Changes in Serum Concentrations of Bone Turnover Markers in Healthy Pregnant Women.

Background: Changes in bone metabolism during pregnancy have not received sufficient attention because of the lack of effective screening tools. Bone turnover markers (BTMs) could reflect the changes of bone metabolism. Currently, reference intervals for bone metabolism during normal pregnancy are inconclusive. This study aimed to determine reference intervals for BTMs in pregnant women taking prenatal care and to facilitate clinical research on diseases affecting bone metabolism during pregnancy. Methods: We surveyed 120 low-risk pregnant women attending routine antenatal care from January 2020 to March 2020. The serum levels of procollagen type I N-propeptide (PINP), N-terminal osteocalcin (N-MID), and C-terminal telopeptide of type I collagen (ß-CTX) were measured in the first trimester (<13 weeks), second trimester (14-27 weeks), and third trimester (>28 weeks). Reference intervals for BTMs during pregnancy were analyzed. The Kruskal-Wallis test and paired t-test are used to analyze differences between groups. Spearman correlation coefficients expressed the measure of linear association. Results: The bone resorption marker ß-CTX in third trimester increases compared to the first trimester and the second trimester (P < 0.001, P < 0.001). The bone formation markers PINP and N-MID were decreased from the first trimester to the second trimester (P = 0.01, P < 0.001) and then raised from the second trimester to the third trimester (P < 0.001, P < 0.001). Two indices of bone turnover rate, ß-CTX/PINP and ß-CTX/N-MID, were increased from the first trimester to the second trimester (P < 0.001, P < 0.001) and then decreased from the second trimester to the third trimester (P = 0.02, P < 0.001). Conclusion: This study established reference intervals for BTMs in pregnant women and observed the changes in BTMs during the different trimesters of pregnancy. The present findings can help in clinical monitoring of the effects of pregnancy diseases on the bone metabolism of pregnant women.

Variation of Bone Turnover Markers in Childhood and Adolescence.

Objectives: To determine the bone metabolic marker changes from childhood to adolescence and to provide reference values for monitoring bone development in children in Southwest China. Methods: We surveyed 703 participants attending physical examinations from April 2019 and August 2021. Twenty-eight participants were excluded for lack of laboratory tests, and 14 people were excluded for diseases that might affect bone metabolism. A total of 661 children were selected for the study. According to the main developmental periods, the children were divided into preschool, preadolescence, and adolescence groups. Serum bone turnover markers including ß-isomerized C-terminal telopeptide of type I collagen (ß-CTx), N-terminal midfragment of osteocalcin (N-MID), and procollagen type 1 N-propeptide (P1NP) as well as growth and development indices such as serum calcium (Ca), phosphorus (Pi), alkaline phosphatase (ALP), and vitamin D were measured. The changes in bone metabolism-related markers and the correlations between the indices were analyzed. Results: During the development in boys, the levels of ß-CTx and N-MID increased with age from preschool to adolescence, while the levels of P1NP decreased and then increased. In girls, the levels of ß-CTx and N-MID plateaued in early adolescence and showed little change in subsequent adolescence, while the levels of P1NP exhibited a downward trend. The correlations between bone metabolism markers and vitamin D were not significant. Conclusions: The levels of bone metabolism markers differed between boys and girls. Reference intervals can be used as essential tools to examine the levels of bone metabolism markers reasonably.

Relationship between Body Mass Index and Bone Turnover Markers in Girls with Idiopathic Central Precocious Puberty.

Background: This study aimed to determine the effect of body mass index (BMI) on bone turnover markers in girls with idiopathic central precocious puberty (ICPP) according to weight status at diagnosis. Methods: Two hundred and eleven girls with ICPP were divided according to their weight status at diagnosis into three groups: normal weight, overweight, and obese. The serum levels of total procollagen type 1 N-terminal propeptide (P1NP), N-terminal midfragment of osteocalcin, ß-C-terminal telopeptide of type 1 collagen, and some biochemical indicators were measured. Associations between variables were evaluated by multiple regression analysis. Results: Serum P1NP concentrations were significantly different among groups (p < 0.001). No other significant differences were noted in N-terminal midfragment of osteocalcin and ß-C-terminal telopeptide of type 1 collagen. BMI was associated with estradiol (r = 0.155, p < 0.05) and inversely associated with P1NP (r = -0.251, p < 0.01), luteinizing hormone peak (r = -0.334, p < 0.01), follicle-stimulating hormone peak (r = -0.215, p < 0.01), and luteinizing hormone/follicle-stimulating hormone peak (r = -0.284, p < 0.01). Multiple regression analysis of factors associated with BMI showed that it was correlated with P1NP, follicle-stimulating hormone base, and luteinizing hormone peak in the overweight group and the obese group. Conclusions: Our findings showed that BMI was associated with P1NP, revealing the reduction of bone formation in overweight and obese girls with ICPP. During the diagnosis and treatment of girls with ICPP, attention should be paid to body weight and bone metabolism.

The Aetion Coalition to Advance Real-World Evidence through Randomized Controlled Trial Emulation Initiative: Oncology.

Legislative and technological advancements over the past decade have given rise to the proliferation of healthcare data generated from routine clinical practice, often referred to as real-world data (RWD). These data have piqued the interest of healthcare stakeholders due to their potential utility in generating evidence to support clinical and regulatory decision making. In the oncology setting, studies leveraging RWD offer distinct advantages that are complementary to randomized controlled trials (RCTs). They also permit the conduct of investigations that may not be possible through prospective designs due to ethics or feasibility. Despite its promise, the use of RWD for the generation of clinical evidence remains controversial due to concerns of unmeasured confounding and other sources of bias that must be carefully addressed in the study design and analysis. To facilitate a better understanding of when RWD can provide reliable conclusions on drug effectiveness, we seek to conduct 10 RWD-based studies that emulate RCTs in oncology using a systematic, protocol-driven approach described herein. Results of this investigation will help inform clinical, scientific, and regulatory stakeholders on the applications of RWD in the context of product labeling expansion, drug safety, and comparative effectiveness in oncology.

Broad application prospects of bone turnover markers in pediatrics.

BACKGROUND: Bone turnover markers (BTMs) have been studied for application in clinical medicine. However, BTMs in children are challenging, and few studies explore these BTMs in children. The application of BTMs is complicated mainly due to pre-analytical factors, variable reference intervals of age- and sex-related BTMs for adolescents and children in different regions and laboratories. Therefore, laboratory testing of BTMs is critical for understanding pediatric bone development and metabolism, which provides additional information about bone development and diseases. METHODS: Literature search was conducted using the MeSH term "child" combined with the terms that bone turnover markers such as "osteocalcin," "Procollagen type I N-terminal propeptide," "procollagen type I C-terminal propeptide," "osteocalcin," "N-terminal cross-linked telopeptide," and "C-terminal cross-linked telopeptide," Several databases including Web of Science, Google Scholar, and PubMed were searched to obtain the relevant studies. RESULTS: BTMs represent the combined effects of skeletal development, growth, and remodeling in children, which can be used in clinical pediatrics to assist in the diagnosis and prognosis of bone metabolic disorders. CONCLUSION: BTMs are clearly helpful for diagnosis and monitoring of bone growth and development as well as bone metabolic disorders.

Consistency analysis of the Sysmex UF-5000 and Atellica UAS 800 urine sedimentation analyzers.

OBJECTIVE: To evaluate the consistency between the results of Sysmex UF-5000 system and Atellica® UAS 800 Urine Sediment Analyzer. METHODS: A total of 636 random urine samples were collected from inpatients and outpatients from March to September 2021. Urine was collected for analysis by the Sysmex UF-5000, Atellica UAS 800 systems, and manual microscopic examination. The results of manual microscopy as the gold standard, the coincidence rate and false-negative rate of Sysmex UF-5000 and Atellica UAS 800 systems in the detection of red blood cells, white blood cells, and casts were calculated. RESULTS: The coincidence rates of red blood cells, white blood cells, and cast, crystals, and other sediment components for the Sysmex UF-5000 system were 85.37%, 87.89%, 91.67%, 88.36%, and 71.86%. The false-negative rates were 28.47%, 3.75%, 68.97%, 37.25%, and 30.63%. The coincidence rates of red blood cells, white blood cells, and cast, crystals, and other sediment components for the Atellica UAS 800 system were 85.06%, 90.25%, 59.12%, 91.67%, and 67.45% and the false-negative rates were 60.42%, 21.25%, 36.21%, 19.64%, and 35.80%. CONCLUSION: Two instruments are superior in the detection of red blood cells and white blood cells. The Atellica UAS 800 system with image review has a good coincidence rate in the identification of crystals and casts. The identification of various sediment components in urine by both instruments meets the laboratory requirements. Two instruments with different methodologies have their own characteristics, and we should reasonably use them according to the conditions of the laboratory.

Effectiveness of China's Protected Areas in Mitigating Human Activity Pressure.

Global protected areas are the key factor in maintaining biodiversity and ecosystem services. However, few studies use human activity pressure to assess the effectiveness of protected areas. This study constructed a human activity pressure index to assess the effectiveness of China's protected areas, and predicted the change trend in 2050 under the SSP scenarios. The results are as follows: (1) From 2000 to 2020, the pressure of human activities in 75.15% of China's protected areas is on the rise, accounting for 37.98% of the total area of the reserves. (2) China's protected areas can relieve the pressure of human activities by 1.37%, and there are regional differences in the effectiveness. (3) Under the SSP scenarios, the protected areas can alleviate the effect of the pressure of the population well. These results can provide a systematic and scientific reference for the planning, construction, evaluation and management of global protected areas.

Novel serological biomarker models composed of bone turnover markers, vitamin D, and estradiol and their auxiliary diagnostic value in girls with idiopathic central precocious puberty.

OBJECTIVE: To establish serological biomarker models composed of bone turnover markers (BTMs), vitamin D (Vit D), and estradiol (E2) and to explore their auxiliary diagnostic value in girls with idiopathic central precocious puberty (ICPP). METHODS: Ninety-three girls with ICPP and 93 healthy girls were included in the ICPP group and the control group, respectively. The serum levels of total procollagen type 1 N-terminal propeptide (P1NP), N-terminal midfragment of osteocalcin (N-MID), ß-C-terminal telopeptide of type 1 collagen (ß-CTX), Vit D, E2, and other biochemical parameters were detected in all participants. Serological biomarker models for assistance with ICPP diagnosis were established by logistic regression analyses. RESULTS: Serum P1NP, ß-CTX, Vit D, and E2 levels differed significantly between the two groups (p < 0.05). Three models were established. Model 1 consisted of P1NP and ß-CTX, and had an area under curve (AUC) of 0.764, sensitivity of 74.19%, and specificity of 72.04%. Model 2 consisted of P1NP, ß-CTX, and Vit D, and had an AUC of 0.840, sensitivity of 83.87%, and specificity of 72.04%. Model 3 consisted of P1NP, ß-CTX, Vit D, and E2, and had an AUC of 0.917, sensitivity of 82.80%, and specificity of 86.02%. CONCLUSIONS: Serum P1NP, ß-CTX, Vit D, and E2 levels may be effective indicators for auxiliary diagnosis of ICPP. Serological biomarker models composed of P1NP, ß-CTX, Vit D, and E2 (models 1, 2, and 3) may have auxiliary diagnostic value for ICPP.

Cost Effectiveness of Durvalumab in Unresectable Stage III NSCLC: 4-Year Survival Update and Model Validation from a UK Healthcare Perspective.

BACKGROUND: In the phase III PACIFIC study, durvalumab improved survival versus placebo in patients with unresectable stage III non-small-cell lung cancer (NSCLC) whose disease had not progressed after platinum-based concurrent chemoradiotherapy. The appraisal by the UK's National Institute for Health and Care Excellence (NICE) included a cost-effectiveness analysis based on an early data readout from PACIFIC [March 2018 data cut-off (DCO); median follow-up duration 25.2 months; range 0.2-43.1]. Uncertainties regarding long-term survival outcomes with durvalumab led to some challenges in estimating the cost effectiveness of this therapy. OBJECTIVE: Here, we validate the survival extrapolations used in the original company base-case analysis by benchmarking them against updated survival data from the 4-year follow-up analysis of PACIFIC (i.e. approximately 4 years after the last patient was randomised; March 2020 DCO; median follow-up duration 34.2 months; range 0.2-64.9). Moreover, we update the original analysis with these more mature survival data to examine the consistency of key economic outputs with the original analysis. METHODS: The original analysis used a semi-Markov (state-transition) approach and was based on patients whose tumours expressed programmed cell death-ligand 1 on ≥ 1% of cells (to reflect the European licence for durvalumab). We benchmarked the survival extrapolations used in the original company base-case analysis against survival data from the 4-year follow-up of PACIFIC and updated the cost-effectiveness analysis with these more mature survival data. Early deaths avoided by the adoption of durvalumab into the UK Cancer Drugs Fund (CDF) in March 2019 were estimated using the 4-year follow-up survival data and an assumed uptake of 125 patients/year (lower estimate) and 367 patients/year (higher estimate). RESULTS: The original company base-case analysis had a good visual fit with the observed overall survival (OS) distribution for the durvalumab arm and accurately predicted the 48-month OS rate (predicted 55%; observed 55%); by comparison, the fit was less precise for the placebo arm, for which the analysis underestimated the 48-month OS rate (predicted 32%; observed 38%). In the updated company base-case analysis, durvalumab yielded 2.51 incremental quality-adjusted life-years (QALYs) (- 0.43 vs. the original company base-case analysis), corresponding to an incremental cost-effectiveness ratio of £22,665/QALY (+£3298 vs. the original analysis), which falls within the upper bound of NICE's willingness-to-pay threshold (£30,000/QALY gained). We estimate that between 31 and 91 early patient deaths may have been avoided by the adoption of durvalumab into the CDF. CONCLUSIONS: These findings reinforce the patient benefit observed with durvalumab in unresectable stage III NSCLC, support the routine use and cost effectiveness of this therapy, and demonstrate how appropriate modelling can inform the early adoption of therapies by payers to achieve patient benefit.

Based on the results of a clinical trial, the European Medicines Agency approved durvalumab for the treatment of adults with a specific type of advanced lung cancer whose tumours cannot be removed surgically and whose disease has not progressed after chemotherapy and radiotherapy. The UK's National Institute for Health and Care Excellence (NICE) invites companies to submit cost-effectiveness analyses to help with decision making about adopting new therapies. The company included an analysis based on early trial data that suggested durvalumab was cost effective compared with other previous treatments. As patients in the study at the time of the initial submission to NICE were only followed for approximately 2 years, the long-term survival benefit that could be achieved with durvalumab was uncertain. Therefore, NICE recommended durvalumab for use within the Cancer Drugs Fund (CDF) to allow patients to access the drug while more data were being collected. Here, we demonstrate that the original cost-effectiveness model accurately predicted the rates of long-term survival for patients receiving durvalumab and that durvalumab remains a cost-effective use of healthcare resources based on recently published data from the trial (which added approximately 2 further years of follow-up). Moreover, we estimate that adopting durvalumab into the CDF may have avoided 31­91 early patient deaths from lung cancer. These findings support NICE's early decision to make durvalumab available within the CDF and the adoption of durvalumab for routine use within the UK national health service.

The diagnostic and predictive values of N-terminal pro-B-type natriuretic peptides in pregnancy complications and neonatal outcomes.

OBJECTIVE: To investigate the plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels relative to pregnancy complications and clarify the role of NT-proBNP in predicting pregnancy outcomes. METHODS: A retrospective cohort study was conducted on 208 singleton pregnant women from August 2015 to October 2018. They were categorized into the early-onset PE (n=52), late-onset PE (n=32), GH (n=21), GDM (n=49), and healthy control (n=54) groups. The NT-proBNP concentrations were measured for all groups, and the correlation between the NT-proBNP levels and the pregnancy complications was analyzed. RESULTS: The NT-proBNP levels were significantly higher in the early-onset and late-onset PE groups than in the other groups (P<0.05). The receiver operating characteristic curve showed that the plasma NT-proBNP levels had excellent diagnostic performance for early-onset and late-onset PE. The areas under the curve (AUCs) were 0.864 and 0.825 at the cut-off values of 142.3 pg/mL and 183.5 pg/mL for these two groups, respectively. The plasma NT-proBNP concentrations were positively correlated with the neonatal outcomes. The AUC was 0.788 when the cut-off value was 257.5 pg/mL. The high NT-proBNP level was associated with a low Apgar score and low birth weight. CONCLUSION: NT-proBNP is an effective indicator for assisting in the diagnosis of pregnancy complications and predicting newborn outcomes. NT-proBNP can be used to monitor early-onset and late-onset PE.

Assessing the Influence of Subsequent Immunotherapy on Overall Survival in Patients with Unresectable Stage III Non-Small Cell Lung Cancer from the PACIFIC Study.

BACKGROUND: Historically, the standard of care for patients with unresectable, Stage III non-small cell lung cancer had been concurrent chemoradiotherapy. However, outcomes had been poor, with approximately 15% to 32% of patients alive at 5 years. In the placebo-controlled Phase III A PACIFIC trial, consolidation treatment with durvalumab after concurrent chemoradiotherapy significantly improved overall survival (OS) and progression-free survival in patients with unresectable, Stage III non-small cell lung cancer, establishing this regimen as a new standard of care in this setting. In the PACIFIC trial, crossover between treatment arms (durvalumab or placebo) was not permitted. However, after discontinuation from study treatment, patients from both arms of PACIFIC could switch to subsequent anticancer therapy, including durvalumab and other immunotherapies, which is known to influence standard intention-to-treat analysis of OS, potentially underestimating the effect of an experimental drug. Moreover, the introduction of immunotherapies has demonstrated marked improvements in the postprogression, metastatic non-small cell lung cancer setting. OBJECTIVE: To examine the influence of subsequent immunotherapy on OS in the PACIFIC trial. METHODS: Both a Rank Preserving Structural Failure Time Model (RPSFTM) and modified 2-stage method were used. RPSFTM assumes that a patient's survival time with no immunotherapy (counterfactual survival time) is equal to the observed time influenced by immunotherapy, multiplied by an acceleration factor, plus the time not influenced. The modified 2-stage method estimates the effect of immunotherapy by comparing postsubsequent-treatment-initiation survival times between patients with and without subsequent immunotherapy. In both models, OS was adjusted to reflect a hypothetical scenario in which no patients received subsequent immunotherapy. RPSFTM was also used for scenarios in which subsequent immunotherapy was received by increasing proportions of placebo patients but none of the durvalumab patients. RESULTS: In the intention-to-treat analysis (3-year follow-up), durvalumab improved OS versus placebo (stratified hazard ratio = 0.69; 95% CI, 0.55-0.86). Overall, 10% and 27% of durvalumab and placebo patients, respectively, received subsequent immunotherapy. With subsequent immunotherapy removed from both arms, estimated hazard ratio was 0.66 (95% CI, 0.53-0.84) with RPSFTM and 0.68 (95% CI, 0.54-0.85) with the modified 2-stage method. With subsequent immunotherapy removed from the durvalumab arm only (RPSFTM), estimated hazard ratio increased as the proportion of placebo patients receiving subsequent immunotherapy increased, up to 0.75 (95% CI, 0.60-0.94) maximum (assuming all placebo patients with subsequent treatment received immunotherapy). CONCLUSIONS: Results were consistent with the intention-to-treat analysis, supporting the conclusion that durvalumab after chemoradiotherapy provides substantial OS benefit in patients with Stage III, unresectable non-small cell lung cancer. ClinicalTrials.gov identifier: NCT02125461 (Curr Ther Res Clin Exp. 2021; 82:XXX-XXX).

Pyramiding of Fusarium Head Blight Resistance Quantitative Trait Loci, Fhb1, Fhb4, and Fhb5, in Modern Chinese Wheat Cultivars.

Wheat production is increasingly threatened by the fungal disease, Fusarium head blight (FHB), caused by Fusarium spp. The introduction of resistant varieties is considered to be an effective measure for containment of this disease. Mapping of FHB-resistance quantitative trait locus (QTL) has promoted marker-assisted breeding for FHB resistance, which has been difficult through traditional breeding due to paucity of resistance genes and quantitative nature of the resistance. The lab of Ma previously cloned Fhb1, which inhibits FHB spread within spikes, and fine mapped Fhb4 and Fhb5, which condition resistance to initial infection of Fusarium spp., from FHB-resistant indigenous line Wangshuibai (WSB). In this study, these three QTLs were simultaneously introduced into five modern Chinese wheat cultivars or lines with different ecological adaptations through marker-assisted backcross in early generations. A total of 14 introgression lines were obtained. All these lines showed significantly improved resistance to the fungal infection and disease spread in 2-year field trials after artificial inoculation. In comparison with the respective recipient lines, the Fhb1, Fhb4, and Fhb5 pyramiding could reduce the disease severity by 95% and did not systematically affect plant height, productive tiller number, kernel number per spike, thousand grain weight, flowering time, and unit yield (without Fusarium inoculation). These results indicated the great value of FHB-resistance QTLs Fhb1, Fhb4, and Fhb5 derived from WSB, and the feasibility and effectiveness of early generation selection for FHB resistance solely based on linked molecular markers.

Clinical significance of MDRO screening and infection risk factor analysis in the ICU.

OBJECTIVE: This study aimed to investigate the clinical significance of multi-drug resistant organism (MDRO) screening and infection risk factor analysis in the intensive care unit (ICU). METHOD: A total of 210 patients treated in the ICU of our hospital were enrolled as the study subjects, and were divided into the MDRO group (n=100 cases) and the non-MDRO group (n=110) according to the presence or absence of MDRO infection after examination of the pharyngeal swabs. The pathogens of MDRO infection and drug resistance were analyzed. The single-factor as well as multifactor logistic regression analysis of MDRO infections were carried out and the 30-d mortality rate, hospitalization time and treatment costs were compared between the two groups. RESULTS: A total of 158 MDRO strains were detected in 100 patients with MDRO infection, of which G-84 accounted for 53.16% and G+ 74 accounted for 46.84%. The resistance analysis revealed that G-MDRO was sensitive to imipenem and G+ MDRO was sensitive to vancomycin, and no vancomycin-resistant MDROs were found. The logistic regression model and multifactorial analysis showed that mechanical ventilation, arterial and venous intubation, implementation of fiberoptic bronchoscopy, concurrent chronic lung disease and chronic cardiovascular disease were independent risk factors for the development of MDRO infection (P<0.05). The length of hospital stay, cost of treatment, and 30-d mortality rate in the MDRO group were significantly higher than those in the non-MDRO group (P<0.05). CONCLUSION: ICU mechanical ventilation, arterial and intravenous intubation, fiberoptic bronchoscopy, concurrent chronic lung disease and chronic cardiovascular disease are the independent risk factors for MDRO infection.

STROBE-sequencing analysis of the vaginal microecology of 4- to 6-year-old girls in Southwest China.

ABSTRACT: We investigated the vaginal flora diversity of preschool-aged (ie, 4-6-year-old) girls in southwest China.Fourteen preschool-aged girls were enrolled in this study. The statuses and differences in their vaginal flora were evaluated by Gram staining, bacterial culturing, and sequencing analysis.Gram staining and microbial culturing showed that the main vaginal flora of the preschool-aged girls were Gram-negative bacilli, whereas the main vaginal flora of healthy adult controls were large Gram-positive bacilli such as Lactobacillus crispatus. Shannon and Simpson indexes indicated that the bacterial diversity tended to decrease with age. The species abundance heat map showed that the vaginal microecology of the girls differed slightly at different ages but mainly comprised Pseudomonas, Methylobacterium, Sphingomona,s and Escherichia. The functional abundance heat map indicated that the bacterial functions increased with age.The vaginal microecology of preschool-aged girls differs from that of adults. A comprehensive understanding of the vaginal flora diversity of preschool-aged girls will aid in clinically diagnosing vulvovaginitis in preschool-aged girls.

Patient-reported outcomes with durvalumab by PD-L1 expression and prior chemoradiotherapy-related variables in unresectable stage III non-small-cell lung cancer.

Aim: We retrospectively investigated the impact of tumor PD-L1 expression and prior chemoradiotherapy (CRT)-related variables on patient-reported outcomes (PROs) from PACIFIC. Patients & methods: PACIFIC was a Phase III study of durvalumab versus placebo after CRT in patients with unresectable, stage III non-small-cell lung cancer. If available, pre-CRT tumor tissue was tested for PD-L1 tumor-cell expression, scored at prespecified (25%) and post-hoc (1%) cut-offs. PROs were assessed using EORTC QLQ C30/-LC13. Results: Similar to the intent-to-treat (ITT) population, most PROs remained stable over time across PD-L1 and CRT subgroups, with few clinically relevant differences between treatment arms. Time to deterioration was generally similar to the ITT population. Conclusion: Neither PD-L1 expression nor prior CRT-related variables influenced PROs with durvalumab therapy. Clinical trial registration: NCT02125461 (ClinicalTrials.gov).

Cost-Effectiveness of Durvalumab After Chemoradiotherapy in Unresectable Stage III NSCLC: A US Healthcare Perspective.

BACKGROUND: Durvalumab was approved by the FDA in February 2018 for patients with unresectable stage III NSCLC that has not progressed after platinum-based concurrent chemoradiotherapy (cCRT), and this regimen is the current standard of care. The objective of this study was to examine the cost-effectiveness of durvalumab following cCRT versus cCRT alone in patients with locally advanced, unresectable stage III NSCLC. METHODS: A 3-state semi-Markov model was used. Modeling was performed in a US healthcare setting from Medicare and commercial payer perspectives over a 30-year time horizon. Clinical efficacy (progression-free and post progression survival) and utility inputs were based on PACIFIC study data (ClinicalTrials.gov identifier: NCT02125461; data cutoff March 22, 2018). Overall survival extrapolation was validated using overall survival data from a later data cutoff (January 31, 2019). The main outcome was the incremental cost-effectiveness ratio (ICER) of durvalumab following cCRT versus cCRT alone, calculated as the difference in total costs between treatment strategies per quality-adjusted life-year (QALY) gained. RESULTS: In the base-case analysis, durvalumab following cCRT was cost-effective versus cCRT alone from Medicare and commercial insurance perspectives, with ICERs of $55,285 and $61,111, respectively, per QALY gained. Durvalumab was thus considered cost-effective at the $100,000 willingness-to-pay (WTP) threshold. Sensitivity analyses revealed the model was particularly affected by variables associated with subsequent treatment, although no tested variable increased the ICER above the WTP threshold. Scenario analyses showed the model was most sensitive to assumptions regarding time horizon, treatment effect duration, choice of fitted progression-free survival curve, subsequent immunotherapy treatment duration, and use of a partitioned survival model structure. CONCLUSIONS: In a US healthcare setting, durvalumab was cost-effective compared with cCRT alone, further supporting the adoption of durvalumab following cCRT as the new standard of care in patients with unresectable stage III NSCLC.

Long-term survival trends in patients with unresectable stage III non-small cell lung cancer receiving chemotherapy and radiation therapy: a SEER cancer registry analysis.

BACKGROUND: To evaluate the value of new therapies for non-small cell lung cancer (NSCLC), it is necessary to understand overall survival (OS) rates associated with previous standard therapies and how these rates have evolved over time. METHODS: We retrospectively analyzed data from patients enrolled in the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Adults with unresectable, stage III NSCLC treated with chemoradiotherapy were grouped by diagnosis year (2000-2002; 2003-2005; 2006-2008; 2009-2011; 2012-2013). The primary endpoint was OS (data cut-off, December 31, 2014), estimated using the Kaplan-Meier estimator. Temporal survival-trend significance was tested using a two-sided log-rank trend test. RESULTS: Of 12,865 eligible patients, 59.1% were male, 59.9% had stage IIIB disease, and 62.7% had non-squamous histology. Median age at diagnosis was 67 years. Overall, 10,899 (84.7%) patients died and 1966 (15.3%) were censored/lost to follow-up. Median follow-up (95% confidence interval [CI]) was 80 (77-82) months; median OS (95% CI) was 15 (15-16) months; 1- and 3-year survival probabilities (95% CI) were 57.7% (56.9-58.6) and 24.1% (23.3-24.8), respectively. Stratification by diagnosis year showed consistent improvements in survival over time (p < 0.0001 for trend). Median OS was 12, 14, 15, 18, and 19 months in successive cohorts. CONCLUSIONS: OS in patients diagnosed with unresectable, stage III NSCLC between 2003 and 2013 was consistent with that from clinical studies of sequential/concurrent chemoradiotherapy. Despite improvement over time, median OS was < 2 years and mortality remained high during the first year post-diagnosis.

Cronobacter sakazakii induces necrotizing enterocolitis by regulating NLRP3 inflammasome expression via TLR4.

Introduction. Neonatal infection with Cronobacter sakazakii can cause severe intestinal damage and necrotizing enterocolitis (NEC). The inflammasome and Toll-like receptors mediate intestinal damage caused by other intestinal pathogens causing NEC, but the exact mechanism is unclear.Aim. We evaluated the molecular mechanisms underlying C. sakazakii-induced NEC.Methodology. The effects of C. sakazakii treatment on two cell lines and a Sprague-Dawley rat model of NEC were evaluated by a cell death assay, western blot and real-time PCR analyses of the NLRP3 inflammasome and downstream factors, and observation of cell and intestinal damage.Results. C. sakazakii caused cellular damage in vitro, as well as intestinal damage in an animal model. NLRP3, caspase-1, TLR4 and MyD88, as well as the downstream factor IL-1ß, were upregulated in C. sakazakii-infected J774A.1 and HT-29 cells. Western blotting showed that C. sakazakii-infected J774A.1 and HT-29 cells and the NEC rat model had higher expression levels of N-terminal gasdermin D (GSDMD) compared with those in the control groups. C. sakazakii and its components promote NF-κB expression via the TLR4/MyD88 signalling pathway, thereby regulating the NLRP3 inflammasome and mediating GSDMD cleavage, resulting in pyroptosis-induced intestinal damage.Conclusion. We found that C. sakazakii upregulates NF-κB via TLR4/MyD88 to promote activation of the NLRP3 inflammasome, leading to the up-regulation of downstream caspase-1, release of IL-1ß, GSDMD-mediated pyroptosis and development of NEC. These findings clarify the mechanisms by which C. sakazakii contributes to NEC.

Characteristics of bone turnover markers in women with gestational diabetes mellitus.

BACKGROUND: Bone turnover markers (BTMs) can be applied to the assessment of bone formation and bone resorption activity. The aim of this study was to investigate the changes in BTMs in women with gestational diabetes mellitus (GDM). METHODS: One hundred and five women with gestational diabetes mellitus defined as the GDM group and 46 healthy pregnant women with normal glucose tolerance selected as the control group were enrolled in this study. Serum samples were collected during regular obstetric examinations and the serum levels of total procollagen type 1 N-terminal propeptide (P1NP), N-terminal midfragment of osteocalcin (N-MID), and ß-C-terminal telopeptide of type 1 collagen (ß-CTX) were measured. An independent-sample t-test, the Mann-Whitney U test, and a Pearson correlation analysis were performed for data analyses. RESULTS: Serum ß-CTX levels in the GDM group were significantly higher than those in the control group (296.00 [235.00-369.00] pg/mL vs. 218.5 [165.25-292.50] pg/mL, p < 0.05), while P1NP and N-MID levels did not differ between the two groups. The Pearson correlation analysis revealed that ß-CTX level was correlated with blood glucose level. CONCLUSIONS: The difference in ß-CTX levels indicated that bone resorption in patients with GDM diabetes was higher than that in pregnant women with normal glucose tolerance. No obvious differences in bone formation markers P1NP and N-MID were found between the two groups.

Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study.

BACKGROUND: In the ongoing, phase 3 PACIFIC trial, durvalumab improved the primary endpoints of progression-free survival and overall survival compared with that for placebo, with similar safety, in patients with unresectable, stage III non-small-cell lung cancer. In this analysis, we aimed to evaluate one of the secondary endpoints, patient-reported outcomes (PROs). METHODS: PACIFIC is an ongoing, international, multicentre, double-blind, randomised, controlled, phase 3 trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0 or 1, with histologically or cytologically documented stage III, unresectable non-small-cell lung cancer, for which they had received at least two cycles of platinum-based chemoradiotherapy, with no disease progression after this treatment. We randomly assigned patients (2:1) using an interactive voice response system and a blocked design (block size=3) stratified by age, sex, and smoking history to receive 10 mg/kg intravenous durvalumab or matching placebo 1-42 days after concurrent chemoradiotherapy, then every 2 weeks up to 12 months. The primary endpoints of progression-free survival and overall survival have been reported previously. PROs were a prespecified secondary outcome. We assessed PRO symptoms, functioning, and global health status or quality of life in the intention-to-treat population with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) at the time of random allocation to groups, at weeks 4 and 8, every 8 weeks until week 48, and then every 12 weeks until progression. Changes from baseline to 12 month in key symptoms were analysed with mixed model for repeated measures (MMRM) and time-to-event analyses. A 10-point or greater change from baseline (deterioration or improvement) was deemed clinically relevant. This study is registered with ClinicalTrials.gov, NCT02125461, and EudraCT, 2014-000336-42. FINDINGS: Between May 9, 2014, and April 22, 2016, 476 patients were assigned to receive durvalumab, and 237 patients were assigned to receive placebo. As of March 22, 2018, the median follow-up was 25·2 months (IQR 14·1-29·5). More than 79% of patients given durvalumab and more than 82% of patients given placebo completed questionnaires up to week 48. Between baseline and 12 months, the prespecified longitudinal PROs of interest, cough (MMRM-adjusted mean change 1·8 [95% CI 0·06 to 3·54] in the durvalumab group vs 0·7 [-1·91 to 3·30] in the placebo group), dyspnoea (3·1 [1·75 to 4·36] vs 1·4 [-0·51 to 3·34]), chest pain (-3·1 [-4·57 to -1·60] vs -3·5 [-5·68 to -1·29]), fatigue (-3·0 [-4·53 to -1·50] vs -5·2 [-7·45 to -2·98]), appetite loss (-5·8 [-7·28 to -4·36] vs -7·0 [-9·17 to -4·87]), physical functioning (0·1 [-1·10 to 1·28] vs 2·0 [0·22 to 3·73]), and global health status or quality of life (2·6 [1·21 to 3·94] vs 1·8 [-0·25 to 3·81]) remained stable with both treatments, with no clinically relevant changes from baseline. The between-group differences in changes from baseline to 12 months in cough (difference in adjusted mean changes 1·1, 95% CI -1·89 to 4·11), dyspnoea (1·6, -0·58 to 3·87), chest pain (0·4, -2·13 to 2·93), fatigue (2·2, -0·38 to 4·78), appetite loss (1·2, -1·27 to 3·67), physical functioning (-1·9, -3·91 to 0·15), or global health status or quality of life (0·8, -1·55 to 3·14) were not clinically relevant. Generally, there were no clinically important between-group differences in time to deterioration of prespecified key PRO endpoints. INTERPRETATION: Our findings suggest that a clinical benefit with durvalumab can be attained without compromising PROs. This result is of note because the previous standard of care was observation alone, with no presumed detriment to PROs. FUNDING: AstraZeneca.