Association of Metabolic Syndrome and Albuminuria with Cardiovascular Risk in Occupational Drivers

Background and Aim

Metabolic syndrome (MetS) and albuminuria increase cardiovascular risk. However, in occupational drivers, the clinical significance of albuminuria and its association with MetS remain unclear. We investigated the prevalence of MetS, albuminuria and cardiovascular risk, and its associated risk factors in occupational drivers;

Methods

441 occupational drivers and 432 age- and sex-stratified matched counterpart controls were enrolled. MetS was defined using Adult Treatment Panel III for Asians. Albuminuria was defined as urine albumin-to-creatinine ratio ≥ 30 mg/g. Cardiovascular disease risk was evaluated by Framingham Risk Score (FRS);

Results

A significantly higher prevalence of MetS (43.1% vs. 25.5%, p < 0.001), albuminuria (12.0% vs. 5.6%, p = 0.001) and high FRS risk ≥ 10% of 10-year risk (46.9% vs. 35.2%, p < 0.001) was found in occupational drivers compared with their counterpart controls. Multiple logistic regression analysis showed that old age, a history of diabetes, gout and betel nut chewing, less exercise and albuminuria (odds ratio [OR], 2.75; p = 0.01) were risk factors for MetS, while a history of renal disease, diabetes and hypertension, and MetS (OR, 2.28; p = 0.01) were risk factors for albuminuria in occupational drivers;

Conclusions

Our study demonstrated that MetS and albuminuria were public health problems in occupational drivers. An education program for promoting healthy lifestyle and a regular occupational health visit for early detection and interventions should be established.     

Long-Term Adverse Effect of Liver Stiffness on Glycaemic Control in Type 2 Diabetic Patients with Nonalcoholic Fatty Liver Disease: A Pilot Study

Currently, there are limited data regarding the long-term effect of liver stiffness on glycaemic control in patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). We prospectively followed an outpatient sample of 61 consecutive postmenopausal women with T2DM and NAFLD who had baseline data on liver ultrasonography and Fibroscan^®-assessed liver stiffness measurement (LSM) in 2017 and who underwent follow-up in 2022. Haemoglobin A1c (HbA1c) was measured both at baseline and follow-up. At baseline, 52 patients had NAFLD (hepatic steatosis) alone, and 9 had NAFLD with coexisting clinically significant fibrosis (defined as LSM ≥ 7 kPa on Fibroscan^®). At follow-up, 16 patients had a worsening of glycaemic control (arbitrarily defined as HbA1c increase ≥ 0.5% from baseline). The prevalence of NAFLD and coexisting clinically significant fibrosis at baseline was at least three times greater among patients who developed worse glycaemic control at follow-up, compared with those who did not (31.3% vs. 8.9%; p = 0.030). In logistic regression analysis, the presence of NAFLD and clinically significant fibrosis was associated with an approximately 4.5-fold increased likelihood of developing worse glycaemic control at follow-up (odds ratio 4.66, 95% confidence interval 1.07–20.3; p = 0.041), even after adjustment for baseline confounding factors, such as age, body mass index, haemoglobin A1c (or HOMA-estimated insulin resistance) and use of some glucose-lowering agents that may positively affect NAFLD and liver fibrosis. In conclusion, our results suggest that the presence of Fibroscan^®-assessed significant fibrosis was associated with a higher risk of developing worse glycaemic control in postmenopausal women with T2DM and NAFLD.     

Associations between Endogenous Dimethylarginines and Renal Function in Healthy Children and Adolescents

The structural isomer of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), is eliminated almost entirely by urinary excretion and considered a sensitive index of glomerular filtration rate (GFR). However, reports on this relationship in healthy subjects younger than 18 years of age are rare. Therefore, our aim was to investigate relations between endogenous dimethylarginines and renal function indices in healthy children and adolescents. We studied 40 subjects aged 3–18 years free of coexistent diseases or subclinical carotid atherosclerosis. A serum creatinine-derived estimated GFR (eGFR) was calculated by the revised bedside Schwartz equation. L-arginine, ADMA and SDMA were measured by liquid chromatography-tandem mass spectrometry. Mean eGFR was 122 ± 22 (SD) mL/min per 1.73 m². Creatinine and eGFR exhibited closer correlations with the SDMA/ADMA ratio (r = 0.64, p < 0.0001; r = −0.63, p < 0.0001, respectively) than with SDMA (r = 0.31, p = 0.05; r = −0.35, p = 0.03). Neither creatinine nor eGFR correlated with ADMA or L-arginine. Adjustment for age or height only slightly attenuated the associations between the SDMA/ADMA ratio and eGFR or creatinine. Our findings suggest the superiority of the SDMA/ADMA ratio over SDMA as a renal function index in healthy children. Thus, further studies are warranted to verify our preliminary results in a larger group of subjects below 18 years of age.     

Effect of Hepatitis C Virus Genotype 1b Core and NS5A Mutations on Response to Peginterferon Plus Ribavirin Combination Therapy

We examined whether hepatitis C virus (HCV) genotype 1b core- and NS5A-region mutations are associated with response to peginterferon α-2b plus ribavirin combination therapy. A total of 103 patients with high HCV genotype 1b viral loads (≥100 KIU/mL) were treated with the combination therapy. Pretreatment mutations in the core region and interferon sensitivity determining region (ISDR) in the NS5A region were analyzed. In univariate analysis, arginine and leucine at positions 70 and 91 in the core region, defined as double wild (DW)-type, were associated with early virologic response (p = 0.002), sustained virologic response (SVR) (p = 0.004), and non-response (p = 0.005). Non-threonine at position 110 was associated with SVR (p = 0.004). Multivariate analysis showed the following pretreatment predictors of SVR: hemoglobin level ≥ 14 g/dL (odds ratio (OR) 6.2, p = 0.04); platelet count ≥ 14 × 10⁴/mm³ (OR 5.2, p = 0.04); aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio < 0.9 (OR 6.17, p = 0.009); DW-type (OR 6.8, p = 0.02); non-threonine at position 110 (OR 14.5, p = 0.03); and ≥2 mutations in the ISDR (OR 12.3, p = 0.02). Patients with non-DW-type, non-threonine at position 110, and <2 ISDR mutations showed significantly lower SVR rates than others (11/45 (24.4%) vs. 27/37 (73.0%), respectively; p < 0.001). SVR can be predicted through core and NS5A region mutations and host factors like hemoglobin, platelet count, and AST/ALT ratio in HCV genotype 1b-infected patients treated with peginterferon and ribavirin combination therapy.     

Immunosenescence in Aging-Related Vascular Dysfunction

The immunosenescence-related disproportion in T lymphocytes may have important consequences for endothelial dysfunction, which is a key event in vascular aging. The study was designed to assess the prognostic values of the inflammatory-immune profile to better predict and prevent vascular diseases associated with old age. Eighty individuals aged 70.9 ± 5.3 years were allocated to a low- (LGI) or high-grade inflammation (HGI) group based on CRP (<3 or ≥3 mg/L) as a conventional risk marker of cardiovascular diseases. Significant changes in inflammatory and endothelium-specific variables IL-1β, IL-6, TNFα, oxLDL, H₂O₂, NO, 3-nitrotyrosine, and endothelial progenitor cells (OR 7.61, 95% CI 2.56–29.05, p < 0.0001), confirmed their interplay in vascular inflammation. The flow-cytometry analysis demonstrated a high disproportion in T lymphocytes CD4⁺ and CD8⁺ between LGI and HGI groups. CRP was <3 mg/mL for the CD4/CD8 ratio within the reference values ≥ 1 or ≤2.5, unlike for the CD4/CD8 ratio < 1 and >2.5. The odds ratios for the distribution of CD4⁺ (OR 5.98, 95% CI 0.001–0.008, p < 0.001), CD8⁺ (OR 0.23, 95% CI 0.08–0.59, p < 0.01), and CD8CD45RO⁺ T naïve cells (OR 0.27, 95% CI 0.097–0.695, p < 0.01) and CD4/CD8 (OR 5.69, 95% CI 2.07–17.32, p < 0.001) indicated a potential diagnostic value of T lymphocytes for clinical prognosis in aging-related vascular dysfunction.     

Preserved Sleep for the Same Level of Respiratory Disturbance in Children with Prader-Willi Syndrome

Debate remains as to how to balance the use of recombinant human growth hormone (rhGH) as an important treatment in Prader-Willi syndrome (PWS) with its potential role in obstructive sleep apnea. This single-center, retrospective study assessed differences in overnight polysomnography results between children with and without PWS and changes in respiratory parameters before and after the initiation of rhGH treatment in those with PWS. Compared with age-, sex-, and body-mass-index-matched controls (n = 87), children with PWS (n = 29) had longer total sleep time (434 ± 72 vs. 365 ± 116 min; p < 0.01), higher sleep efficiency (86 ± 7 vs. 78 ± 15%; p < 0.05), and lower arousal events (8.1 ± 4.5 vs. 13.0 ± 8.9 events/h; p < 0.05). Mean oxygen saturation was lower in PWS children (94.3 ± 6.0 vs. 96.0 ± 2.0%; p < 0.05), with no other differences in respiratory parameters between groups. Eleven children with PWS (38%) met the criteria for further analyses of the impact of rhGH; polysomnography parameters did not change with treatment. Compared with other children undergoing polysomnography, children with PWS had more favorable markers of sleep continuity and lower oxygen saturation for the same level of respiratory disturbance. rhGH administration was not associated with changes in respiratory parameters in PWS.     

Accuracy of FIB-4 to Detect Elevated Liver Stiffness Measurements in Patients with Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study in Referral Centers

The identification of advanced fibrosis by applying noninvasive tests is still a key component of the diagnostic algorithm of NAFLD. The aim of this study is to assess the concordance between the FIB-4 and liver stiffness measurement (LSM) in patients referred to two liver centers for the ultrasound-based diagnosis of NAFLD. Fibrosis 4 Index for Liver Fibrosis (FIB-4) and LSM were assessed in 1338 patients. A total of 428 (32%) had an LSM ≥ 8 kPa, whereas 699 (52%) and 113 (9%) patients had an FIB-4 < 1.3 and >3.25, respectively. Among 699 patients with an FIB-4 < 1.3, 118 (17%) had an LSM ≥ 8 kPa (false-negative FIB-4). This proportion was higher in patients ≥60 years, with diabetes mellitus (DM), arterial hypertension or a body mass index (BMI) ≥ 27 kg/m². In multiple adjusted models, age ≥ 60 years (odds ratio (OR) = 1.96, 95% confidence interval (CI) 1.19–3.23)), DM (OR = 2.59, 95% CI 1.63–4.13), body mass index (BMI) ≥ 27 kg/m² (OR = 2.17, 95% CI 1.33–3.56) and gamma-glutamyltransferase ≥ 25 UI/L (OR = 2.68, 95% CI 1.49–4.84) were associated with false-negative FIB-4. The proportion of false-negative FIB-4 was 6% in patients with none or one of these risk factors and increased to 16, 31 and 46% among those with two, three and four concomitant risk factors, respectively. FIB-4 is suboptimal to identify patients to refer to liver centers, because about one-fifth may be false negative at FIB-4, having instead an LSM ≥ 8 KPa.     

Atherogenic Plasma Index or Non-High-Density Lipoproteins as Markers Best Reflecting Age-Related High Concentrations of Small Dense Low-Density Lipoproteins

The study aimed to assess the strength of the relationships between small dense low-density lipoproteins (sdLDL) and other parameters describing metabolic disorders and determine which of the lipid profile parameters can be used as markers of increased sdLDL concentration. The proposed model of sdLDL (examined by heparin–magnesium precipitation method) as a function of lipid parameters and atherogenic plasma indexes non-high-dense lipoproteins (non-HDL) and total cholesterol to high-dense lipoprotein ratio (TC/HDL), Atherogenic plasma index (API) is based on data from 485 participants divided into two age groups, <35≥ years. In multiple linear regression, sdLDL concentration was associated with the concentration of non-HDL-C (p = 0.043) and API value (p < 0.001) in participants <35 years, and with non-HDL-C (p < 0.001) and triglycerides (p = 0.020) concentration ≥35 years. The presence of abnormal values of API in participants <35 years and non-HDL-C in participants ≥35 years is a significant factor increasing the chances of the highest sdLDL (≥1.03 mmol/L) corresponding to Q4 in people without metabolic disorders. Different lipid parameters and atherogenicity indexes are associated with a high concentration of sdLDL depending on the age group. Abnormal API <35 years and non-HDL ≥35 years are associated with the highest sdLDL values and may be an indication for further specialist diagnosis of cardiovascular disease risk factors.     

Deep Transcranial Magnetic Stimulation Affects Gut Microbiota Composition in Obesity: Results of Randomized Clinical Trial

Growing evidence highlights the crucial role of gut microbiota in affecting different aspects of obesity. Considering the ability of deep transcranial magnetic stimulation (dTMS) to modulate the cortical excitability, the reward system, and, indirectly, the autonomic nervous system (ANS), we hypothesized a potential role of dTMS in affecting the brain-gut communication pathways, and the gut microbiota composition in obesity. In a hospital setting, 22 subjects with obesity (5 M, 17 F; 44.9 ± 2.2 years; BMI 37.5 ± 1.0 kg/m²) were randomized into three groups receiving 15 sessions (3 per week for 5 weeks) of high frequency (HF), low frequency (LF) dTMS, or sham stimulation. Fecal samples were collected at baseline and after 5 weeks of treatment. Total bacterial DNA was extracted from fecal samples using the QIAamp DNA Stool Mini Kit (Qiagen, Italy) and analyzed by a metagenomics approach (Ion Torrent Personal Genome Machine). After 5 weeks, a significant weight loss was found in HF (HF: −4.1 ± 0.8%, LF: −1.9 ± 0.8%, sham: −1.3 ± 0.6%, p = 0.042) compared to LF and sham groups, associated with a decrease in norepinephrine compared to baseline (HF: −61.5 ± 15.2%, p < 0.01; LF: −31.8 ± 17.1%, p < 0.05; sham: −35.8 ± 21.0%, p > 0.05). Furthermore, an increase in Faecalibacterium (+154.3% vs. baseline, p < 0.05) and Alistipes (+153.4% vs. baseline, p < 0.05) genera, and a significant decrease in Lactobacillus (−77.1% vs. baseline, p < 0.05) were found in HF. Faecalibacterium variations were not significant compared to baseline in the other two groups (LF: +106.6%, sham: +27.6%; p > 0.05) as well as Alistipes (LF: −54.9%, sham: −15.1%; p > 0.05) and Lactobacillus (LF: −26.0%, sham: +228.3%; p > 0.05) variations. Norepinephrine change significantly correlated with Bacteroides (r² = 0.734; p < 0.05), Eubacterium (r² = 0.734; p < 0.05), and Parasutterella (r² = 0.618; p < 0.05) abundance variations in HF. In conclusion, HF dTMS treatment revealed to be effective in modulating gut microbiota composition in subjects with obesity, reversing obesity-associated microbiota variations, and promoting bacterial species representative of healthy subjects with anti-inflammatory properties.     

Relationship between Serum Osteocalcin Levels and Non-Alcoholic Fatty Liver Disease in Adult Males,South China

AIM

To determine serum osteocalcin levels in South Chinese males with non-alcoholic fatty liver disease (NAFLD) and to examine the relation between serum osteocalcin and NAFLD.

METHODS

Data were collected from 1683 men attending the Fangchenggang Area Male Healthy and Examination Survey (FAMHES) from September 2009 to December 2009. Serum osteocalcin was measured with electrochemiluminescence immunoassay. An abdominal ultrasonographic examination for all individuals was performed by two experienced ultrasonographers. The associations of serum osteocalcin with NAFLD were evaluated.

RESULTS

The levels of serum osteocalcin were lower in 364 NAFLD participants than in 1319 non-NAFLD participants (24.51 ± 1.38 ng/mL vs. 20.81 ± 1.33 ng/mL, p < 0.001). Serum osteocalin level was associated with the scale of NAFLD (r = −0.150, p < 0.01). Serum osteocalin level tended to decrease with the scale of NAFLD. Binary logistic regression analysis showed that decreased ORs for NAFLD were observed from the first to the fourth osteocalcin quartiles.

CONCLUSIONS

Our findings suggest that a lower serum osteocalcin level is associated with the presence of NAFLD.     

PD-L1 Expression in Non-Small Cell Lung Cancer Specimens: Association with Clinicopathological Factors and Molecular Alterations

Immune checkpoint inhibitors (ICI) targeting programmed cell death-1 or its ligand (PD-L1) have improved outcomes in non-small cell lung cancer (NSCLC). High tumor PD-L1 expression, detected by immunohistochemistry (IHC) typically on formalin-fixed paraffin-embedded (FFPE) histological specimens, is linked to better response. Following our previous investigation on PD-L1 in cytological samples, the aim of this study was to further explore the potential impacts of various clinicopathological and molecular factors on PD-L1 expression. Two retrospective NSCLC cohorts of 1131 and 651 specimens, respectively, were investigated for PD-L1 expression (<1%/1–49%/≥50%), sample type, sample site, histological type, and oncogenic driver status. In both cohorts, PD-L1 was positive (≥1%) in 55% of the cases. Adenocarcinomas exhibited lower PD-L1 expression than squamous cell carcinomas (p < 0.0001), while there was no difference between sample types, tumor locations, or between the two cohorts in multivariate analysis (all p ≥ 0.28). Mutational status correlated significantly with PD-L1 expression (p < 0.0001), with the highest expression for KRAS-mutated cases, the lowest for EGFR-mutated, and the KRAS/EGFR wild-type cases in between. There was no difference in PD-L1 levels between different prevalent KRAS mutations (all p ≥ 0.44), while mucinous KRAS-mutated adenocarcinomas exhibited much lower PD-L1 expression than non-mucinous (p < 0.0001). Our data indicate that cytological and histological specimens are comparable for PD-L1 evaluation. Given the impact of KRAS mutations and the mucinous growth pattern on PD-L1 expression, these factors should be further investigated in studies on ICI response.     

Ficolin-2 Plasma Level Assesses Liver Fibrosis in Non-Alcoholic Fatty Liver Disease

Fibrosis is the strongest predictor for disease-specific mortality in non-alcoholic fatty liver diseases (NAFLD), but the need for liver biopsy limits its diagnosis. We assessed the performance of plasma ficolin-2 (FCN-2) as a biomarker of fibrosis identified by an in silico discovery strategy. Two hundred and thirty-five morbidly obese (MO) subjects with biopsy-proven NAFLD stratified by fibrosis stage (F0, n = 44; F1, n = 134; F2, n = 46; F3/F4, n = 11) and 40 cirrhotic patients were enrolled. The cohort was subdivided into discovery (n = 76) and validation groups (n = 159). The plasma level of FCN-2 and other candidate markers was determined. FCN-2 was inversely correlated with the stage of liver fibrosis (ρ = −0.49, p < 0.001) independently of steatosis (p = 0.90), inflammation (p = 0.57), and ballooning (p = 0.59). In the global cohort, FCN-2 level decreased significantly in a stepwise fashion from F0/F1 (median 4753 ng/mL) to F2–F3–F4 (2760 ng/mL) and in cirrhotic subjects (1418 ng/mL). The diagnostic performance of FCN-2 in detecting F ≥ 2 was higher than other indexes (APRI, FIB-4) (AUROC 0.82, 0.68, and 0.6, respectively). The accuracy improved when combined with APRI score and HDL values (FCNscore, AUROC 0.85). Overall, the FCN-2 plasma level can accurately discriminate liver fibrosis status (minimal vs. moderate/advanced) significantly improving the fibrosis diagnostic algorithms.     

Impact of Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein in Patients with Hepatitis C Virus-Related Compensated Liver Cirrhosis

We aimed to examine the effect of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA⁺-M2BP) level on survival comparing with other laboratory liver fibrosis markers in hepatitis C virus (HCV)-related compensated liver cirrhosis (LC) (n = 165). For assessing prognostic performance of continuous fibrosis markers, we adapted time-dependent receiver operating characteristics (ROC) curves for clinical outcome. In time-dependent ROC analysis, annual area under the ROCs (AUROCs) were plotted. We also calculated the total sum of AUROCs in all time-points (TAAT score) in each fibrosis marker. WFA⁺-M2BP value ranged from 0.66 cutoff index (COI) to 19.95 COI (median value, 5.29 COI). Using ROC analysis for survival, the optimal cutoff point for WFA⁺-M2BP was 6.15 COI (AUROC = 0.79348, sensitivity = 80.0%, specificity = 74.78%). The cumulative five-year survival rate in patients with WFA⁺-M2BP ≥ 6.15 COI (n = 69) was 43.99%, while that in patients with WFA⁺-M2BP < 6.15 COI (n = 96) was 88.40% (p < 0.0001). In the multivariate analysis, absence of hepatocellular carcinoma (p = 0.0008), WFA⁺-M2BP < 6.15 COI (p = 0.0132), achievement of sustained virological response (p < 0.0001) and des-γ-carboxy prothrombin < 41 mAU/mL (p = 0.0018) were significant favorable predictors linked to survival. In time-dependent ROC analysis in all cases, WFA⁺-M2BP had the highest TAAT score among liver fibrosis markers. In conclusion, WFA⁺-M2BP can be a useful predictor in HCV-related compensated LC.     

IL-17 Pathway Members as Potential Biomarkers of Effective Systemic Treatment and Cardiovascular Disease in Patients with Moderate-to-Severe Psoriasis

Psoriasis is a chronic inflammatory condition associated with atherosclerotic cardiovascular disease (CVD). Systemic anti-psoriatic treatments mainly include methotrexate and biological therapies targeting TNF, IL-12/23 and IL-17A. We profiled plasma proteins from patients with moderate-to-severe psoriasis to explore potential biomarkers of effective systemic treatment and their relationship to CVD. We found that systemically well-treated patients (PASI < 3.0, n = 36) had lower circulating levels of IL-17 pathway proteins compared to untreated patients (PASI > 10, n = 23). Notably, IL-17C and PI3 were decreased with all four examined systemic treatment types. Furthermore, in patients without CVD, we observed strong correlations among IL-17C/PI3/PASI (r ≥ 0.82, p ≤ 1.5 × 10⁻¹²) pairs or between IL-17A/PASI (r = 0.72, p = 9.3 × 10⁻⁸). In patients with CVD, the IL-17A/PASI correlation was abolished (r = 0.2, p = 0.24) and the other correlations were decreased, e.g., IL-17C/PI3 (r = 0.61, p = 4.5 × 10⁻⁵). Patients with moderate-to-severe psoriasis and CVD had lower levels of IL-17A compared to those without CVD (normalized protein expression [NPX] 2.02 vs. 2.55, p = 0.013), and lower IL-17A levels (NPX < 2.3) were associated with higher incidence of CVD (OR = 24.5, p = 0.0028, 95% CI 2.1–1425.1). As a result, in patients with moderate-to-severe psoriasis, we propose circulating IL-17C and PI3 as potential biomarkers of effective systemic anti-psoriatic treatment, and IL-17A as potential marker of CVD.     

Plasma Levels of Homocysteine and Cysteine Increased in Pediatric NAFLD and Strongly Correlated with Severity of Liver Damage

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of metabolic abnormalities ranging from simple triglyceride accumulation in the hepatocytes to hepatic steatosis with inflammation, ballooning and fibrosis. It has been demonstrated that the pathogenesis of NAFLD involves increased oxidative stress, with consumption of the major cellular antioxidant, glutathione (GSH). Liver has a fundamental role in sulfur compound metabolism, although the data reported on plasma thiols status in NAFLD are conflicting. We recruited 63 NAFLD patients, and we analyzed all plasma thiols, such as homocysteine (Hcy), cysteine (Cys), cysteinylglycine (CysGly) and GSH, by high-performance liquid chromatography (HPLC) with fluorescence detection. Hcy, Cys and CysGly plasma levels increased in NAFLD patients (p < 0.0001); whereas GSH levels were decreased in NAFLD patients when compared to controls (p < 0.0001). On the contrary, patients with steatohepatitis exhibited lower levels of Hcy and Cys than subjects without. Furthermore, a positive correlation was found between Hcy and Cys and the presence of fibrosis in children with NAFLD. Taken together, these data demonstrated a defective hepatic sulfur metabolism in children with NAFLD, and that high levels of Hcy and Cys probably correlates with a pattern of more severe histological liver damage, due to mechanisms that require further studies.     

Proliferation to Apoptosis Tumor Cell Ratio as a Biomarker to Improve Clinical Management of Pre-Malignant and Symptomatic Plasma Cell Neoplasms

Proliferation and apoptosis of neoplastic cells are prognostic biomarkers in plasma cell neoplasms (PCNs). The prognostic capacity of proliferation to apoptosis ratio (Ratio-PA) in the era of immunomodulatory treatments is re-evaluated in 316 gammopathy of undetermined significance (MGUS), 57 smoldering multiple myeloma (SMM), and 266 multiple myeloma (MM) patients. Ratio-PA of 0.77 ± 0.12, 1.94 ± 0.52, and 11.2 ± 0.7 (p < 0.0001) were observed in MGUS, SMM, and MM patients. Ten-year overall survival (10y-OS) rates for patients with low/high Ratio-PA were 93.5%/77.3% p < 0.0001) for MGUS, 82.5%/64.7% (p < 0.05) for SMM, and 62.3%/47.0% (p < 0.05) for MM. For patients with low, intermediate, and high risk, 10y-OS for low/high Ratio-PA were 95.5%/72.9% (p < 0.0001), 74.2%/50.4% (p < 0.0001), and 35.3%/20.0% (p = 0.836), respectively. Ratio-PA was an independent prognostic factor for OS (HR = 2.119, p < 0.0001, Harrell-C-statistic = 0.7440 ± 0.0194) when co-analyzed with sex, age, and standard risk. In patients with Ratio-PA^high, only first-line therapy with VRd/VTd, but not PAD/VCD, coupled with ASCT was associated with high 10y-OS (82.7%). Tumor cell Ratio-PA estimated at diagnosis offers a prognostic biomarker that complements standard risk stratification and helps to guide the clinical management of pre-malignant and symptomatic PCNs. Every effort should be made to provide first-line therapies including VTd or VRd associated with ASCT to patients with Ratio-PA^high at higher risk of progression and death.     

Non-Alcoholic Fatty Liver Disease Is not Related to the Incidence of Diabetic Nephropathy in Type 2 Diabetes

To analyze the association between non-alcoholic fatty liver disease (NAFLD) and the incidence of diabetic nephropathy in patients with type 2 diabetes, the incidence of diabetic nephropathy was assessed in 413 type 2 diabetic patients, by testing the 24 h urinary albumin excretion rate (UAER). The NAFLD was diagnosed based on patient’s medical history and liver ultrasound. The difference in diabetic nephropathy incidence between patients with and without NAFLD was tested by χ². Multivariate logistic regression analysis was used to assess the factors associated with diabetic nephropathy among type 2 diabetic patients. Total 363 out of 413 type 2 diabetic patients were enrolled in this study. The incidences of NAFLD and diabetic nephropathy in participants were approximately 56% (202/363) and 38% (137/363) respectively, and there was no significant difference in the prevalence of diabetic nephropathy between patients with and without NAFLD (37.1% vs. 38.5%, p = 0.787). The duration of diabetes (odds ratio [OR] 1.065, 95% confidence interval [CI] 1.014–1.120, p = 0.012), waist circumference (OR 1.077, 95% CI 1.040–1.116, p = 0.000), and fasting blood glucose (FBG; OR 1.136, 95% CI 1.023–1.1262, p = 0.017) were significantly associated with diabetic nephropathy, whereas sex, high blood pressure, total cholesterol (TC), triglyceride (TG), and ankle brachial pressure index (ABI) were not significantly associated with the disorder. The present results suggest that NAFLD is not related to the incidence of diabetic nephropathy in type 2 diabetes, but the duration of diabetes, waist circumference, and FBG are important factors for diabetic nephropathy in type 2 diabetes.     

Comparison of Body Composition,Muscle Strength and Cardiometabolic Profile in Children with Prader-Willi Syndrome and Non-Alcoholic Fatty Liver Disease: A Pilot Study

Syndromic and non-syndromic obesity conditions in children, such as Prader-Willi syndrome (PWS) and non-alcoholic fatty liver disease (NAFLD), both lower quality of life and increase risk for chronic health complications, which further increase health service utilization and cost. In a pilot observational study, we compared body composition and muscle strength in children aged 7–18 years with either PWS (n = 9), NAFLD (n = 14), or healthy controls (n = 16). Anthropometric and body composition measures (e.g., body weight, circumferences, skinfolds, total/segmental composition, and somatotype), handgrip strength, six minute-walk-test (6MWT), physical activity, and markers of liver and cardiometabolic dysfunction (e.g., ALT, AST, blood pressure, glucose, insulin, and lipid profile) were measured using standard procedures and validated tools. Genotyping was determined for children with PWS. Children with PWS had reduced lean body mass (total/lower limb mass), lower handgrip strength, 6MWT and increased sedentary activity compared to healthy children or those with NAFLD (p < 0.05). Children with PWS, including those of normal body weight, had somatotypes consistent with relative increased adiposity (endomorphic) and reduced skeletal muscle robustness (mesomorphic) when compared to healthy children and those with NAFLD. Somatotype characterizations were independent of serum markers of cardiometabolic dysregulation but were associated with increased prevalence of abnormal systolic and diastolic blood pressure Z-scores (p < 0.05). Reduced lean body mass and endomorphic somatotypes were associated with lower muscle strength/functionality and sedentary lifestyles, particularly in children with PWS. These findings are relevant as early detection of deficits in muscle strength and functionality can ensure effective targeted treatments that optimize physical activity and prevent complications into adulthood.     

Analysis of the Circulating Tumor Cell Capture Ability of a Slit Filter-Based Method in Comparison to a Selection-Free Method in Multiple Cancer Types

Circulating tumor cells (CTCs) are a promising biomarker for cancer liquid biopsy. To evaluate the CTC capture bias and detection capability of the slit filter-based CTC isolation platform (CTC-FIND), we prospectively compared it head to head to a selection-free platform (AccuCyte^®-CyteFinder^® system). We used the two methods to determine the CTC counts, CTC positive rates, CTC size distributions, and CTC phenotypes in 36 patients with metastatic cancer. Between the two methods, the median CTC counts were not significantly different and the total counts were correlated (r = 0.63, p < 0.0001). The CTC positive rate by CTC-FIND was significantly higher than that by AccuCyte^®-CyteFinder^® system (91.7% vs. 66.7%, p < 0.05). The median diameter of CTCs collected by CTC-FIND was significantly larger (13.0 μm, range 5.2–52.0 vs. 10.4 μm, range 5.2–44.2, p < 0.0001). The distributions of CTC phenotypes (CK+EpCAM+, CK+EpCAM− or CK−EpCAM+) detected by both methods were similar. These results suggested that CTC-FIND can detect more CTC-positive cases but with a bias toward large size of CTCs.