTCH1 2/2, SF3B1 0/0, TP53 2/1) and found to be caused by low variant allele frequency (5 miscalls, VAF < 5%) and/or filtering out of low quality variants (5 cases). IGHV rearrangements analyzed by Sanger (248 patients), WGS (242/248 patients), and WTS (236/248 patients) data were compared for matches in the rearranged IGHV. IGHVms calling employed 98% of sequence identity as cutoff. Calling the rearranged IGHV was concordant in 93%, 95%, and 92% when comparing Sanger/MiXCR, Sanger/IgCaller, and MiXCR/IgCaller calls, respectively. For IGHVms, the corresponding percentages of concordance were 91%, 86%, and 83%. Mismatches in calling the IGHVms were found in borderline cases. Detection of stereotyped IGHV was fully concordant. In addition to reliably replicating routine results, we find that WGS/WTS data can also outperform routine procedures. In our hands, the highest hazard ratio (4.94) in survival analysis distinguishing mutated CLL (mCLL) from unmutated CLL (uCLL) is observed using WTS for IGHVms determination and 97% sequence identity as cutoff (208 patients, up to 30 years follow up). Survival for borderline cases (97.00-97.99% sequence identity) was statistically indistinguishable from uCLL in routine diagnostics as well as WGS/WTS. Furthermore, using WGS, CN-LOH regions and deletions below the detection limit of CBA (10 MB) can be detected. We observed such regions in samples with mutated TP53 (5 CN-LOH), ATM (2 CN-LOH, 4 deletions < 10MB), and deletions of minimally overlapping region chr8:21,700,000-23,600,000, whose loss was associated with poor survival (3/29 deletions < 3.1 MB). Conclusions: WGS/WTS data reliably replicate results obtained by standard procedures in a diagnostic setting. Sequencing offers advantages such as a unified workflow, better sensitivity for small deletions, CN-LOH detection, genome-wide analyses of coding and non-coding mutations, among others. Challenges of short read based sequencing regard the detection limit for point mutations and specificity/sensitivity in detecting chromosomal aberrations.

2 years is a reasonable age cut-off level for prognostic assessment of children with hepatoblastoma.

We aimed to elucidate the prognostic significance of age in hepatoblastoma patients. Data from 783 patients with hepatoblastoma were obtained from the Surveillance, Epidemiology and End Results database (2000-2018). The best age cut-off level was determined by X-tile, and the Kaplan-Meier method was used to estimate overall survival (OS) and cancer-specific survival (CSS). The results of the X-tile were verified by selecting the appropriate cut-off value to maximize the difference in survival outcomes at intervals of 1 year. The Cox regression model was used to determine the prognostic impact of risk factors and age. X-tile analysis determined that 2 years was the best cut-off age for OS and CSS. The overall prognosis in the ≥ 2 years group was worse than that in the < 2 years group (OS: p = 0.00017; CSS: p < 0.0001). In Cox univariate analysis, when 2 years was used as the standard group, the numbers of patients in the two groups were similar, with high hazard ratio (HR) value and narrow 95% confidence interval (CI) (OS: HR, 1.834; 95% CI, 1.329 - 2.532; p < 0.001; CSS: HR, 1.988; 95% CI, 1.410 - 2.801; p < 0.001), which was consistent with the age cut-off point determined by X-tile. Cox multivariate analysis showed that age ≥ 2 years, black ethnicity, no surgery, no chemotherapy, distant metastasis, and tumor size ≥ 5 cm were independent predictors of poor OS and CSS. On subgroup analysis, patients aged ≥ 2 years had worse survival if they were Caucasian, had elevated alpha-fetoprotein, tumor size ≥ 5 cm, or distant metastasis. Age is an important prognostic factor for hepatoblastoma. Age ≥ 2 years at diagnosis may predict poor prognosis and more active treatment measures can be implemented.

Prognostic Utility of Skeletal Muscle Mass Metrics in Patients With Heart Failure.

Sarcopenia is associated with risks of various adverse outcomes, and the assessment of skeletal muscle mass is necessary for its diagnosis. However, heart failure (HF) is a syndrome characterised by fluid retention, which affects muscle mass measurements. Different measurement methods have been reported to have different prognostic implications. We investigated the association between skeletal muscle mass metrics measured with the use of bioelectrical impedance analysis (BIA) and anthropometric measures and prognosis in patients with HF. The findings of 869 consecutive patients with HF were reviewed. We investigated the skeletal muscle mass index (SMI) measured with the use of BIA, the mid-upper arm circumference (MUAC), the arm muscle circumference (AMC), and the calf circumference (CC), and the patients were divided into 3 groups according to the sex-specific tertiles of the skeletal muscle mass metrics. The end points were all-cause death and readmission due to HF. The high MUAC and AMC groups showed significantly better prognoses than their respective low groups (combined events: high MUAC group hazard ratio [HR] 0.559, 95% confidence interval [CI] 0.395-0.789 [P < 0.01]; high AMC group HR 0.505, 95% CI 0.359-0.710 [P < 0.01]), although high SMI and high CC were not associated with better prognoses. Among patients with HF, MUAC and AMC are more associated with prognosis than SMI and CC, which are recommended in preexisting sarcopenia guidelines. MUAC and AMC may also be useful measures in sarcopenia assessments.

Cuproptosis-related molecular patterns and gene (ATP7A) in hepatocellular carcinoma and their relationships with tumor immune microenvironment and clinical features.

Cuproptosis has been studied in various aspects as a new form of cell death. We hope to explore the molecular patterns and genes related to cuproptosis in evaluating and predicting the prognosis of hepatocellular carcinoma (HCC), as well as the impact of tumor immune microenvironment. Sixteen cuproptosis related gene (CRGs) and cuproptosis related molecular and gene characteristics were comprehensively analyzed from 492 HCC samples. Cuproptosis related molecular patterns were generated by consensus clustering algorithm, including cuproptosis clusters, cuproptosis gene clusters (CGC) and cuproptosis score (CS). The characteristics of tumor microenvironment (TME) and tumor immune cells were described by the ssGSEA and ESTIMATE algorithms. Cuproptosis score was established to assess the clinical characteristics, prognostic and immunotherapy. The role and mechanism of CRG (ATP7A) in HCC, as well as its relationship with TME and immune checkpoints, have been further explored. The results of somatic mutation, copy number variations (CNV), and CRGs expression in HCC suggested the CRGs might participate in the HCC oncogenesis. The cuproptosis clusters were closely related to the clinical pathological characteristics, biological processes, and prognosis of HCC. The three CGC was revealed to be consistent with the three immune infiltration characterizations, including immune-high, immune-mid, and immune-low subtypes. Higher CS was characterized by decreased TMB, activated immunity, higher immune cell proportion score (IPS) and better overall survival (OS), which indicated higher CS was immune-high type and with better treatment effect and prognosis. The ATP7A had the highest hazard ratio (HR = 1.465, p < .001), was high expression in HCC tissues and with a shorter 5-year OS. Knocking down ATP7A could enhance intracellular copper concentration, cause a decrease in DLAT expression, and induce cuproptosis and inhibit cell proliferation and migration. ATP7A was also positively correlated with most cancer immune cells and immune checkpoints. Taken together, this research revealed the cuproptosis related molecular patterns and genes associated with the clinical pathological characteristics, TME phenotype and prognosis of HCC. The CS will further deepen our understanding of the TME characteristics of HCC, and the involvement of ATP7A in cuproptosis will provide new ideas for predicting HCC prognosis and immunotherapy.

Prevalence and predictors of post-COVID-19 symptoms in general practice - a registry-based nationwide study

BackgroundWith Norwegian national registry data, we assessed the prevalence of post-COVID-19 symptoms at least 3 months after confirmed infection, and whether sociodemographic factors and pre-pandemic health problems were risk factors for these symptoms.MethodsAll persons with a positive SARS-CoV-2 PCR test from February 2020 to February 2021 (exposed) were compared to a group without a positive test (unexposed) matched on age, sex, and country of origin. We used Cox regression to estimate hazard ratios (HR) for 18 outcome symptoms commonly described as post-COVID-19 related, registered by GPs. We compared relative risks (RR) for fatigue, memory disturbance, or shortness of breath among exposed and unexposed using Poisson regression models, assessing sex, age, education, country of origin, and pre-pandemic presence of the same symptom and comorbidity as possible risk factors, with additional analyses to assess hospitalisation for COVID-19 as a risk factor among exposed.ResultsThe exposed group (N = 53 846) had a higher prevalence of most outcome symptoms compared to the unexposed (N = 485 757), with the highest risk for shortness of breath (HR 2.75; 95%CI 2.59–2.93), fatigue (2.08; 2.00-2.16) and memory disturbance (1.41;1.26–1.59). High HRs were also found for disturbance of smell/taste and hair loss, but frequencies were low. Concerning risk factors, sociodemographic factors were at large similarly associated with outcome symptoms in both groups. Registration of the outcome symptom before the pandemic increased the risk for fatigue, memory disturbance and shortness of breath after COVID-19, but these associations were weaker among exposed. Comorbidity was not associated with fatigue and shortness of breath in the COVID-19 group. For memory disturbance, the RR was slightly increased with the higher comorbidity score both among exposed and unexposed.ConclusionCOVID-19 was associated with a range of symptoms lasting more than three months after the infection.

Association of mineral and bone biomarkers with adverse cardiovascular outcomes and mortality in the German Chronic Kidney Disease (GCKD) cohort

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30–60 mL·min−1 per 1.73 m2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters (n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35–2.30), CV death (HR 2.18, 95% CI: 1.50–3.16), MACE (HR 1.38, 95% CI: 1.12–1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56–2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.

Modification of Association of Cystatin C With Kidney and Cardiovascular Outcomes by Obesity

Cystatin C-based estimated glomerular filtration rate (eGFRcys) has stronger associations with adverse clinical outcomes than creatinine-based eGFR (eGFRcr). Obesity may be associated with higher cystatin C levels, independent of kidney function, but it is unknown whether obesity modifies associations of eGFRcys with kidney and cardiovascular outcomes. Cohort study. 27,249 US adults in the Reasons for Geographic and Racial Differences in Stroke Study. eGFRcys, eGFRcr, waist circumference, and body mass index (BMI). All-cause mortality, kidney failure, incident atherosclerotic cardiovascular disease (ASCVD), and incident heart failure (HF). Multivariable Cox and Fine-Gray models with multiplicative interaction terms were constructed to investigate whether waist circumference quartiles or BMI categories modified associations of eGFRcys with risks of 4 clinical outcomes. Participants had a mean age of 65 years; 54% were women, 41% were Black, and 21% had an eGFRcys<60mL/min/1.73m2. The baseline prevalence of abdominal obesity (waist circumference≥88cm for women or≥102cm for men) was 48% and obesity was 38%. In multivariable adjusted analyses, each 15mL/min/1.73m2 lower eGFRcys was associated with higher HR and 95% CI of mortality in each waist circumference quartile (first quartile, 1.19 [1.15-1.24]; second quartile, 1.22 [1.18-1.26]; third quartile, 1.20 [1.16-1.24]; fourth quartile, 1.19 [1.15-1.23]) as well as within each BMI category (BMI<24.9: 1.21 [1.17-1.25]; BMI 25.0-29.9: 1.21 [1.18-1.25]; BMI 30.0-34.9: 1.20 [1.16-1.25]; BMI≥35: 1.17, [1.12-1.22]). Neither waist circumference nor BMI modified the association of eGFRcys with mortality, kidney failure, incident ASCVD, or incident HF (all Pinteraction>0.05). Included only Black and White persons in the United States. Obesity did not modify the association of eGFRcys with all-cause mortality, kidney failure, incident ASCVD, or incident HF. Among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes. Cystatin C is increasingly used in clinical practice to estimate kidney function, and cystatin C-based eGFR (eGFRcys) may be used to determine risk for adverse clinical outcomes. Adiposity may increase serum levels of cystatin C, independent of kidney function. This cohort study investigated whether associations of eGFRcys with adverse kidney and cardiovascular outcomes are modified by measures of obesity, waist circumference, and body mass index. We found that obesity does not modify associations of eGFRcys with 4 clinical outcomes and conclude that among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes.

Association of Central Nervous System-Affecting Medications With Occurrence and Short-Term Mortality of Traumatic Brain Injury.

The use of medications commonly prescribed after traumatic brain injury (TBI) has been little studied before TBI. This study examined the association between the use of medications that affect the central nervous system (CNS) and the occurrence and short-term mortality of TBI. Mandatory Finnish registries were used to identify TBI admissions, fatal TBIs, and drug purchases during 2005-2018. Patients with TBI were 1:1 matched to nontrauma control patients to investigate the association between medications and the occurrence of TBI and 30-day mortality after TBI. Number needed to harm (NNH) was calculated for all medications. The cohort included 59 606 patients with TBI and a similar number of control patients. CNS-affecting drugs were more common in patients with TBI than in controls [odds ratio = 2.07 (2.02-2.13), P < .001)]. Benzodiazepines were the most common type of medications in patients with TBI (17%) and in controls (11%). The lowest NNH for the occurrence of TBI was associated with benzodiazepines (15.4), selective serotonin uptake inhibitors (18.5), and second-generation antipsychotics (25.8). Eight percent of the patients with TBI died within 30 days. The highest hazard ratios (HR) and lowest NNHs associated with short-term mortality were observed with strong opioids [HR = 1.41 (1.26-1.59), NNH = 33.1], second-generation antipsychotics [HR = 1.36 (1.23-1.50), NNH = 37.1], and atypical antidepressants [HR = 1.17 (1.04-1.31), NNH = 77.7]. Thirty-seven percent of patients with TBI used at least 1 CNS-affecting drug. This proportion was significantly higher than in the control population (24%). The highest risk and lowest NNH for short-term mortality were observed with strong opioids, second-generation antipsychotics, and atypical antidepressants. The current risks underscore the importance of weighing the benefits and risks before prescribing CNS-affecting drugs in patients at risk of head injury.

Prediction of outcomes in patients with metabolic dysfunction-associated steatotic liver disease based on initial measurements and subsequent changes in magnetic resonance elastography.

The prognosis of metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with liver fibrosis. We aimed to investigate whether liver stiffness measurement (LSM) and changes in LSM (ΔLSM) on magnetic resonance elastography (MRE) can predict clinical events in patients with MASLD. We included 405 patients with MASLD who underwent at least two MREs. The patients were divided into five groups corresponding to fibrosis stages (0-4) based on initial LSM and classified as progressors (ΔLSM ≥ 19%) or non-progressors (ΔLSM < 19%) based on the difference between the first and last LSM. The mean follow-up period was 72.6months, and the mean interval between MREs was 23.5months. There were 52 (12.8%) progressors and 353 (87.2%) non-progressors. The initial LSM was significantly associated with the cumulative probabilities of decompensated cirrhosis, hepatocellular carcinoma (HCC), liver-related events, extrahepatic malignancies, and overall mortality but not with cardiovascular disease. Progressors had significantly higher hazard ratios (HRs) for decompensated cirrhosis, HCC, and liver-related events but not for extrahepatic malignancies, cardiovascular disease, or overall mortality. Among patients without cirrhosis, the HR for developing cirrhosis among progressors was 60.15. Progressors had a significantly higher risk of liver-related events, even in the low initial LSM (fibrosis stage 0-2) subgroups. Both initial LSM and ΔLSM can predict liver-related events in patients with MASLD, even for low initial LSM. This integrated assessment can allow more detailed risk stratification compared with single LSM assessments and identify high-risk patients with MASLD among those previously considered as low risk.

Tumor characteristics and survival rate of HER2-low breast cancer patients: a retrospective cohort study

HER2 is an important prognostic marker in breast cancer (BC) patients, which also plays a crucial role in their therapeutic plan. Consequently, a great desire is to thoroughly assess the patients based on their HER2 status. In the current study, we aimed to evaluate HER2-low breast cancer as a new subtype in the standard classification of BC patients and review its characteristics and survival rate in a tertiary center in Iran. We retrospectively evaluated disease-free survival (DFS), overall survival (OS), and clinicopathological characteristics of BC patients referred to the Cancer Research Center in Tehran, Iran from 1991 to 2022. Patients’ clinical characteristics, including HER2 status, which is classified as HER2-low, HER2-positive, or HER2-negative, were obtained from prospectively maintained registries. Among the total 3582 recruited patients, 60.2%, 13.6%, and 26.2% were HER2-negative, HER2-low, and HER2-positive, respectively. HER2-positive patients showed a significantly higher Hazard Ratio (HR) for DFS (HR 1.44, 95% CI 1.01–2.05) and OS (HR 2.05, 95% CI 1.31–3.20), compared to HER2-low. Moreover, HER2-low and HER2-negative were found to show the same proportion of high-grade tumors (28 and 28.4%), while 40% of the HER2-positive tumors were high-grade. Accordingly, HER2-low patients had a lower metastasis risk than the others (P-value = 0.01). The Ki67 percentage was significantly lower in the HER2-low group compared to the HER2-positive (P-value < 0.001). HER2-low, a new subtype of HER2-status classification with distinct biological and clinicopathological traits, represented the highest survival rate and less invasive characteristics. This difference was statistically significant when compared to HER2-positive, but not when compared to HER2-negative.Research registration unique identifying number: NCT05754047.

Identification of SYT10 as a potential prognostic biomarker in esophageal cancer by comprehensive analysis of a mRNA-pseudogene/lncRNA-miRNA ceRNA network

BackgroundEsophageal carcinoma (ESCA) is often diagnosed at the advanced stages, has a poor survival rate and overall is one of the deadliest cancers world-wide. Recent studies have elaborated the significance of non-coding RNAs such as pseudogenes, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in cancer progression. In this study, we constructed a four-component competing endogenous RNA (ceRNA) network in ECSA and suggested an RNA with prognostic potential. Materials and methodsExpression profiles of mRNAs, pseudogenes, lncRNAs and miRNAs were collected from The Cancer Genome Atlas (TCGA) database. A ceRNA network was then constructed based on the differentially-expressed RNAs (DERs). KEGG (Kyoto Encyclopedia of Genes and Genomes) and GO (Gene Ontology) functional analysis and PPI (Protein-Protein Interaction) network analysis was carried out on differentially-expressed (DE) mRNAs of the ceRNA network. Survival analysis was carried out on a selection of RNAs with the highest degree centrality ranks to discover potential prognostic biomarkers. ResultsA four-component ceRNA network with 529 nodes and 729 edges was constructed. The most significant GO biological process terms included positive regulation of transcription from RNA polymerase II promoter, negative regulation of transcription from RNA polymerase II promoter and positive regulation of transcription, DNA-templated. The analysis of KEGG pathways showed that DE mRNAs were significantly enriched in pathways such as pathways in cancer, PI3K-Akt signaling pathways and MicroRNAs in cancer. Among the RNAs that were found to be associated with survival, Synaptotagmin 10 (SYT10) had the highest hazard ratio and thus, proved to be a potential prognostic biomarker for ESCA. ConclusionOur study presented a four-component ceRNA network for ESCA, and identified RNA candidates that were associated with survival of ECSA. Further experimental evaluations and precise validation studies are needed for their clinical significance and roles in the progression of ESCA.

Alcohol consumption, smoking, and risk of dementia in community-dwelling Japanese people aged 40-74years: The Murakami cohort study.

Alcohol drinking and tobacco smoking have impacts on lifestyle-related diseases, but their association with dementia remains a debated topic. This study aimed to examine longitudinal associations between alcohol consumption, smoking, and dementia risk in middle-aged and older Japanese people. This study used a cohort design with an 8-year follow-up. Participants were community-dwelling Japanese people (N=13,802) aged 40-74years. The baseline survey, including a self-administered questionnaire, was conducted in 2011-2013. Predictors were alcohol consumption and tobacco smoking. The outcome was incident dementia obtained from a long-term care insurance database. Covariates were demographics, lifestyle factors, body mass index, general health status, and history of stroke, diabetes, and depression. Participant mean age was 59.0years. The 1-149, 150-299, and 300-449g ethanol/week groups had significantly lower adjusted hazard ratios (HRs) (0.62, 0.59, and 0.47, respectively) compared with the reference group, with no significant linear association. HRs increased toward 1 when past-drinkers and those with poor health status and a disease history were excluded (0.80, 0.66, and 0.82, respectively). Higher smoking levels were dose-dependently associated with a higher HR (adjusted P for trend=0.0105), with the ≥20 cigarettes/day group having a significantly higher adjusted HR (1.80). Heavy drinkers (≥449g ethanol/week) with smoking habits, but not those without smoking habits, had higher dementia risk (P for interaction=0.0046). Light-to-moderate alcohol consumption is associated with decreased dementia risk, and smoking is dose-dependently associated with increased dementia risk, with an interaction between high alcohol consumption and smoking on dementia risk.

Risk factors associated with overall survival in patients with multiple myeloma following carfilzomib treatment: A retrospective study from a large claims database in Japan.

Carfilzomib is a selective proteasome inhibitor approved for treating relapsed or refractory multiple myeloma (RRMM). Carfilzomib improves overall survival (OS) and progression-free survival (PFS); however, treatment with carfilzomib results in a higher incidence of cardiovascular and renal toxicity. More than 70% of patients with RRMM in clinical practice do not meet the eligibility criteria for randomized clinical trials (RCT). OS and PFS are negatively influenced by complications, concomitant medications and prior treatments. Therefore, we assessed the risk factors influencing the OS and time to next treatment (TTNT) in the real world. TTNT has emerged as a relevant alternative clinical endpoint to PFS. A retrospective analysis of a large claims database prepared during the post-marketing stages in Japan was performed. The patients treated with carfilzomib for the first time were identified. Multivariable Cox proportional hazards regression analysis was performed to evaluate the risk factors influencing OS and TTNT following carfilzomib treatment. A total of 732 patients with RRMM who received carfilzomib-containing chemotherapy between April 2014 and September 2021 were identified. Multivariable Cox regression analysis for OS and TTNT showed a significantly higher hazard ratio (HR) of 1.48 (95% confidence interval [Cl]: 1.10-2.00; p = 0.010) and 1.38 (95% Cl: 1.15-1.65; p < 0.001), respectively, for patients with renal impairment compared to those without renal impairment. Multivariable Cox regression analysis for OS and TTNT showed a significantly higher HR of 1.80 (95% Cl: 1.27-2.55; p = 0.0010) and 1.38 (95% Cl: 1.14-1.66; p < 0.001), respectively, for patients with prior lenalidomide treatment compared to those without prior lenalidomide treatment. Complication of renal impairment and prior lenalidomide treatment could be risk factors influencing OS and TTNT during carfilzomib treatment.

Noninfectious Uveitis Risk After COVID-19 Vaccination: A Nationwide Retrospective Cohort Study

To investigate the incidence and risk of noninfectious uveitis (NIU) following COVID-19 vaccination compared with an unvaccinated, uninfected control group. Retrospective population-based cohort study. We included 5,185,153 individuals who received the first vaccine dose in the exposed group and 2,680,164 individuals in the unexposed, uninfected control group. The study observed for 180 days from their index date. Cumulative incidence and risk of NIU following COVID-19 vaccination, and attributable risk factors were assessed. Multivariable analysis showed elevated risk of nonanterior NIU within 60 days (hazard ratio [HR] 1.27 [95% confidence interval {CI} 1.03-1.55] and 61-180 days (HR 1.39 [95% CI 1.20-1.62]). Subgroup analysis highlighted an increased risk in females for early and delayed nonanterior uveitis (HR 1.44 [95% CI 1.08-1.92]; HR 1.78 [95% CI 1.43-2.20], respectively). Regardless of the location and onset timing of uveitis, a history of NIU was identified as the most significant risk factor, with a high hazard ratio ranging from 100 to 200. COVID-19 vaccination may modestly increase the risk of nonanterior uveitis especially in females. Despite adjustments, bias may persist in the exposed group, owing to significant differences between unexposed and exposed groups and low incidence of nonanterior uveitis in the unexposed group. Future research should aim to refine these findings by assessing uveitis risk in prior NIU patients and by enlarging the sample size or cohort matching.

B7-H3 and CD47 co-expression in gastric cancer is a predictor of poor prognosis and potential targets for future dual-targeting immunotherapy.

Gastric cancer (GC) is one of the most prevalent types of cancer worldwide. B7-H3, an immune checkpoint molecule with promising potential, has been found to be overexpressed in various cancers. CD47 is an anti-phagocytic molecule that interacts with the signal regulatory protein alpha (SIRPα) to affect phagocytes. The relationship between the expression of B7-H3 and CD47, two potential therapeutic targets found in tumor cells, remains unknown. In this study, our objective is to investigate the clinical significance of co-expression of B7-H3 and CD47, as well as the potential therapeutic value of combination therapy in GC. We utilized immunohistochemistry (IHC) to assess the expression of B7-H3, CD47, CD68, CD86 and CD163 in tissue microarrays obtained from 268 GC patients who underwent surgeries. Western blotting was employed to assess the protein level of B7-H3 and CD47 in GC tissues. The co-localization of B7-H3/CD47 and CD68 in GC tissues was determined using multiplex immunohistochemistry (m-IHC). We further verified the relationship between B7-H3/CD47 and macrophage infiltration via flow cytometry. To estimate the clinical outcomes of patients from different subgroups, we employed the Kaplan-Meier curve and the Cox model. Among the 268 GC cases, a total of 180 cases exhibited positive expression of B7-H3, while 122 cases showed positive expression of CD47. In fresh GC clinical tissues, B7-H3 and CD47 protein level was also higher in tumor tissue than in adjacent normal tissue. Remarkably, 91 cases demonstrated co-expression of B7-H3 and CD47. We observed a significant correlation between B7-H3 expression and tumor stage (P = 0.001), differentiation (P = 0.045), and depth (P = 0.003). Additionally, there was a significant association between B7-H3 and CD47 expression (P = 0.018). The percentage of B7-H3 and CD47 double positive cells in fresh GC tumor tissues were elevated compared with control adjacent tissues regardless of CD45- or CD45+ cells (P = 0.0029, P = 0.0012). Patients with high B7-H3 or CD47 expression had significantly lower overall survival (OS) rates compared to those with low expression levels (P = 0.0176 or P = 0.0042). Surprisingly, patients with combined high expression of B7-H3 and CD47 exhibited a considerably worse prognosis than others (P = 0.0007). Univariate analysis revealed that cases with high expression of B7-H3, CD47, or both had significantly higher hazard ratios (HR) than cases with low expression of these markers. Furthermore, the results of multivariate analysis indicated that B7-H3/CD47 co-expression and CD47 expression alone are independent prognostic factors for overall survival. Moreover, significant correlations were observed between B7-H3 and CD68 expression, CD47 and CD68 expression, as well as B7-H3/CD47 co-expression and CD68 expression in GC patients (P < 0.001, P = 0.003, and P < 0.001). Flow cytometry test showed that the percentage of CD68-positive cells but not CD86-positive cells among B7-H3-positive or CD47-positive immune cells in GC tumor tissue was elevated significantly compared with adjacent tissue. Our findings demonstrated a correlation between B7-H3 expression and CD47 expression in GC patient tissues. Co-expression of B7-H3 and CD47 can serve as an indicator of poor prognosis in GC patients. In GC tumor tissue, but not adjacent tissue, B7-H3 and CD47 expression was accompanied with macrophage infiltration.

Impact of preoperative red blood cell transfusion on long-term mortality of liver transplantation: A retrospective cohort study.

Preoperative red blood cell (RBC) transfusion can induce immune modulation and alloimmunization; however, few studies have investigated the effect of preoperative transfusion and hemoglobin levels that need to be corrected before surgery, especially in critically ill patients such as those with end-stage liver disease who undergo liver transplantation (LT). This study aimed to investigate the effects of preoperative RBC transfusion on long-term mortality in LT recipients. A total of 249 patients who underwent LT at a single center between January 2012 and December 2021 were included in this study. The patients were divided into 2 groups: preoperative transfusion and preoperative non-transfusion. Since the baseline characteristics were significantly different between the 2 groups, we performed propensity score matching, including factors such as the Model for End-Stage Liver Disease score and intraoperative RBC transfusion, to exclude possible biases that could affect prognosis. We analyzed the 5-year mortality rate as the primary outcome. The preoperative transfusion group showed a 4.84-fold higher hazard ratio than that in the preoperative non-transfusion group. There were no differences in 30-day mortality, duration of intensive care unit stay, or graft rejection rate between the 2 groups. Preoperative transfusion could influence long-term mortality in LT, and clinicians should pay attention to RBC transfusion before LT unless the patient is hemodynamically unstable. A large-scale randomized controlled trial is needed to determine the possible mechanisms related to preoperative RBC transfusion, long-term mortality, and the level of anemia that should be corrected before surgery.

Prediction of prognosis, immune infiltration, and personalized treatment of hepatocellular carcinoma by analysis of cuproptosis-related long noncoding RNAs and verification in vitro.

The correlations between cuproptosis and long noncoding RNAs (lncRNAs) with the tumor microenvironment (TME), immunotherapy, and some other characteristics of hepatocellular carcinoma (HCC) remain unclear. Sixteen cuproptosis regulators and 356 cuproptosis-related lncRNAs (CRLnc) were identified from 374 HCC profiles in The Cancer Genome Atlas (TCGA) database. Six differentially expressed CRLnc were selected, and a prognostic risk model based on the CRLnc signature (CRLncSig) was constructed. The prognostic power of the model was verified. Moreover, a cuproptosis-related gene cluster (CRGC) was generated based on six lncRNAs and differentially expressed genes. The relationship between immune cell infiltration in the TME, immunotherapy, CRLncSig, and CRGC was demonstrated through various algorithms, Tumor Immune Dysfunction and Exclusion (TIDE), tumor mutational burden (TMB), etc. Potential drugs and sensitivity to those agents were evaluated for the risk model. LncRNA AL158166.1 was selected and verified in HCC tissues and cell lines, the impact of its knockdown and overexpression in HCC cells was examined, and the copper (Cu) concentration and the cuproptosis-related gene expression were detected. A CRLncSig prognostic risk model with good predictive ability was constructed. The low-risk group had a longer overall survival (OS), lower tumor purity, more extensive immune cell infiltration, higher immune score, enrichment in immune-activated pathways, and more positive response to immunotherapy versus the high-risk group. CRGC-B exhibited the best OS and the lowest tumor stage; the immune cell infiltration analysis was similar to the low-risk group in CRLncSig. CRGC-B belonged to the "immune-high" group of the TME. The low-risk group had a higher TIDE score and susceptibility to antitumor drugs. The lncRNA AL158166.1 had the highest hazard ratio. The levels of AL158166.1 were higher in HCC tissues versus healthy tissues. Knockdown of AL158166.1 could lead to an increase in intracellular Cu concentration, induce DLAT low expression, and inhibit the proliferation and migration of HCC cells, whereas overexpression of AL158166.1 exerted the reverse effect. Overall, a new CRLncSig prognostic risk model and a cuproptosis-related molecular signature were constructed and evaluated. The model and signature were associated with the prognosis, immune infiltration, and immunotherapy of HCC. Inhibiting the lncRNA AL158166.1 may induce cuproptosis and showed potential for the inhibition of tumors. Evaluation of the CRLnc, CRLncSig, and CRGC may enhance our understanding of the TME, determine the effectiveness of immunotherapy, and act as a marker for the prognosis of HCC.

Evaluation of a 3-Item Health Index in Predicting Mortality Risk: A 12-Year Follow-Up Study.

This study was carried out using a large cohort (N = 4265; 416 deceased) of older, community-dwelling adults from The Irish Longitudinal Study on Ageing (TILDA). The study compared the performance of a new 3-item health index (HI) with two existing measures, the 32-item frailty index (FI) and the frailty phenotype (FP), in predicting mortality risk. The HI was based on the objective measurement of resting-state systolic blood pressure sample entropy, sustained attention reaction time performance, and usual gait speed. Mortality data from a 12-year follow up period were analyzed using Cox proportional regression. All data processing was performed using MATLAB and statistical analysis using STATA 15.1. The HI showed good discriminatory power (AUC = 0.68) for all-cause mortality, similar to FI (AUC = 0.68) and superior to FP (AUC = 0.60). The HI classified participants into Low-Risk (84%), Medium-Risk (15%), and High-Risk (1%) groups, with the High-Risk group showing a significant hazard ratio (HR) of 5.91 in the unadjusted model and 2.06 in the fully adjusted model. The HI also exhibited superior predictive performance for cardiovascular and respiratory deaths (AUC = 0.74), compared with FI (AUC = 0.70) and FP (AUC = 0.64). The HI High-Risk group had the highest HR (15.10 in the unadjusted and 5.61 in the fully adjusted models) for cardiovascular and respiratory mortality. The HI remained a significant predictor of mortality even after comprehensively adjusting for confounding variables. These findings demonstrate the effectiveness of the 3-item HI in predicting 12-year mortality risk across different causes of death. The HI performed similarly to FI and FP for all-cause mortality but outperformed them in predicting cardiovascular and respiratory deaths. Its ability to classify individuals into risk groups offers a practical approach for clinicians and researchers. Additionally, the development of a user-friendly MATLAB App facilitates its implementation in clinical settings. Subject to external validation in clinical research settings, the HI can be more useful than existing frailty measures in the prediction of cardio-respiratory risk.

Bone Mineral Density and the Risk of Parkinson's Disease in Postmenopausal Women.

Whether bone mineral density (BMD) is related to the risk of Parkinson's disease (PD) is unclear. The objective of this study was to examine the association between BMD status and incident PD in postmenopausal women. We retrospectively examined a nationwide cohort of 272,604 women aged 66 years who participated in the 2009-2012 Korean national health screening for transitional ages. BMD was evaluated using dual-energy X-ray absorptiometry of the central bones. The use of antiosteoporosis medications (AOMs) was assessed. We performed multivariable Cox proportional hazards regression to evaluate the association between BMD and PD risk by calculating hazardratios (HRs) and 95% confidence intervals (CIs). During the median follow-up of 7.7 years, 2,884 (1.1%) incident PD cases developed. After adjusting for confounding factors, lower BMD was associated with an increased risk of PD (P for trend <0.001). Individuals with osteoporosis had a 1.40-fold higher HR (1.40, 95% CI: 1.25-1.56) than those with a normal BMD. Sensitivity analyses suggested the associations robust to longer lag periods and further adjustment. These associations were prominent in individuals without AOM use before or after enrollment (P for interaction = 0.031 and 0.014). Increased risks of PD in individuals with osteopenia and osteoporosis who did not use AOMs were attenuated by the medication use during the follow-up period, regardless of previous AOM use. Lower postmenopausal BMD and osteoporosis were associated with an increased risk of PD. In addition, this association could be mitigated using AOMs. Proper management of BMD in postmenopausal women may help prevent PD. © 2023 International Parkinson and Movement Disorder Society.