Phase Ⅱ study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA

Objective:Apatinib is an oral TKI targeting VEGFR-2.Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated m BC.Oral vinorelbine also holds promise as a treatment of choice in patients with m BC.This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated m BC.In addition,we detected gene variants in ct DNA to explore the therapeutic implications.Methods:This study enrolled patients with HER2-negative m BC who were pretreated with anthracycline/taxanes.Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1,8,and 15 of every cycle(3 weeks).The primary endpoint was PFS.The secondary endpoints were ORR,CBR,OS,and safety.Patients eligible for ct DNA detection were evaluated before and during treatment.Results:Forty patients were enrolled.The median PFS was 5.2 months(95%CI,3.4–7.0 months),and the median OS was 17.4 months(95%CI,8.0–27.0 months).The ORR was 17.1%(6/35),and the CBR was 45.7%(16/35).The most common AEs included gastrointestinal reaction,myelosuppression,and hypertension.In 20 patients,ct DNA was detected at baseline and during treatment.A significant difference was found in PFS for undetected vs.detected baseline ct DNA(13.9 months vs.3.6 months,P=0.018).Conclusions:All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative m BC,with acceptable and manageable toxicity profiles.Patients with no gene variant detected and lower variant allele frequencies in ct DNA at baseline showed longer PFS.

Anti-corisin immunotherapy:therapeutic perspective for reducing the risk of developing COVID-19 coagulopathy?

Corisin,a 19 amino acid proapoptotic peptide derived from the lung microbiota(i.e.,by Staphylococci),is implicated in the pathogenesis of acute lung injury and exacerbation of pulmonary fibrosis.Recent evidence also suggests that this molecule may have a role in lung thrombosis,as its concentration correlates with a prothrombotic state.It has also been demonstrated that corisin inhibition by using monoclonal antibodies is effective inhibiting pulmonary fibrosis and venous thrombosis in patients with coronavirus disease 2019(COVID-19).Further studies should hence be planned to verify whether anti-corisin immunotherapy could become a reliable therapeutic perspective against the risk of developing COVID-19 coagulopathy.

Prognostic significance of red blood cell distribution width in gastrointestinal disorders

The red blood cell distribution width(RDW) is a routinely measured and automatically reported blood parameter,which reflects the degree of anisocytosis. Recently,the baseline RDW was found to have clinical significance for assessing clinical outcome and severity of various pathological conditions including cardiovascular diseases,sepsis,cancers,leukemia,renal dysfunction and respiratory diseases. A myriad of factors,most of which ill-defined,have an impact on the red cell population dynamics(i.e.,production,maturation and turnover). A delay in the red blood cell clearance in pathological conditions represents one of the leading determinants of increased anisocytosis. Further study of RDW may reveal new insight into inflammation mechanisms. In this review,we specifically discuss the current literature about the association of RDW in various disease conditions involving the gastrointestinal and hepatobiliary systems. We also present some of the related measurements for their value in predicting clinical outcomes in such conditions. According to our data,RDW was found to be a valuable prognostic index in gastrointestinal disorders along with additional inflammatory biomarkers(i.e.,C reactive protein,erythrocyte sedimentation rate,and platelet count) and current disease severity indices used in clinical practice.

Red blood cell distribution width: A marker of anisocytosis potentially associated with atrial fibrillation

The incorporation of biomarkers in the actually used risk scores seem to be helpful for early identifying atrial fibrillation(AF)patients at higher risk.The aim of this critical review of the scientific literature is to investigate the potential clinical significance of red blood cell distribution width(RDW)in AF.A systematic electronic search was carried out to identify all articles describing an epidemiological association between RDW and AF in adult human populations.Data abstraction was conducted on a final number of 35 articles(13 crosssectional,12 prospective and 10 retrospective studies).The results of these epidemiological investigations were all virtually concordant to emphasize that an enhanced RDW value is not only a predictive factor and a marker of AF but its measurement may also be helpful for predicting the risk of developing many adverse complications in patients with AF,such as recurrence and duration of AF,hospitalization for heart failure,bleeding,left atrial thrombosis and stasis,thromboembolic events and mortality.AF patients with RDW values exceeding the local reference range may be more aggressively investigated and managed,in order to identify and attenuate the impact of possible underlying disorders causing both anisocytosis and AF.

Elevated fibrinogen plasma level is not an independent predictor of poor prognosis in a large cohort of Western patients undergoing surgery for colorectal cancer

AIM To evaluate the clinical significance of the preoperative fibrinogen plasma level as a prognostic marker after surgery for colorectal cancer.METHODS This retrospective study analysed 652 patients undergoing surgery for stage Ⅰ-Ⅳ colorectal cancer between January 2005 and December 2012, at the Division of General Surgery A, University of Verona Hospital Trust, in whom preoperative fibrinogen plasma values were assessed at baseline. Fibrinogen is involved in tumourigenesis as well as tumour progression in several malignancies. Correlations between preoperative plasma fibrinogen values and clinicopathological characteristics were investigated. Univariate and multivariate survival analyses were performed to identify factors associated with overall and tumour-related survival.RESULTS Among the 652 patients, the fibrinogen value was higher than the threshold of 400 mg/dL in 345 patients(53%). The preoperative mean ± SD of fibrinogen was 426.2 ± 23.2 mg/dL(median: 409 mg/dL; range: 143-1045 mg/d L). Preoperative fibrinogen values correlated with age(P = 0.003), completeness of tumour resection, potentially curative vs palliative(P < 0.001), presence of systemic metastasis(P < 0.001), depth of tumour invasion p T(P < 0.001), nodes involvement p N(P = 0.001) and CEA serum level(P < 0.001). The mean fibrinogen value(± SD) was 395.6 ± 120.4 mg/d L in G1 tumours, 424.1 ± 121.4 mg/dL in G2 tumours and 453.4 ± 131.6 mg/dL in G3 tumours(P = 0.045). The overall survival and tumourrelated survival were significantly higher in patients with fibrinogen values ≤ 400 mg/d L(P < 0.001). However, hyperfibrinogenemia did not retain statistical significance regarding either overall(P = 0.313) or tumour-related survival(P = 0.355) after controlling for other risk factors in a multivariate analysis.CONCLUSION Preoperative fibrinogen levels correlate with cancer severity but do not help in predicting patient prognosis after colorectal cancer surgery.

Myalgia may not be associated with severity of coronavirus disease 2019 (COVID-19)

Dear editor,A recent study based on the use of experimental artificial intelligence(AI)tool showed 70%–80%accuracy in predicting development of severe disease in coronavirus disease 2019(COVID-19)based on predictive parameters alanine aminotransferase(ALT),myalgia and hemoglobin,whilst only 5 of 53 patients developed acute respiratory distress syndrome(ARDS),2 of whom reporting myalgia.

Misuse of the metabolic modulator meldonium in sports

1.Biochemical structure and molecular activity of meldonium Meldonium(commercial name Mildronate)was originally synthesized in the mid-1970s at the Institute of Organic Synthesis of the Latvian Soviet Socialist Republic Academy of Sciences.The chemical structure of this compound(3-(2,2,2-

Retrospective analysis of early COVID-19 vaccine efficacy in older individuals receiving primary cycle, first booster and second booster

Background:We analysed data garnered during the ongoing Italian nationwide coronavirus disease 2019(COVID-19)vaccination campaign for comparing early COVID-19 monovalent vaccine efficacy in older persons who received the primary vaccination cycle,the first vaccine booster,and the second vaccine booster.Methods:We conducted a retrospective analysis of early COVID-19 monovalent vaccine efficacy(i.e.,within 120 days)against COVID-19 related hospitalizations,intensive care unit(ICU)admissions and deaths in older persons(i.e.,aged≥80 years),by accessing official data of the COVID-19 national integrated surveillance program instituted by the Italian National Institute of Health.Vaccine efficacy was compared(odds ratio;OR)among cohorts receiving the primary vaccination cycle,the first vaccine booster,and the second vaccine booster.Results:A consistent decline could be seen in the rate of COVID-19 hospitalizations,ICU admissions and deaths with increasing number of monovalent immunizations.Within 120 days of administration,the first and second vaccine boosters had superior efficacy compared to the primary vaccination cycle,reducing the odds of all endpoints between 62%-71%and 69%-84%,respectively.A modestly superior early efficacy could also be noted for the second versus the first monovalent vaccine booster(ORs of all endpoints further reduced by 18%-48%).Conclusion:Since an increasing number of immunizations is associated with a lower risk of unfavourable COVID-19 outcomes,vaccine boosters may be useful for limiting the clinical burden of this infectious disease in elderly populations.

Harmonization of SARS-CoV-2 antigen immunoassays:are they measuring the same“thing”?

Background:This study was planned to assess the accuracy and comparability of two commercially available,laboratory-based SARS-CoV-2(severe acute respiratory syndrome)antigen(Ag)immunoassays.Methods:We studied a cohort of subjects with acute SARS-CoV-2 infection,from whom a nasopharyngeal swab was taken and tested with a molecular assay(Altona Diagnostics RealStar SARS-CoV-2 RT-PCR Kit)and two laboratory-based,fully automated SARS-CoV-2 Ag immunoassays(Fujirebio Lumipulse G SARS-CoV-2 Ag and Roche Elecsys SARS-CoV-2 Ag).Results:The final population consisted in 93 subjects testing positive for SARS-CoV-2 RNA,34 with cycle threshold(Ct)values<29.5.The results of the two SARS-CoV-2 Ag immunoassays were significantly intercorrelated(r=0.77;P<0.001)in the entire cohort,though such correlation considerably improved in patients with high viral load(cycle threshold values<29.5:r=0.96;P<0.001).The accuracy for identifying samples with high viral load was excellent for both Lumipulse G SARS-CoV-2 Ag(AUC,0.99;P<0.001)and Elecsys SARS-CoV-2 Ag(AUC,0.99;P<0.001),with best cut-offs of 2.03 ng/mL for Lumipulse G SARS-CoV-2 Ag(1.00 sensitivity and 0.88 specificity)and 0.70 COI for Elecsys SARS-CoV-2 Ag(1.00 sensitivity and 0.80 specificity),respectively.Conclusion:The results of this study provide valuable support to usability of fully-automated,rapid,high throughput and accurate SARS-CoV-2 Ag immunoassays for complementing molecular assays.

The impact of COVID-19 pandemic on teeth grinding in the US and UK

Background:Preliminary evidence suggests that the burden of stress and anxiety may have considerably increased during the coronavirus disease 2019(COVID-19)pandemic.Since these two mental health-related factors are important causes of teeth grinding,we carried out an infodemiological analysis to define whether the burden of teeth grinding may have increased as a consequence of COVID-19.Methods:We conducted an electronic search in Google Trends,with the term“teeth grinding”,setting the geographical area to“US”or“UK”and the search period between July 2017 and July 2022.The weekly Google Trends score for“teeth grinding”was downloaded,and the difference in the volume Google searches for“teeth grinding”was compared between the pre-COVID-19 and COVID-19 periods in both countries.Results:The median value of weekly Google Trends score for“teeth grinding”was found to be significantly increased after emergence of the COVID-19 pandemic both in the UK(57 with interquartile range[IQR]51-64 vs.48 with IQR 42-53;+19%and P<0.001)and the US(78 with IQR 73-83 vs.70 with IQR 66-74;+11%and P<0.001),compared to the homologous period before.Conclusion:The results of this infodemiological analysis reveal that the volume of Web searches for“teeth grinding”in both the UK and US has considerably increased after emergence of the COVID-19 pandemic,thus probably reflecting an increased burden of this condition in the general population.

Pooled analysis of efficacy of the fourth mRNA-based COVID-19 vaccine dose in eliciting anti-SARS-CoV-2 serum antibody response in the general immunocompetent population

Objective:Since the opportunity of widespread administration of the fourth mRNA-based coronavirus disease 2019(COVID-19)vaccine dose remains controversial,this article provides a pooled analysis of the efficacy of the second COVID-19 mRNA-based homologous vaccine booster in eliciting anti-SARS-CoV-2 serum antibody response in general immunocompetent populations.Methods:We conducted a digital search in Medline using the keywords"fourth dose"or"second booster"and"antibodies"and"COVID-19"or"SARS-CoV-2"and"BNT162b2"or"mRNA-1273",to identify all clinical studies which evaluated the anti-SARS-CoV-2 serum antibody response after the fourth mRNA-based COVID-19 homologous vaccine dose administration in general immunocompetent populations compared to the response seen before its administration and after the first booster.Results:Four studies totaling 571 recipients of the second mRNA-based COVID-19 vaccine booster were finally included in our analysis.The weighted mean difference(WMD)ratio of anti-SARS-CoV-2 serum antibodies levels measured after and before administration of the fourth vaccine dose was 9.7(95%CI,6.5-12.9)in those receiving BNT162b2 and 12.0(95%CI,5.8-18.2)in those receiving mRNA-1273,respectively.The WMD ratio of anti-SARS-CoV-2 serum antibodies levels measured at the peak of the fourth and third vaccine doses was 1.4(95%CI,1.2-1.7)in those receiving BNT162b2 and 1.9(95%CI,1.5-2.4)in those receiving mRNA-1273,respectively.Conclusion:Our data confirm the efficacy of the fourth mRNA-based COVID-19 vaccine dose in restoring a satisfactory level of anti-SARS-CoV-2 serum antibodies,though such effectiveness seems only marginally superior to that of the first booster.

Red blood cell distribution width in heart failure: A narrative review

The red blood cell distribution width(RDW) is a simple, rapid, inexpensive and straightforward hematological parameter, reflecting the degree of anisocytosis in vivo. The currently available scientific evidence suggests that RDW assessment not only predicts the risk of adverse outcomes(cardiovascular and all-cause mortality, hospitalization for acute decompensation or worsened left ventricular function) in patients with acute and chronic heart failure(HF), but is also a significant and independent predictor of developing HF in patients free of this condition. Regarding the biological interplay between impaired hematopoiesis and cardiac dysfunction, many of the different conditions associated with increased heterogeneity of erythrocyte volume(i.e., ageing, inflammation, oxidative stress, nutritional deficiencies and impaired renal function), may be concomitantly present in patients with HF, whilst anisocytosis may also directly contribute to the development and worsening of HF. In conclusion, the longitudinal assessment of RDW changes over time may be considered an efficient measure to help predicting the risk of both development and progression of HF.

Procalcitonin in inflammatory bowel disease: Drawbacks and opportunities

The measurement of procalcitonin has recently become a mainstay for the diagnosis and therapeutic management of severe bacterial infections, especially those sustained by Gram-negative bacteria. Therefore, the aim of this article is to provide a narrative overview on the potential role of procalcitonin measurement in patients with inflammatory bowel disease(IBD). According to the available scientific literature, the clinical significance of procalcitonin for diagnosing IBD or monitoring disease activity remains elusive, and its association with disease severity is confined to a limited number of case-control studies, with low sample size. Nevertheless, literature data also suggests that a supranormal procalcitonin serum concentration(i.e., > 0.5 ng/m L) may reflect the presence of a number of infective complications in IBD, especially bacterial enterocolitis, bacterial gastroenteritis, intraabdominal abscess, postsurgical infection and sepsis. Rather than for diagnosing or assessing disease activity, the measurement of this biomarker may hence retain practical clinical significance for early prediction, timely diagnosis and therapeutic monitoring of many IBDassociated infections and complications.

Updates on larynx cancer epidemiology

Objective: Laryngeal cancer is an important oncologic entity, whose prognosis depends on establishing appropriate preventive and diagnostic measures, especially in populations at higher risk.Methods: Epidemiologic information including worldwide incidence, prevalence, burden of health loss(disability-adjusted life year;DALYs) and mortality of larynx cancer was obtained from the Global Health Data Exchange(GHDx) database.Results: The current incidence, prevalence and mortality of laryngeal cancer are estimated at 2.76 cases/year per 100,000 inhabitants, 14.33 cases/year per 100,000 inhabitants and 1.66 deaths/year per 100,000 inhabitants,respectively, averaging 3.28 million DALYs each year. Incidence and prevalence have increased by 12% and 24%,respectively during the past 3 decades, whilst mortality has declined by around 5%. The epidemiologic burden of this malignancy is approximately 5-fold higher in males and increases in parallel with ageing, peaking after 65 years of age. Both incidence and mortality rates are higher in Europe and lower in Africa, but the ratio between deaths and incidence is the highest in Africa. Incidence has gradually declined in Europe during the past 3 decades, whilst it has increased in South-East Asia and Western Pacific. Cigarette smoking and alcohol abuse contribute for about 90% of overall worldwide mortality for laryngeal cancer.Conclusions: Laryngeal cancer still poses a high clinical and societal burden, with an escalating temporal trend not expected to reverse soon.

Updated overview on interplay between physical exercise,neurotrophins,and cognitive function in humans

The many important benefits of physical exercise also encompass maintenance or improvement of cognitive functions. Among the variousmechanisms underlying the association between physical exercise and brain health, recent evidence attests that neurotrophin receptor signalingmay have an important role, because the activation of this pathway leads to growth and differentiation of new neurons and synapses, supportsaxonal and dendritic growth, fosters synaptic plasticity, and preserves survival of existing neurons. In this review of published evidence, we highlightthat a positive relationship exists between physical exercise and circulating brain-derived neurotrophic factor levels and that the postexercisevariation of this molecule is associated with improvement of neurocognitive functioning. Less clear evidence has instead been published forother neurotrophins, such as nerve growth factor, neurotrophin-3, and neurotrophin-4. Overall, promotion of adequate volumes and intensities ofphysical exercise (i.e., approximately 3 months of moderate-intensity aerobic exercise, with 2—3 sessions/week lasting not less than 30 min)may hence be regarded as an inexpensive and safe strategy for boosting brain-derived neurotrophic factor release, thus preserving or restoringcognitive functions.

STARD指南:评估科技出版物质量复杂难题的另一面

《转化医学年鉴》本期焦点是关于2015版诊断实验准确度研究报告标准（简称STARD）指南的复杂争论。一些权威杂志的编辑们对这一问题提出了他们自己的观点，他们回顾了很多专业人士的意见但在如何出版高质量的诊断实验研究这一问题上仍然有不同见解。作为本期的客座编辑，我希望能给出一些简明的要点，帮助读者对新版STARD2015指南的实质性贡献有一个直观感受，但仍然有一些关键性问题没有答案。

在这个资源紧缺的世界提高诊断研究的准确度:路在前方

世界范围内的宏观经济刚开始从史无前例的经济危机中复苏，这场经济危机已经深刻的改变了全球主要国家公共卫生体系的组织结构[1]。在大多数发达国家和新兴发展中国家，公共卫生健康支出在整个国民生产总值（Gross Domestic Product，GDP）中的比重呈现增加趋势，其增速远远高于其他经济门类，并成为名副其实的国家预算最大组成部分（高达10%~12%）[2-3]。由于在诊断技术和靶向治疗领域中的显著进步，多数国家的公共卫生体系都遭遇到两难境地：不断增加的尤其是住院护理和医药相关的费用与不断减少的政府资金资助。如何对整个卫生体系进行重新调整以适应并有效提供更高质量的健康服务--这一问题对于私人和公共医疗服务购买者而言是至关重要的。

An update on common inherited thrombophilic conditions

The term thrombophilia refers to a number of inherited and/or acquired conditions that may be associated with an increased tendency to develop thrombosis.In this sense,hereditary thrombophilia is a genetic disorder of hemostatic proteins that is present at birth and contributes to individuals being at increased risk for venous thrombosis.Three important questions arise from the still ongoing debate about the benefits and limitations of testing for hereditary thrombophilia,which can be summarized as follows:“which tests?”,“when?”,and“how?”.This article attempts to answer these questions by providing an up-to-date overview of the most common and clinically significant inherited thrombophilic disorders(i.e.,antithrombin,protein S and protein C deficiencies,activated protein C resistance,factor V Leiden,and prothrombin gene mutationG20210A),their prevalence,clinical severity,and diagnostic approach,while also highlighting the potential advantages and limitations of testing for inherited thrombophilia.

Monitoring humoral and cellular immunity over 6 months after mRNA-based bivalent COVID-19 vaccine administration

Dear Editor,Although the World Health Organization(WHO)has declared an end to the global emergency for coronavirus disease 2019(COVID-19)[1],the clinical burden of severe acute respiratory syndrome coronavirus disease(SARS-CoV-2)has not yet subsided[2,3],especially after the emergence of new variants such as EG.5 and BA.2.86,whose genetic leap is so large that it may contribute to increase the number of new COVID-19 cases,hospitalizations,and deaths[3].Some physical preventive measures,such as mask-wearing,hand hygiene,and isolation of positive cases,play an important role.However,widespread vaccination remains the cornerstone to contain the spread of the virus and mitigate the potential harm to human health.