Platelet RNA enables accurate detection of ovarian cancer: an intercontinental, biomarker identification study.

Platelets are reprogrammed by cancer via a process called education, which favors cancer development. The transcriptional profile of tumor-educated platelets (TEPs) is skewed and therefore practicable for cancer detection. This intercontinental, hospital-based, diagnostic study included 761 treatment-naïve inpatients with histologically confirmed adnexal masses and 167 healthy controls from nine medical centers (China, n = 3; Netherlands, n = 5; Poland, n = 1) between September 2016 and May 2019. The main outcomes were the performance of TEPs and their combination with CA125 in two Chinese (VC1 and VC2) and the European (VC3) validation cohorts collectively and independently. Exploratory outcome was the value of TEPs in public pan-cancer platelet transcriptome datasets. The AUCs for TEPs in the combined validation cohort, VC1, VC2, and VC3 were 0.918 (95% CI 0.889-0.948), 0.923 (0.855-0.990), 0.918 (0.872-0.963), and 0.887 (0.813-0.960), respectively. Combination of TEPs and CA125 demonstrated an AUC of 0.922 (0.889-0.955) in the combined validation cohort; 0.955 (0.912-0.997) in VC1; 0.939 (0.901-0.977) in VC2; 0.917 (0.824-1.000) in VC3. For subgroup analysis, TEPs exhibited an AUC of 0.858, 0.859, and 0.920 to detect early-stage, borderline, non-epithelial diseases and 0.899 to discriminate ovarian cancer from endometriosis. TEPs had robustness, compatibility, and universality for preoperative diagnosis of ovarian cancer since it withstood validations in populations of different ethnicities, heterogeneous histological subtypes, and early-stage ovarian cancer. However, these observations warrant prospective validations in a larger population before clinical utilities.

The disease stage-associated imbalance of Th1/Th2 and Th17/Treg in uterine cervical cancer patients and their recovery with the reduction of tumor burden.

BACKGROUND: Nearly all uterine cervical cancer (UCC) cases result from human papillomavirus (HPV) infection. After high-risk HPV infection, most HPV infections are naturally cleared by humoral and cell-mediated immune responses. Thus, cervical lesions of only few patients progress into cervical cancer via cervical intraepithelial neoplasia (CIN) and lead to persistent oncogenic HPV infection. This suggests that immunoregulation plays an instrumental role in the carcinogenesis. However, there was a few studies on the relation between the immunologic dissonance and clinical characteristics of UCC patients. METHOD: We examined the related immune cells (Th1, Th2, Th17, and Treg cells) by flow cytometric analysis and analyzed their relations with UCC stages, tumor size, differentiation, histology type, lymph node metastases, and vasoinvasion. Next, we quantified the Th1, Th2, Th17, and Treg cells before and after the operation both in UCC and CIN patients. RESULTS: When compared with stage I patients, decreased levels of circulating Th1 cells and elevated levels of Th2, Th17, and Treg cells were detected in stage II patients. In addition, the imbalance of Th1/Th2 and Th17/Treg cells was related to the tumor size, lymph node metastases, and vasoinvasion. We found that immunological cell levels normalized after the operations. In general, immunological cell levels in CIN patients normalized sooner than in UCC patients. CONCLUSIONS: Our findings suggested that peripheral immunological cell levels reflect the patient's condition.

Growth differentiation factor-15 is a prognostic marker in patients with intermediate coronary artery disease.

BACKGROUND: Growth differentiation factor-15 (GDF-15) is involved in multiple processes that are associated with coronary artery disease (CAD). However, little is known about the association between GDF-15 and the future ischemic events in patients with intermediate CAD. This study was conducted to investigate whether plasma GDF-15 constituted risk biomarkers for future cardiovascular events in patients with intermediate CAD. METHODS: A prospective study was performed based on 541 patients with intermediate CAD (20%-70%). GDF-15 of each patient was determined in a blinded manner. The primary endpoint was major adverse cardiac event (MACE), which was defined as a composite of all-cause death, nonfatal myocardial infarction, revascularization and readmission due to angina pectoris. RESULTS: After a median follow-up of 64 months, 504 patients (93.2%) completed the follow-up. Overall, the combined endpoint of MACE appeared in 134 patients (26.6%) in the overall population: 26 patients died, 11 patients suffered a nonfatal myocardial infarction, 51 patients underwent revascularization, and 46 patients were readmitted for angina pectoris. The plasma levels of GDF-15 (median: 1172.02 vs. 965.25 pg/mL, P = 0.014) were higher in patients with ischemic events than those without events. After adjusting for traditional risk factors, higher GDF-15 levels were significantly associated with higher incidence of the composite endpoint of MACE (HR = 1.244, 95% CI: 1.048-1.478, Quartile 4 vs. Quartile 1, P = 0.013). CONCLUSIONS: The higher level of GDF-15 was an independent predictor of long-term adverse cardiovascular events in patients with intermediate CAD.

Echocardiographic strain in hypertrophic cardiomyopathy and hypertensive left ventricular hypertrophy.

BACKGROUND: The myocardial structure differs between secondary left ventricular hypertrophy (LVH) and hypertrophic cardiomyopathy (HCM). We investigated left ventricular function of these two types of hypertrophy using multilayer strain analysis with two-dimensional echocardiography. METHODS: Transthoracic echocardiography (Vivid-E9) was performed in 240 patients with preserved left ventricular ejection fraction (LVEF ≥50%) and with either HCM (n = 80, 63 men, age 49.8 ± 14.1 years), hypertensive LVH (n = 80, 63 men, age 51.4 ± 13.3 years) or normal blood pressure and left ventricular structure (n = 80, 63 men, 50.8 ± 12.4 years). Quantitative multilayer longitudinal strain (LS), circumferential strain (CS), and radial strain (RS) were analyzed. The ratio of endo-/epi-myocardial strain was calculated. RESULTS: Longitudinal strain was significantly (P < 0.001) lower in HCM patients than normal controls (15.2 ± 4.2% vs 23.1 ± 2.7%), especially in hypertrophic segments (14.5 ± 4.4% vs 17.2 ± 3.2% in nonhypertrophic segments, P < 0.01). LS was lower in patients with hypertensive LVH, similarly in all left ventricular segments (20.7 ± 3.7%, P < 0.001 vs controls). CS was lower in the mid- and epicardium (P < 0.01), but not endocardium in HCM (P = 0.4), and preserved in all myocardial layers in hypertensive LVH. The endo-/epi-myocardial ratios of both LS and CS were higher in HCM than hypertensive LVH (P < 0.01). RS was higher (P < 0.01) in HCM than hypertensive LVH and controls. Endocardial CS and global RS were correlated with LVEF (r ≥ 0.32, P < 0.01). CONCLUSIONS: Hypertrophic cardiomyopathy patients had marked reductions in LS and CS, whereas patients with hypertensive LVH had less reduction in LS and preserved CS. The increased endo-/epi-myocardial ratios of LS and CS may be useful in differentiating HCM from hypertensive LVH.

The risk factors of residual lesions and recurrence of the high-grade cervical intraepithelial lesions (HSIL) patients with positive-margin after conization.

The aim of this study was to illuminate risks factors of residual lesions, and recurrence of the high-grade cervical intraepithelial lesions (HSIL) patients with positive margin who underwent cervical conization.A retrospective cohort study of 218 patients with positive margin after conization, including cold knife conization (CKC) and loop electrosurgical excisional procedure (LEEP), and follow-up from 2013 through 2016. The diagnosis of residual disease and recurrence were established and confirmed by biopsy. We evaluate the correlations among residual rate, recurrence rate, and clinical parameters, such as age, menopausal status, gravity, parity, glandular involvement, thinprep cytologic test (TCT), and human papillomavirus (HPV) results. We also detect the difference between CKC and LEEP.There was statistical difference between the positive margin rate of CKC group and LEEP regarding the surgery methods (5.8% and 12.09% separately, P < .001). Residual disease was found in 53.66% cases where 41 patients received second surgery after conization. Besides, age (P = .027), menopausal status (P = .006), and HPV infection (P = 0.018) were significantly associated with residual lesion. Among 177 cases with histopathologic follow-up, 15.91% women relapsed from 4 to 27 months. As for recurrence we found it was more frequent with HPV infection and glandular involvement (P < .001). TCT was also an independent factor in patients with recurrence of lesion. No evidence shows difference between CKC and LEEP for recurrence rate (P = .918).The factors related to rate of residual lesion were age, menopausal status, and HPV infection. HPV infection, TCT, and glandular involvement were associated with HSIL recurrence. LEEP was as effective as CKC with regard to recurrence rate. Further large-scale studies are needed to confirm our findings.

Junior medical student performed focused cardiac ultrasound after brief training to detect significant valvular heart disease.

BACKGROUND: Focused cardiac ultrasound (FOCUS) examination using a portable device is increasingly used for bedside diagnosis of cardiovascular diseases. This is a 4-week pilot project aiming to teach medical students to perform FOCUS to detect valvular heart lesions. METHODS: Patients undergoing routine transthoracic echocardiography (TTE) were recruited by third year medical students who performed physical examination (PE) and FOCUS after 6-hour training to detect significant (moderate-to-severe) valvular lesions. Performance of FOCUS and PE was compared to TTE as reference using kappa statistics. RESULTS: 10 medical students performed 212 PE and FOCUS on 107 patients with mean age 63.7 ±â€¯14.9 years. TTE detected 126 significant valvular lesions of which FOCUS correctly identified 54 lesions (κ = 0.45) compared to 32 lesions by PE (κ = 0.28, p < 0.01). FOCUS was better than PE in identifying mitral stenosis (κ = 0.51 vs. 0.17), aortic stenosis (κ = 0.45 vs. 0.16) and tricuspid regurgitation (κ = 0.39 vs. 0.09, all p < 0.01). Students became more proficient in performing FOCUS examination with time. CONCLUSIONS: Teaching junior medical students to perform and interpret FOCUS was feasible after brief training and better than PE in detecting significant valvular lesions. Further studies are warranted to determine the utility of incorporating this new technology into mainstream medical training.

Incidence of venous thromboembolism following the neoadjuvant chemotherapy regimen for epithelial type of ovarian cancer.

This study aims to analyze the risk of venous thromboembolism (VTE) in patients receiving neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer (EOC).A retrospective audit was conducted examining 147 patients treated for EOC. Surgical treatment with curative intent, with or without NACT and adjuvant chemotherapy, is the treatment approach, which was modified according to the patient's condition. The incidence of VTE with the most commonly used chemotherapy regimen, carboplatin, cisplatin, paclitaxel, docetaxel, and others were evaluated.This study found a 13.6% incidence of VTE in patients undergoing therapy with curative intent for EOC. No association was seen between NACT and VTE compared to VTE after standard treatment: 2/16 (12.5%) vs 5/131 (3.8%) (P = .16). Univariate and multivariate analyses also demonstrated that NACT has no risk for VTE with odds ratio (OR) = 0.89 (95% CI = 0.18-4.28) and P = 1. Results did not vary significantly with the type of chemotherapy used. Furthermore, increased incidence of VTE as an incidental finding supports the well-established role of malignancy in VTE occurrence. Univariate and multivariate analyses demonstrated that VTE occurred more frequently in menopausal women than nonmenopausal women (17.9% vs 5.8%) with OR = 3.55 (95% CI = 0.99-12.78) and P = .04 in patients aged ≥60 (19.3% vs 10%) with OR = 2.15 (95% CI = 0.83-5.57) and P = .13 but is not statistically significant.We conclude that NACT has no association with VTE and the currently used common chemotherapeutic drug combinations for ovarian cancer carry the minimal risk of thromboembolic events.

Prevalence of atrial septal pouch and risk of ischemic stroke.

BACKGROUND: It has been postulated that atrial septal pouch (ASP) may favor the stasis of blood and predispose to thromboembolic complications. We sought to evaluate the prevalence of ASP, and its association with ischemic stroke. METHODS: We retrospectively studied 500 patients, who underwent transesophageal echocardiography (TEE) due to clinical indications. Seventy two patients due to image quality, and 104 patients with atrial septal defect or PFO were excluded. The remaining 324 patients were included in the analysis. The depth of ASP was measured. RESULTS: ASP was detected in 98 patients [left side ASP (LASP) in 58 (59.2%), and right side ASP (RASP) in 40 (40.8%) patients]. LASPs were significant deeper than RASPs (10.1±5.2 vs 4.4±1.4mm, p<0.0001). Patient characteristics were categorized by the presence or absence of LASP. The age (61±12 vs 61±12), gender and stroke risk factors were no significant difference between patients with or without LAPS. Ischemic stroke occurred in 21 patients without LASP, 10 patients with LASP. The presence of a LASP was found to be associated with an increased risk of ischemic stroke, in either univariable analysis (17.2 vs. 7.9%, p=0.03; OR=2.43, 95% CI=1.1-5.5, p=0.033) or after adjustment for other stroke risk factors using multiple logistic regression analysis (OR=2.45, 95% CI 1.1-5.8, p=0.036). CONCLUSIONS: This study demonstrated evidence of association between LASP and ischemic stroke. Among 324 patients, the risk of ischemic stroke was twice more among patients with LASP than cases without LASP.

Prediction of risk of cardiovascular events in patients with mild to moderate coronary artery lesions using naïve Bayesian networks.

BACKGROUND: This prospective study integrated multiple clinical indexes and inflammatory markers associated with coronary atherosclerotic vulnerable plaque to establish a risk prediction model that can evaluate a patient with certain risk factors for the likelihood of the occurrence of a coronary heart disease event within one year. METHODS: This study enrolled in 2686 patients with mild to moderate coronary artery lesions. Eighty-five indexes were recorded, included baseline clinical data, laboratory studies, and procedural characteristics. During the 1-year follow-up, 233 events occurred, five patients died, four patients suffered a nonfatal myocardial infarction, four patients underwent revascularization, and 220 patients were readmitted for angina pectoris. The Risk Estimation Model and the Simplified Model were conducted using Bayesian networks and compared with the Single Factor Models. RESULTS: The area under the curve was 0.88 for the Bayesian Model and 0.85 for the Simplified Model, while the Single Factor Model had a maximum area under the curve of 0.65. CONCLUSION: The new models can be used to assess the short-term risk of individual coronary heart disease events and may assist in guiding preventive care.

Metabolic behavior prediction of pazopanib by cytochrome P450 (CYP) 3A4 by molecular docking.

Metabolism-mediated drug adverse effects (e.g., drug-drug interaction, bioactivation, etc.) strongly limit the utilization of clinical drugs. The present study aims to predict the metabolic capability of cytochrome P450 (CYP) 3A4 toward pazopanib which is an excellent drug exhibiting therapeutic role toward various cancers especially for ovarian cancer. Pazopanib can be well docked into the activity cavity of CYP3A4, and the interaction structure in pazopanib was methyl group located besides nitrogen in the five-membered ring. The distance between the hydrogen atom in methyl group and active center is 3.64 Å. The interaction amino acid is Glu374. Furthermore, both pazopanib and ketoconazole were docked into the activity cavity of CYP3A4 to compare their binding potential. The distance between ketoconazole and activity center (2.10 Å) is closer than the distance between pazopanib and activity center of CYP3A4, indicating the easy influence of CYP3A4 inhibitor toward the metabolism of pazopanib. All these data were helpful for the clinical application of pazopanib, and R&D of other tinib drug candidates as new anti-tumor drugs.

Evaluation of left ventricular function by three-dimensional speckle-tracking echocardiography in patients with myocardial bridging of the left anterior descending coronary artery.

BACKGROUND: To understand the influence of myocardial bridging (MB) on left ventricular (LV) function, myocardial function was studied in patients with MB of the left anterior descending coronary artery (LAD) using three-dimensional speckle-tracking echocardiography (STE). METHODS: Left anterior descending coronary artery MB was diagnosed by coronary angiography in 82 subjects. Patients were divided into three groups according to the percentage of systolic narrowing of the compressed segment: 30% to 49% was defined as group I (24 patients), 50% to 74% as group II (28 patients), and ≥75% as group III (30 patients). Thirty gender- and age-matched normal subjects were included as controls. Left ventricular myocardial deformation was estimated by three-dimensional STE. RESULTS: Left ventricular ejection fractions were normal in all patients, but diastolic function was impaired in groups II and III (E/E' ratio, 9 ± 3 and 10 ± 3, respectively). The amplitudes of longitudinal strain (LS) and area strain (AS) of the LAD territory was significantly reduced in groups II and III compared with controls and group I (LS, -15 ± 2% and -12 ± 1% vs -19 ± 2% and -18 ± 2%; AS, -22 ± 2% and -13 ± 2% vs -33 ± 4% and -33 ± 3%; P < .0001), but the amplitudes of circumferential and radial strain showed no intergroup differences. Longitudinal strain and AS were significantly lower in patients with fractional flow reserve < 0.75 than in those with fractional flow reserve ≥ 0.75 (P < .0001), with relative preservation of circumferential and radial strain. The severity of LAD compression was significantly associated with AS and LS of the LAD territory (r = -0.92 and r = -0.84, respectively, P < .0001), but the correlations with circumferential and radial strain were modest (r = -0.36 and r = -0.32, respectively, P < .05). CONCLUSIONS: With the increasing severity of systolic compression of the mural coronary artery, LV diastolic function and regional systolic deformation (AS and LS) of the MB perfusion territory were reduced. Three-dimensional STE can detect subtle myocardial dysfunction in patients with MB.

Evaluation of several screening approaches for detection of cervical lesions in rural Shandong, China.

PURPOSE: The study was designed to: (1) investigate the prevalence of high-risk human papillomavirus (HR- HPV) infection and cervical neoplasia; and (2) evaluate clinical performance of visual inspection with acetic acid/ Lugol's iodine (VIA /VILI), Pap smear, high-risk human papillomavirus (HR-HPV) DNA test for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and (3) explore appropriate screening approach in rural areas of Shandong Province. MATERIALS AND METHODS: A total of 3,763 eligible women from Yiyuan County in Yimeng mountainous areas of rural Shandong, China, were enrolled and underwent Pap smear, HR-HPV DNA testing by Hybrid Capture 2 (HC2), and VIA /VILI tests. Women positive in any test were referred to colposcopy and biopsy as indicated. RESULTS: The prevalence of HR-HPV infection among all enrolled women was 11.1% and that in healthy women was 9.9%. In total 33 cases of CIN1, 16 cases of CIN2, 6 cases of CIN3 but none of cervical cancer were detected and the crude prevalence of CIN2+ was 0.58%. For detecting CIN2+, the sensitivity of HR-HPV DNA testing, VIA/VILI, Pap smear was 90.9%, 77.3%, 81.8%, respectively. Pap smear had the best specificity of 98.2%, followed by HR-HPV DNA testing with specificity of 89.4%, VIA/VILI had the lowest specificity of 81.2%. Colposcopy referral rate of HR-HPV DNA testing, VIA/VILI, Pap smear was 11.1%, 18.5%, 2.3%, respectively. CONCLUSIONS: Our results suggest that HR-HPV DNA testing alone might be appropriate for primary cervical cancer screening in rural low-resource areas of Shandong Province, China.

Early diastolic dyssynchrony in relation to left ventricular remodeling and function in hypertension.

BACKGROUND: Cardiac synchronization is important in maintaining myocardial performance, but the mechanism of diastolic dyssynchrony leading to failing myocardium is unclear. We aim to study the relation of left ventricular (LV) diastolic dyssynchrony with diastolic dysfunction in patients with hypertension. METHODS: Two-D, three-D and Doppler echocardiography were performed using the GE Vivid E9 system on 230 subjects. Among them, 154 patients with hypertension were divided into group 1 (86 patients with mild to moderate hypertension, BP 152 ± 8/91 ± 11 mm Hg) and group 2 (68 patients with severe hypertension, BP 188 ± 12/105 ± 24 mm Hg), age 76, gender matched normotensive subjects (119 ± 6/76 ± 9 mm Hg) as control. The routine 2D and Doppler parameters were measured and LV systolic and diastolic dyssynchrony indices were determined as the standard deviation of the time interval from the peak R of the QRS complex to peak myocardial systolic strain rate (Ts-SD), and to early diastolic strain rate (Te-SD) of 12 LV segments. RESULTS: LV relative wall thickness, mass index, and Te-SD were significantly higher in patients with hypertension than in control group (p<0.0001), but Ts-SD showed no significant differences. Te-SD and diastolic dysfunction worsened progressively with increasing severity of hypertension (p<0.05). Te-SD was significantly and independently associated with parameters of LV remodeling and diastolic function. CONCLUSION: Our study demonstrated that LV diastolic dyssynchrony was associated with LV remodeling, which seems to contribute to diastolic dysfunction in hypertension. This diastolic dyssynchrony index derived from speckle tracking echocardiography can be used as a marker for studying the LV function and effects of therapy in hypertensive heart disease.

Association of CYP17A1 gene -34T/C polymorphism with polycystic ovary syndrome in Han Chinese population.

PURPOSE: To investigate the influence of the cytochrome P450 17α (CYP17A1) gene -34T/C polymorphism in the pathogenesis of polycystic ovary syndrome (PCOS) in Han Chinese population. METHODS: Three-hundred eighteen patients with PCOS and 306 controls were recruited and the CYP17A1 -34T/C polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Furthermore, the relationship of CYP17A1 -34T/C polymorphism and clinical feature parameters of PCOS patients was also analyzed. RESULTS: The prevalence rates of CYP17A1 genotype TT, TC and CC were 49.69%, 43.71% and 6.6% in the case group and those were 44.77%, 46.08% and 9.15% in the control group. The frequencies of CYP17A1 T and C alleles were 71.54% and 28.46% in the case group, and those were 67.81% and 32.19% in the control group. Neither the genotypic nor the allelic distribution was significantly different between the cases and controls. However, the PCOS patients with the genotype of CC had significantly higher total testosterone levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) than those with the genotype of TT or TC. CONCLUSIONS: The CYP17A1 gene -34T/C polymorphism might not be directly correlated with the PCOS, but might influence PCOS via the association of testosterone level and the HOMA-IR.