Up-regulation of BTN3A1 on CD14+ cells promotes Vγ9Vδ2 T cell activation in psoriasis.

Vγ9Vδ2 T cells play an important role in the development and progression of psoriasis vulgaris (PV), but how they promote skin inflammation and the molecular mechanisms underlying Vγ9Vδ2 T cell dysfunction are poorly understood. Here, we show that circulating Vγ9Vδ2 T cells are decreased and exhibit enhanced proliferation and increased production of IFN-γ and TNF-α in PV patients. Monocytes from PV patients express higher levels of the phosphoantigen sensor butyrophilin 3A1 (BTN3A1) than monocytes from healthy controls. Blockade of BTN3A1 suppresses Vγ9Vδ2 T cell activation and abolishes the difference in Vγ9Vδ2 T cell activation between PV patients and healthy controls. The CD14+ cells in PV skin lesions highly express BTN3A1 and juxtapose to Vδ2 T cells. In addition, IFN-γ induces the up-regulation of BTN3A1 on monocytes. Collectively, our results demonstrate a crucial role of BTN3A1 on monocytes in regulating Vγ9Vδ2 T cell activation and highlight BTN3A1 as a potential therapeutic target for psoriasis.

Efficacy of medical education combined with extended care on adherence to inhaled glucocorticoids and clinical effects in patients with bronchial asthma.

OBJECTIVE: To observe the clinical efficacy of medical education combined with extended care in patients with bronchial asthma and its effect on adherence to inhaled glucocorticoids. METHODS: Ninety-eight patients with bronchial asthma were divided into the control group and the experimental group, n = 49, by utilizing the random number table method. The control group was given routine education and care as well as routine out-of-hospital instructions, and the experimental group was given medical education and extended care based on the control group. Asthma disease knowledge mastery, asthma control, quality of life, medication adherence and lung function were compared between both groups, and the number of asthma attacks and re-hospitalizations were recorded. RESULTS: The experimental group performed higher scores of health knowledge, asthma control test and quality of life, rate of complete adherence, forced expiratory volume in one second (FEV1), peak expiratory flow rate, and FEV1/forced vital capacity. The number of asthma attacks and the times of re-hospitalizations were lower in the experimental group (all p < 0.05). CONCLUSION: Medical education combined with extended care can improve bronchial asthma patients' mastery of asthma disease knowledge, effectively control patients' conditions, enhance patients' quality of life and lung function, increase patients' adherence to inhaled glucocorticoids, and reduce the recurrence of bronchial asthma patients.

A Chinese cross-sectional study on depression and anxiety symptoms in patients with psoriasis vulgaris.

Previous studies have reported a higher incidence of depression and anxiety in psoriasis patients compared to the general population, which has important implications for assessment and treatment. In this study, we determined the frequency of depression and anxiety in Chinese patients with psoriasis and its relationship with disease severity and other demographic variables. The study included 208 Chinese patients with psoriasis vulgaris. The Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder scale (GAD-7) were used to screen for depression and anxiety. The Psoriasis Area and Severity Index (PASI) was used to assess the severity of psoriasis. Of the 208 patients included in the study, 29 patients (13.9%) were positive for moderate-to-severe depression (PHQ-9 ≥ 10) and 22 patients (10.6%) were positive for anxiety (GAD-7 ≥ 10) symptoms. Both positive stress reactors who perceived stress as an exacerbating factor of psoriasis and moderate-to-severe psoriasis were found to be positive predictors for the presence of moderate-to-severe depression or anxiety symptoms while longer duration and late onset age played a protective role. In the sample of Chinese patients with psoriasis there was a clinically significant prevalence of depression and anxiety. Our study suggests that Chinese psoriasis patients should be screened for psychiatric comorbidities.

The First Case Report of Inactive Nontuberculous Mycobacterial Pulmonary Disease (NTM-PD) in a Pneumoconiosis Patient Caused by Mycobacterium europaeum in China.

We reported a 51-year-old male electric welder with stage I pneumoconiosis, who had no significant cough, sputum, fever, chest pain, or other discomfort. However, regular physical examination at our hospital revealed bilateral pulmonary nodules with cavity formation. Blood routine, liver or kidney function, and infection-related biomarkers, including interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), and procalcitonin (PCT), were normal. Sputum and alveolar lavage fluid (BALF) acid-fast bacilli (AFB) smears, BALF Mycobacterium tuberculosis (TB) PCR, and T-SPOT.TB were negative. The nucleic acid sequence of Mycobacterium europaeum was detected by BALF metagenomic next-generation sequencing (mNGS), which was confirmed by the subsequent positive culture for NTM. Considering stable conditions, no significant discomfort, and no significant changes in the lung lesion, the patient was diagnosed with inactive nontuberculous mycobacterial pulmonary disease (NTM-PD).

Effectiveness and risk of second primary malignancies after radiotherapy in major salivary gland carcinomas: A retrospective study using SEER database.

OBJECTIVE: To investigate the effectiveness of radiotherapy and its association with second primary malignancies (SPMs) risk in major salivary gland carcinomas (MSGCs) patients. METHODS: Cohort 1 included 7274 surgically treated MSGC patients from the Surveillance, Epidemiology, and End Results database, assessing the effectiveness of radiotherapy. Cohort 2 (n = 4213) comprised patients with ≥5-year survival in Cohort 1 to study SPMs. RESULTS: Radiotherapy decreased overall survival in MSGCs patients, but improved it in high-grade MSGCs. Cumulative SPMs incidences at 25 years were 16.5% in the radiotherapy (RT) group compared to 14.5% in the non-radiotherapy (NRT) group. For second head and neck carcinomas (SHNCs), incidences were 3.4% in RT versus 1.6% in NRT. Radiotherapy increased the relative risks of tumors, particularly SHNCs (RR = 1.78). The 10-year OS rates of SHNCs after radiotherapy were significantly lower. CONCLUSION: Radiotherapy improves survival in advanced-stage MSGCs but increases the risk of developing SPMs, particularly SHNCs.

RNA-seq reveals differentially expressed lncRNAs and circRNAs and their associated functional network in HTR-8/Svneo cells under hypoxic conditions.

Placental hypoxia is hazardous to maternal health as well as fetal growth and development. Preeclampsia and intrauterine growth restriction are common pregnancy problems, and one of the causes is placental hypoxia. Placental hypoxia is linked to a number of pregnancy illnessesv. To investigate their potential function in anoxic circumstances, we mimicked the anoxic environment of HTR-8/Svneo cells and performed lncRNA and circRNA studies on anoxic HTR-8/Svneo cells using high-throughput RNA sequencing. The miRNA target genes were predicted by integrating the aberrant expression of miRNAs in the placenta of preeclampsia and intrauterine growth restriction, and a ceRNA network map was developed to conduct a complete transcriptomic and bioinformatics investigation of circRNAs and lncRNAs. The signaling pathways in which the genes were primarily engaged were predicted using GO and KEGG analyses. To propose a novel explanation for trophoblastic organism failure caused by lncRNAs and circRNAs in an anoxic environment.

Lacustrine groundwater discharge-derived carbon and nitrogen to regulate biogeochemical processes as revealed by stable isotope signals in a large shallow eutrophic lake.

Eutrophic shallow lakes are hotspots of carbon (C) and nitrogen (N) accumulation and transformation, and are increasingly recognized as important sources of greenhouse gases (GHGs: CO2, CH4 and N2O). Lacustrine groundwater discharge (LGD) is a crucial component of the water budget and terrestrial material delivery for lakes, but its interplays with intrinsic CN biogeochemical processes remain less tackled. In this study, C and N ingredients and multiple stable isotopes (δ2H, δ18O, δ13C, and δ15N) were measured seasonally in groundwater, river water and lake water of a large eutrophic shallow lake in eastern China. The results revealed that groundwater is enriched with various forms of C and N that have similar sources and pathways as surface water in the lake and rivers. The isotope balance model also indicated that LGD derived C and N contribute significantly to lake inventories in addition to river runoff. These allochthonous C and N provide extra substrates for related biogeochemical processes, such as algae proliferation, organic matter degradation, methanogenesis and denitrification. Simultaneously, the excess oxygen consumption leads to depletion and hypoxia in the lake, further facilitating the processes of methanogenesis and denitrification. LGD functions not only as an external source of C and N that directly increases GHG saturations, but also as a mediator of internal CN pathways, which significantly affect hypoxia formation, GHG productions and emissions in the eutrophic lake. This study highlights the unrevealed potential regulation of LGD on biogeochemical processes in the eutrophic lake, and underscores the need for its consideration in environmental and ecological studies of lakes both regionally and globally.

The effect of TFAP2A/ANXA8 axis on ferroptosis of cervical squamous cell carcinoma (CESC) in vitro.

Potential role and associated mechanisms of Annexin A8 (ANXA8), a member of the Annexins family, in cervical squamous cell carcinoma (CESC) are still unclear, despite being upregulated in various malignant tumors. Here, we observed a notably elevated expression of ANXA8 in CESC cells. The inhibition of ANXA8 amplified the susceptibility of CESC cells to Erastin and sorafenib-induced ferroptosis, whereas it exerted minimal influence on DPI7 and DPI10-induced ferroptosis. The results from the Fe2+ concentration assay showed no significant correlation between ANXA8 gene knockdown and intracellular Fe2+ concentration induced by ferroptosis inducers. Western blot analysis demonstrated that the knockdown of ANXA8 did not alter ACSL4 and LPCAT levels under ferroptosis-inducing conditions, but it did result in a reduction in intracellular GSH levels induced by the ferroptosis inducer. Subsequently, we identified TFAP2A as an upstream transcription factor of ANXA8, which plays a role in regulating cell ferroptosis. The knockdown of TFAP2A significantly elevated MDA levels and depressed GSH levels in the presence of a ferroptosis inducer, thereby inhibiting cell ferroptosis. However, this inhibitory effect could be reversed by ANXA8 overexpression. Therefore, our research suggests that the TFAP2A/ANXA8 axis exerts regulatory control over ferroptosis in CESC cells by mediating GSH synthesis in System Xc.

A diagnostic model based on DNA methylation haplotype block characteristics for identifying papillary thyroid carcinoma from thyroid adenoma.

Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid cancer. Methylation of some genes plays a crucial role in the tendency to malignancy as well as poor prognosis of thyroid cancer, suggesting that methylation features can serve as complementary markers for molecular diagnosis. In this study, we aimed to develop and validate a diagnostic model for PTC based on DNA methylation markers. A total of 142 thyroid nodule tissue samples containing 84 cases of PTC and 58 cases of thyroid adenoma (TA) were collected for reduced representation bisulfite sequencing (RRBS) and subsequent analysis. The diagnostic model was constructed by the logistic regression (LR) method followed by 5-cross validation and based on 94 tissue methylation haplotype block (MHB) markers. The model achieved an area under the receiver operating characteristic curve (AUROC) of 0.974 (95% CI, 0.964-0.981) on 108 training samples and 0.917 (95% CI, 0.864-0.973) on 27 independent testing samples. The diagnostic model scores showed significantly high in males (P = 0.0016), age ≤ 45 years (P = 0.026), high body mass index (BMI) (P = 0.040), lymph node metastasis (P = 0.00052) and larger nodules (P = 0.0017) in the PTC group, and the risk score of this diagnostic model showed significantly high in recurrent PTC group (P = 0.0005). These results suggest that the diagnostic model can be expected to be a powerful tool for PTC diagnosis and there are more potential clinical applications of methylation markers to be excavated.

Multi-view progression diagnosis of thyroid cancer by integrating platelet transcriptomes and blood routine tests.

Thyroid cancer is the most common type of endocrine system cancer. The pre-cancer and early stages are usually benign or slowly growing, and do not need invasive treatments. This study investigated the challenging classification task of four classes of samples, i.e., normal controls (N), thyroid adenomas (TA), papillary thyroid cancers (PTC) and metastasized papillary thyroid cancers (MPTC). We proposed a multi-view progression diagnosis framework ThyroidBloodTest to integrate the two views of RNAseq platelet transcriptomes (View-T) and blood routine (View-B) features. Platelet transcriptome represented the molecular-level information, while the blood routine features were easy to obtain in the clinical practice. Eleven feature selection algorithms and seven classifiers were evaluated for both views. The experimental data suggested the importance of choosing appropriate data analysis algorithms and feature engineering techniques like principal component analysis (PCA). The best ThyroidBloodTest model achieved Acc = 0.8750 for the four-class classification of the N/TA/PTC/MPTC samples based on the integrated feature space of View-T and View-B. The cellular localization cytosol and three post-translational modification types acetylation/phosphorylation/ubiquitination were observed to be enriched in the proteins encoded by the View-T biomarkers. The numbers of different immune cells also contributed positively to the progression diagnosis of thyroid cancer. The proposed multi-view prediction model demonstrated the necessity of integrating both platelet transcriptomes and blood routine tests for the progression diagnosis of thyroid cancer.

(1) H-nuclear magnetic resonance-based metabonomic analysis of brain in rhesus monkeys with morphine treatment and withdrawal intervention.

Comprehensive cerebral metabolites involved in morphine dependence have not been well explored. To gain a better understanding of morphine dependence and withdrawal therapy in a model highly related to humans, metabolic changes in brain hippocampus and prefrontal cortex (PFC) of rhesus monkeys were measured by (1) H-nuclear magnetic resonance spectroscopy, coupled with partial least squares and orthogonal signal correction analysis. The results showed that concentrations of myoinositol (M-Ins) and taurine were significantly reduced, whereas lactic acid was increased in hippocampus and PFC of morphine-dependent monkeys. Phosphocholine and creatine increased in PFC but decreased in hippocampus after chronic treatment of morphine. Moreover, N-acetyl aspartate (NAA), γ-aminobutyric acid, glutamate, glutathione, methionine, and homocysteic acid also changed in these brain regions. These results suggest that chronic morphine exposure causes profound disturbances of neurotransmitters, membrane, and energy metabolism in the brain. Notably, morphine-induced dysregulations in NAA, creatine, lactic acid, taurine, M-Ins, and phosphocholine were clearly reversed after intervention with methadone or clonidine. Our study highlights the potential of metabolic profiling to enhance our understanding of metabolite alteration and neurobiological actions associated with morphine addiction and withdrawal therapy in primates.

Zinc oxide nanoparticles cause nephrotoxicity and kidney metabolism alterations in rats.

Although zinc oxide nanoparticles (ZnO NPs) have been widely used, their potential hazards on mammalian and human remain largely unknown. In this study, the biochemical compositions of urine and kidney from the rats treated with ZnO NPs (100, 300 and 1000 mg/kg, respectively) were investigated using (1)H nuclear magnetic resonance (NMR) technique with the pattern recognition of partial least squares-discriminant analysis. Hematology, clinical biochemistry and kidney histopathological examinations were also performed. Metabolic profiles from rats treated with ZnO NP(S) exhibited increases in the levels of taurine, lactate, acetate, creatine, phosphocholine, trimethylamine-N-oxide, α-glucose, and 3-D-hydroxybutyrate, as well as decreases in lipid, succinate, citrate, α-ketoglutarate, hippurate and 4-hydroxyphenylacetic acid in urine after ZnO NPs treatment for 14 days. A similar alteration pattern was also identified in kidney. Urine choline and phosphocholine increased significantly shortly after ZnO NPs treatment, moreover, some amino acids and glucose also increased during the experimental period. However, succinate, citrate and α-ketoglutarate in urine exhibited a different alteration trend, which showed increases on the first day after ZnO NPs treatment, but decreases gradually until the termination of the study. A similar alteration pattern of urinary (1)H NMR spectra was also detected in kidney. Moreover, ZnO NPs (1000 mg/kg) resulted in significant increases in serum creatine and blood urea nitrogen, decreases in hemoglobin, haematocrit and mean corpuscular hemoglobin concentration, and overt tubular epithelial cell necrosis. These findings show that ZnO NPs can disturb the energy metabolism and cause mitochondria and cell membrane impairment in rat kidney, which may contribute to ZnO NPs-induced nephrotoxicity.

Three-Dimensional Reconstruction of a CT Image under Deep Learning Algorithm to Evaluate the Application of Percutaneous Kyphoplasty in Osteoporotic Thoracolumbar Compression Fractures.

In order to investigate the therapeutic evaluation of percutaneous kyphoplasty (PKP) for the treatment of osteoporotic thoracolumbar compression fractures by three-dimensional (3D) reconstruction of computed tomography (CT) based on the deep learning V-Net network, the traditional V-Net was optimized first and a new and improved V-Net was proposed. The introduced U-Net, V-Net, and convolutional neural network (CNN) were compared in this study. Then, 106 patients with osteoporotic thoracolumbar compression fractures were enrolled, and 128 centrums were divided into the test group with 53 cases of PKP and the control group with 53 cases of percutaneous vertebroplasty (PVP) according to different surgical protocols. All patients underwent CT scan based on the improved V-Net, and data of centrum measurement indicators, pain score, and therapeutic evaluation results of the modified Macnab were collected. The Dice coefficient of the improved V-Net was observably higher than that of U-Net, V-Net, and CNN, while the Hausdorff distance was lower than that of U-Net, V-Net, and CNN (P < 0.05). The anterior height, central height, and posterior height of the centrum were significantly higher than those in the control group after operation (3, 5, and 7 days), while the Cobb angle of vertebral kyphosis was significantly lower than that in the control group (P < 0.05). The score of visual analog scale (VAS) and analgesic use score of patients in the test group were markedly lower than those in the control group (3, 5, and 7 days after operation), P < 0.05. Besides, the excellent and good rate of the test group was remarkably higher than that of the control group, P < 0.05. Hence, the improved V-Net had better quality of segmentation and reconstruction than the traditional deep learning network. Compared with PVP, PKP was helpful in restoring the height of the centrum in patients with osteoporotic thoracolumbar compression fractures and correct kyphosis, with better analgesic effect safety.

Elevated Expressions of BTN3A1 and RhoB in Psoriasis Vulgaris Lesions by an Immunohistochemical Study.

Psoriasis is a chronic, immune-mediated inflammatory disease which pathogenesis is closely linked to γδ T cells. Recently, a critical role for butyrophilin 3A1 (BTN3A1) in mediating the activation of Vγ9Vδ2 T cells, which are reported to redistribute from blood to the perturbed skin lesions in psoriasis, has been proposed. Additional molecular partners, including RhoB and periplakin, have also been speculated to interact with BTN3A1 in modulating Vγ9Vδ2 T-cell activation. Immunohistochemical staining was performed to examine the expressions of BTN3A1, RhoB, and the plakin family members, including periplakin, epiplakin, and envoplakin in the psoriasis vulgaris lesions as compared with the normal control. The expressions of BTN3A1 and RhoB were found significantly upregulated in the psoriatic lesions. Besides, a downregulation of periplakin and an upregulation of epiplakin were noticed in the psoriasis vulgaris lesions. Our data suggest that BTN3A1 and RhoB might participate in the pathogenesis of psoriasis through Vγ9Vδ2 T-cell responses. In addition, a potential involvement of the plakin protein family, especially periplakin and epiplakin, in psoriasis pathology was proposed.

Diagnosis of thyroid neoplasm using support vector machine algorithms based on platelet RNA-seq.

OBJECTIVE: To assess the capacity of support vector machine (SVM) algorithms that are developed based on platelet RNA-seq data in identifying thyroid neoplasm patients and differentiating patients with thyroid adenomas, papillary thyroid cancer and metastasized papillary thyroid cancer. METHODS: Platelets were collected and isolated from 109 patients and 63 healthy controls. RNA-seq was performed to find transcripts with differential levels. Genes corresponding to these altered transcripts were identified using R packages. All samples were subsampled into a training set and a validation set. Two SVM algorithms were developed and trained with the training set, using the genes with differential transcript levels (GDTLs) as classifiers, and validated with the validation set. GO and KEGG pathway enrichment analysis were performed using the R package clusterProfiler. RESULTS: We detected 765 GDTLs (442 up-regulated and 323 down-regulated) in platelets of patients and healthy controls. The algorithm identifying thyroid neoplasm patients achieved an accuracy of 97%, with an AUC (area under curve) of 0.998. The other algorithm differentiating patients with multiclass thyroid neoplasms had an average accuracy of 80.5%. GO analysis showed that GDTLs were strongly involved in biological processes such as neutrophil degranulation, neutrophil activation, autophagy and regulation of multi-organism process. KEGG pathway enrichment analysis revealed that GDTLs were mainly enriched in NOD-like receptor signaling pathway and pathways in endocytosis, osteoclast differentiation, human cytomegalovirus infection and tuberculosis. CONCLUSION: Our results indicated that the combination of SVM algorithms and platelet RNA-seq data allowed for thyroid neoplasm diagnostics and multiclass thyroid neoplasm classification.

Impact of frailty on inpatient outcomes in thyroid cancer surgery: 10-year results from the U.S. national inpatient sample.

BACKGROUND: Frailty is linked to perioperative morbidity and mortality. We evaluated the impact of preoperative frailty on inpatient outcomes of patients undergoing surgery for thyroid malignancy. METHODS: This population-based, retrospective observational study extracted data of hospitalized patients who were 18 years and older with a primary diagnosis of thyroid cancer undergoing thyroidectomy from the US Nationwide Inpatient Sample (NIS) database (2005-2014). Participants were stratified into frail and non-frail using the Johns Hopkins (ACG) frailty-defining diagnosis indicator. Study endpoints were in-hospital mortality, incidence of surgical and medical complications and prolonged length of stay. Univariate and multivariate analysis were performed to determine associations between the endpoints and frailty. RESULTS: Data of 38,202 patients were included. After adjusting for possible confounders, frailty remained significantly associated with higher odds of in-hospital mortality (OR: 3.839, 95% CI: 1.738-8.480), prolonged length of stay (OR: 5.420, 95% CI: 3.799-7.733), surgical complications (OR: 3.144, 95% CI: 2.443-4.045) and medical complications (OR: 6.734, 95% CI: 5.099-8.893) compared with non-frailty. In patients > age 65 years, adjusted odds ratio for frailty was 4.099 (95% CI: 1.736-9.679) for in-hospital mortality, 6.164 (95% CI: 3.514-10.812) for prolonged length of stay, 3.736 (95% CI: 2.620-5.328) for surgical complications, and 5.970, 95% CI: 4.088-8.720 for medical complications, all with significance. CONCLUSION: Frailty is associated with increased risk for adverse inpatient outcomes, including prolonged hospital stay, surgical and medical complications and mortality independent of age and comorbidities in thyroid cancer patients undergoing surgery. Study findings may provide valuable information for preoperative risk stratification.

Updating and identifying three novel variants of the CARD14 gene in Chinese Han patients with psoriasis.

Psoriasis-2 (PSORS2) is caused by the heterozygous mutation of the caspase recruitment domain 14 (CARD14) gene on chromosome 17q25. To evaluate the contribution of CARD14 variants in psoriasis of the Chinese Han population, we performed deep sequencing of the CARD14 gene in 372 Chinese Han patients with psoriasis. The exonic nucleotide variants were confirmed by Sanger sequencing in the affected individuals and 1114 controls. In 27 patients with psoriasis, we identified 15 variations, including three novel variants: c.381C[G (p.Cys127Trp), c.712A[G (p.Met238Val) and c.2260_2261delinsGG (p.Gln754Gly). These findings could enrich and update the Human Gene Mutation Database of CARD14 variants for psoriasis.

Sex-related hormone receptor in laryngeal squamous cell carcinoma: correlation with androgen estrogen-ɑ and prolactin receptor expression and influence of prognosis.

BACKGROUND: The expression and function of androgen receptors (AR) and estrogen receptor alpha (ER-ɑ) in laryngeal squamous cell carcinoma (LSCC) have remained controversial for decades. Prolactin receptor (PRLR) is a sex-related hormone, that has been rarely documented in terms of expression or function compared with data on other hormone receptors in laryngeal carcinoma. METHODS: This study reports on immunohistochemical and reverse transcription-polymerase chain reaction (RT-PCR) analysis of tumour tissue and adjacent normal tissue in 96 patients with LSCC (82 males and 14 females). The expression levels of the receptors were related to clinicopathologic parameters and survival data. RESULTS: At both protein and mRNA levels, the expression level of AR, ER-ɑ, and PRLR was much higher in LSCC than in adjacent normal tissues (p < .05). Among them, higher PRLR expression in tumour tissues tended to have a significantly poorer survival rate (p = .03) for patients with LSCC. Furthermore, higher expression of ER-ɑ in tumours was correlated with higher expression level of PRLR (r = .823, p = .03). CONCLUSION: The findings of this study indicate that the sex-related hormone receptors play an important role in the development of LSCC. The PRLR represents a novel prognosticator, because of its negative effect on survival and its interaction with ER-ɑ.

Systematic bias between blinded independent central review and local assessment: literature review and analyses of 76 phase III randomised controlled trials in 45 688 patients with advanced solid tumour.

OBJECTIVE: Unbiased assessment of tumour response is crucial in randomised controlled trials (RCTs). Blinded independent central review is usually used as a supplemental or monitor to local assessment but is costly. The aim of this study is to investigate whether systematic bias existed in RCTs by comparing the treatment effects of efficacy endpoints between central and local assessments. DESIGN: Literature review, pooling analysis and correlation analysis. DATA SOURCES: PubMed, from 1 January 2010 to 30 June 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible articles are phase III RCTs comparing anticancer agents for advanced solid tumours. Additionally, the articles should report objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) or time to progression (TTP); the treatment effect of these endpoints, OR or HR, should be based on central and local assessments. RESULTS: Of 76 included trials involving 45 688 patients, 17 (22%) trials reported their endpoints with statistically inconsistent inferences (p value lower/higher than the probability of type I error) between central and local assessments; among them, 9 (53%) trials had statistically significant inference based on central assessment. Pooling analysis presented no systematic bias when comparing treatment effects of both assessments (ORR: OR=1.02 (95% CI 0.97 to 1.07), p=0.42, I2=0%; DCR: OR=0.97 (95% CI 0.92 to 1.03), p=0.32, I2=0%); PFS: HR=1.01 (95% CI 0.99 to 1.02), p=0.32, I2=0%; TTP: HR=1.04 (95% CI 0.95 to 1.14), p=0.37, I2=0%), regardless of funding source, mask, region, tumour type, study design, number of enrolled patients, response assessment criteria, primary endpoint and trials with statistically consistent/inconsistent inferences. Correlation analysis also presented no sign of systematic bias between central and local assessments (ORR, DCR, PFS: r>0.90, p<0.01; TTP: r=0.90, p=0.29). CONCLUSIONS: No systematic bias could be found between local and central assessments in phase III RCTs on solid tumours. However, statistically inconsistent inferences could be made in many trials between both assessments.