2020年 · 第133卷第21期

Secukinumab demonstrated sustained efficacy in patients with ankylosing spondylitis (AS) through 5 years in pivotal Phase III studies. Here, we present efficacy and safety results (52-week) of secukinumab in patients with AS from the MEASURE 5 study.

MEASURE 5 was a 52-week, Phase III, China-centric study. Eligible patients were randomly assigned (2:1) to receive subcutaneous secukinumab 150 mg or placebo weekly for the first five doses and then once every 4 weeks (q4w). All placebo patients switched to secukinumab 150 mg q4w starting at Week 16. Primary endpoint was Assessments of SpondyloArthritis international Society (ASAS) 20 at Week 16. Randomization was stratified by region (China vs. non-China).

Of 458 patients (secukinumab 150 mg, N= 305; placebo, N= 153) randomized, 327 (71.4%) were from China and 131 (28.6%) were not from China. Of these, 97.7% and 97.4% patients completed Week 16 and 91.1% and 95.3% (placebo-secukinumab) patients completed Week 52 of treatment. The primary endpoint was met; secukinumab significantly improved ASAS20 response at Week 16 vs. placebo (58.4% vs. 36.6%; P < 0.0001); corresponding rate in the Chinese population was 56.0% vs. 38.5% (P < 0.01). All secondary efficacy endpoints significantly improved with secukinumab 150 mg in the overall population at Week 16; responses were maintained with a trend toward increased efficacy from Week 16 to 52. No new or unexpected safety signals were reported up to Week 52.

Secukinumab 150 mg demonstrated rapid and significant improvement in signs and symptoms of AS. Secukinumab was well tolerated and the safety profile was consistent with previous reports. Efficacy and safety results were comparable between the overall and Chinese populations.

ClinicalTrials.gov, NCT02896127; https://clinicaltrials.gov/ct2/show/NCT02896127?term=NCT02896127&draw= 2&rank=1.

Recent studies have demonstrated that microRNAs (miRNAs) in the blood circulation can serve as promising diagnostic markers for cancers. This four-stage study aimed at finding serum miRNAs as potential biomarkers for lung adenocarcinoma (LA) diagnosis.

The study was carried out between 2016 and 2017. The Exiqon miRNA qPCR panel (3 LA vs. 1 normal control [NC] pooled serum samples) was used for initial screening to acquire miRNA profiles. Thirty-five dysregulated miRNAs were further evaluated in the training (24 LA vs. 24 NCs) and testing stages (110 LA vs. 110 NCs) using quantitative real-time polymerase chain reaction assays.

Four serum miRNAs (miR-133a-3p, miR-584-5p, miR-10b-5p, and miR-221-3p) were significantly overexpressed in LA patients compared with NCs. The diagnostic value of the four-miRNA panel was validated by an external cohort (36 LA vs. 36 NCs). The areas under the receiver operating characteristic curve of the four-miRNA panel in the training, testing, and external validation stages were 0.734, 0.803, and 0.894 respectively. Meanwhile, the expression level of miR-221-3p was much higher in LA tumor samples than that in the adjacent normal tissues (19 LA vs. 19 NCs). The expression level of miR-10b-5p was also elevated in the serum-derived exosomes samples (18 LA vs. 18 NCs). The expression of miR-133a-3p, miR-584-5p, and miR-10b-5p was significantly elevated in LA patients with epidermal growth factor receptor mutation compared with NCs.

The study established a four-miRNA signature in serum that could improve the diagnostic capability of LA.

Accumulating evidence has revealed that circulating microRNAs (miRNAs) can serve as non-invasive biomarkers for cancer diagnosis. This study aimed to identify differentially expressed miRNAs in serum which might become potential biomarkers for non-invasive diagnosis of papillary thyroid carcinoma (PTC).

The experiment was carried out between 2015 and 2017. In the screening stage, the Exiqon miRNA quantitative real-time polymerase chain reaction (qPCR) panel was applied to select candidate miRNAs. In the following training, testing, and external validation stages, the serum samples of 100 patients and 96 healthy controls (HCs) were analyzed to compare the expression levels of the identified miRNAs. The areas under the receiver operating characteristic curves (AUCs) were calculated to assess the diagnostic value of the identified signature.

Three miRNAs (miR-25-3p, miR-296-5p, and miR-92a-3p) in serum were consistently up-regulated in PTC patients compared with HCs. A three-miRNA panel was constructed by logistic regression analysis and showed better diagnostic performance than a single miRNA for PTC detection. The AUCs of the panel were 0.727, 0.771, and 0.862 for the training, testing, and external validation stage, respectively. Meanwhile, the panel showed stable capability in differentiating PTC patients from patients with benign goiters, with an AUC as high as 0.969. For further exploration, the three identified miRNAs were analyzed in tissue samples (23 PTC vs. 23 HCs) and serum-derived exosomes samples (24 PTC vs. 24 HCs), and the altered expression in the tumor also indicated their close relationship with PTC disease.

We identify a three-miRNA panel in serum which might serve as a promising biomarker for PTC diagnosis.

Inflammatory breast cancer (IBC) is an aggressive type of cancer with poor prognosis and outcomes. This study aimed to investigate clinicopathological features, molecular characteristics, and treatments among Chinese patients diagnosed with IBC.

We collected data of 95 patients with IBC who were treated by members of the Chinese Society of Breast Surgery, from January 2017 to December 2018. The data, including demographic characteristics, pathological findings, surgical methods, systemic treatment plans, and follow-up, were obtained using a uniform electronic questionnaire. The clinicopathological features of different molecular types in patients without distant metastases were compared using the Kruskal-Wallis (H) test followed by post hoc analyses.

Lymph node metastasis was noted in 75.8% of all patients, while distant metastasis was noted in 21.4%. Pathological findings indicated invasive ductal and lobular carcinomas in 86.8% and 5.3% of cases, respectively. Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (41.5%) and HR-/HER2+ (20.1%) were the most common biologic subtypes, followed by HR+/HER2+ (19.1%) and HR-/HER2-(19.1%). Stage III IBC was treated via pre-operative neoadjuvant chemotherapy in 87.7% of the cases, predominantly using anthracycline and taxanes. A total of 91.9% of patients underwent surgical treatment. Among them, 77.0% of the patients underwent modified radical mastectomy, 8.1% of whom also underwent immediate breast reconstruction. The Kruskal-Wallis test revealed that the efficacy of chemotherapy significantly differed among those with HR+/HER2 -and HR-/HER2-tumors (adjusted P = 0.008), and Ki-67 expression significantly differed in HR-/HER2+ and HR+/HER2+ molecular subtypes (adjusted P = 0.008).

Our study provides novel insight into clinicopathological characteristics and treatment status among patients with IBC in China, and might provide a direction and basis for further studies.

chictr.org.cn, No. ChiCTR1900027179; http://www.chictr.org.cn/showprojen.aspx?proj=45030

Multifocal motor neuropathy (MMN), Lewis-Sumner syndrome (LSS), and many chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs) are representative of acquired multifocal polyneuropathy and are characterized by conduction block (CB). This retrospective study aimed to investigate the demyelinating distribution and the selective vulnerability of MMN, LSS, and CIDP with CB (CIDP-CB) in nerves.

Fifteen LSS subjects (107 nerves), 24 MMN subjects (176 nerves), and 17 CIDP-CB subjects (110 nerves) were included. Their clinical information was recorded, blood and cerebrospinal fluid tests were conducted, and nerve conductions of the median, ulnar, radial, peroneal, and tibial nerves were evaluated. CB, temporal dispersion, distal motor latency (DML), and F-wave latency were recorded, and nerve conduction velocity, terminal latency index, and modified F-wave ratio were calculated.

CB was more likely to occur around the elbow in CIDP-CB than in MMN (78.6% vs. 6.8%, P < 0.01) but less likely to occur between the wrist and the elbow than in LSS (10.7% vs. 39.3%, P < 0.05). Tibial nerve CB was most frequently observed in MMN (47.4%, P < 0.05). CIDP-CB was characterized by a prolonged DML in all nerves, and slow motor nerve velocity of the upper limb was significant when CB nerves were excluded (P < 0.05).

We report the different distributions of segmental and diffuse demyelination of the ulnar and tibial nerves in LSS, MMN, and CIDP-CB. These distinct distributions could help in differentiating among these conditions.

Recent studies have reported circular RNA (circRNA) expression profiles in various tissue types; however, circRNA expression profile in human epicardial adipose tissue (EAT) remains undefined. This work aimed to compare circRNA expression patterns in EAT between the heart failure (HF) and non-HF groups.

RNA-sequencing was carried out to compare circRNA expression patterns in EAT specimens from coronary artery disease cases between the HF and non-HF groups. Quantitative real-time polymerase chain reaction was performed for validation. Comparisons of patient characteristics between the two groups were using t test, Mann-Whitney U test, and Chi-squared test.

A total of 141 circRNAs substantially different between the HF and non-HF groups (P < 0.05; fold change >2) were detected, including 56 up-regulated and 85 down-regulated. Among them, hsa_circ_0005565 stood out, for it had the highest fold change and was significantly increased in HF patients in quantitative real-time polymerase chain reaction validation. The top highly expressed EAT circRNAs corresponded to genes involved in cell proliferation and inflammatory response, including GSE1, RHOBTB3, HIPK3, UBXN7, PCMTD1, N4BP2L2, CFLAR, EPB41L2, FCHO2, FNDC3B, and SPECC1. The top enriched Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway were positive regulation of metabolic processes and insulin resistance, respectively.

These data indicate EAT circRNAs may contribute to the pathogenesis of metabolic disorders causing HF.

Carbapenemase-producing Klebsiella pneumoniae (CP-Kp) poses distinct clinical challenges due to extensively drug resistant (XDR) phenotype, and sequence type (ST) 11 is the most dominant bla_KPC-2-bearing CP-Kp clone in China. The purpose of this current retrospective study was to explore the genetic factors associated with the success of XDR CP-Kp ST11 strains circulated in the intensive care unit (ICU) of a Chinese tertiary hospital.

Six ST11 XDR CP-Kp strains were identified between May and December 2014 and validated by minimum inhibitory concentration examination, polymerase chain reaction, and pyrosequencing. The six ST11 XDR CP-Kp, as well as three multi-drug resistant (MDR) and four susceptible strains, were sequenced using single-molecule real-time method. Comprehensively structural and functional analysis based on comparative genomics was performed to identify genomic characteristics of the XDR ST11 CP-Kp strains.

We found that ST11 XDR bla_KPC-2-bearing CP-Kp strains isolated from inpatients spread in the ICU of the hospital. Functionally, genes associated with information storage and processing of the ST11 XDR CP-Kp strains were more abundant than those of MDR and susceptible strains, especially genes correlative with mobile genetic elements (MGEs) such as transposons and prophages. Structurally, eleven large-scale genetic regions taken for the unique genome in these ST11 XDR CP-Kp strains were identified as MGEs including transposons, integrons, prophages, genomic islands, and integrative and conjugative elements. Three of them were located on plasmids and eight on chromosomes; five of them were with antimicrobial resistance genes and eight with adaptation associated genes. Notably, a new bla_KPC-2-bearing ΔΔTn1721-bla_KPC-2 transposon, probably transposed and truncated from ΔTn1721-bla_KPC-2 by IS903D and ISKpn8, was identified in all six ST11 XDR CP-Kp strains.

Our findings suggested that together with clonal spread, MGEs identified uniquely in the ST11 XDR CP-Kp strains might contribute to their formidable adaptability, which facilitated their widespread dissemination in hospital.

Autografts, allografts, and xenografts are the most widely used methods to enhance effective reconstruction of bone defects, but natural donor bone has some deficiencies, such as limited supply, excessive damage of transplant-suppliedparts, constrained growth and high complication rates.^[1]Bioactive bone replacement materials provide an alternative for bone defect repair and regeneration. Augmented injectable bone scaffold material applied to bone replacement therapies in orthopedics and dentistry has generated much discussion in bone tissue engineering for bone defect repair. Injectable cement materials currently in clinical use and those under research can be classified into three main categories: polymethylmethacrylate (PMMA), calciumphosphate-based bone cements (CPCs), and calciumsulfate-based bone cements (CSCs). Of these, the chemical components of CPCs are most similar to the inorganic components of bones. CPCs mimic the mineral phase of bone to formulate a natural lattice for bone tissue to promote natural bone ingrowth and remodeling.^[2]Furthermore, in comparison with the most widely used PMMA cements, CPCs have a lower exothermic reaction temperature and promote better osteointegration. For these reasons, they have become one of the most promising bone repair materials.^[3]Nevertheless, CPCs have some limitations: (1) Their slow degradation rate and lack of macroporosity to promote the formation of new bone make their osteoinduction capacity insufficient for clinical needs.^[4]Modification efforts include fabricating porous/nano structures and/or drug delivery CPC composites to promote bone growth; (2) Another drawback is that the mechanical strength of CPCs cannot match the strength of human cortical bone; thus, strength modification is another research direction.

Circulating tumor DNA (ctDNA) is a DNA fragment released into the peripheral blood by apoptotic or necrotic tumor cells, which carry the basic genetic information after gene mutation. The detection and analysis of ctDNA can provide genomic information on the size and development of tumor; therefore, it is considered as an emerging and promising tumor biomarker for cancer progression, reoccurrence, and routine monitoring after surgery. Albeit the isolation method is relatively simple due to the stability of ctDNA, the abundance of ctDNA is extremely low, and result from the high content of background cell free DNA (cfDNA), the large difference between individuals, and the need of predicted detection sites, it is necessary to analyze ctDNA in a comprehensive way. At present, the main methods that meet the needs of ctDNA detection with sensitivity and specificity are amplification refractory mutation system PCR (ARMS-PCR), digital-PCR (dPCR) and high-throughput sequencing. Among them, dPCR has advantages in practicality, which can realize absolute quantification of single-molecule DNA, detect and trace DNA molecules and conduct quantitative analysis, providing a reliable basis for clinical monitoring of tumor recurrence and minimal residual diseases. The study reviews the detection and potential value of ctDNA in gynecologic tumors.

Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is an autosomal dominant, life-threatening, and treatable disorder caused byTTRmutation. It is characterized by amyloid deposition in the peripheral nerves and major organs, including the heart, kidneys, and eyes. So far, more than 130TTRmutations have been identified, in which p.Val30Met is the most common in endemic countries. TTR-FAP has been reported in 29 countries, including many countries in Europe, USA, Japan, China, and India. Clinical and genetic features of TTR-FAP are relatively clear in Europe and Japan, however, it still need to be carried out in China. Here, we reported the clinical and genetic features of 8 Chinese TTR-FAP families.

Multiple myeloma (MM) is a blood malignancy characterized by the clonal proliferation of plasma cells, which increases the number of monoclonal immunoglobulins in blood and urine and causes target organ damage. Long non-coding RNAs (lncRNAs) have been reported to have high genetic heterogeneity and to participate in malignancy formation, progression, and metastasis in MM.^[1]Furthermore, lncRNAs and circular RNAs (circRNAs) act as microRNA (miRNA) sponges, by indirectly binding miRNAs and influencing the post-transcriptional regulation of target gene expression. This phenomenon is known as the competing endogenous (ceRNA) relationship, and it may be one of the most important lncRNA mechanisms in cancers. However, the only lncRNA maternally expressed gene 3 (MEG3) was reported to function as a ceRNA to regulate homeobox gene A11 mRNA expression by sponging miR-181a in MM.^[2,3]Therefore, other ceRNA relationships, especially in newly diagnosed MM patients, remain to be investigated.

Immunosuppression (IS) is indispensable for liver trans-plant (LTx) patients to control the unwanted alloimmune responses, which are mainly mediated by T cells. However, antigen-independent homeostasis of T cells is vital for sustaining long-lived T cell-mediated immunity, and excessive IS may increase the risk of opportunistic infections and malignancies. Therefore, IS therapy for LTx patients should be tailored to the immune status of the individual patient.^[1]Biliary complications (BC), including biliary strictures with cholangitis, are the most common complications after LTx. However, the immunological characteristics especially T cell-mediated immunity of these patients are unknown yet.

Reports indicate that peripheral arterial injuries are especially challenging as they are associated with a high risk of limb loss. Rapid diagnosis and intervention is required to provide limb salvage and can be lifesaving. As endovascular techniques and tools continue to evolve, open repair has been not the only option in the management of traumatic vascular injuries. Similarly, minimally invasive percutaneous endovascular therapies offer an attractive treatment alternative. Limb salvage in acute traumatic vascular lesions may be improved because of the endovascular therapies to perform diagnostic evaluation and therapeutic intervention nearly simultaneously.

To the Editor:Current guidelines recommended that patients with acute coronary syndrome (ACS) should receive dual anti-platelet therapy of aspirin plus P2Y12 inhibitors (clopidogrel, prasugrel, or ticagrelor) if without contraindication. Up to now, information on the clinical efficacy and safety of potent anti-platelet drugs in the elderly patients with ACS is limited, especially in very older people (age ≥75 years). We searched PubMed, the Cochrane library, Web of Science, EMBASE (Excerpt Medical Database) from January 2000 to December 2019. Analysis of the data was performed using Stata software, Version 12.0 (StataCorp LP, College Station, TX, USA). The overall polled results were recorded as risk ratios (RRs) and 95% confidence intervals (CIs) with two-sidedPvalues. Finally, seven clinical studies included 8848 patients of potent oral P2Y12-inhibitors versus clopidogrel in elderly patients (age ≥65 years old) with ACS were included in this meta-analysis.^{[1,2,3,4,5,6,7]}Patients older than 65 years in the included trials were mainly treated with aspirin combined with ticagrelor, and those over 75 years were mainly treated with aspirin plus prasugrel. Five thousand six hundred and forty-eight (63.8%) received aspirin plus prasugrel, and 3839 patients (43.4%) received reduced maintenance dose prasugrel (<10 mg). The seven included studies were all high-quality studies.

To the Editor: Worldwide, lung cancer, particularly non-small cell lung cancer (NSCLC), is the leading cause of tumor-related death. Cost-effectiveness analysis show no economic benefits for advanced NSCLC patients over chemotherapy.^[1]Furthermore, tests such as programmed cell death ligand 1 (PD-L1) and tumor mutational burden (TMB) tests, evaluated via immunohistochemical methods and next-generation sequencing, respectively, are widely used for screening potential beneficiaries of immune checkpoint inhibitors (ICIs). However, these two methods have different predictive values, making their comprehensive evaluation the focus of the current controversy.

To the Editor: Charcot-Marie-Tooth disease (CMT) encompasses a genetically heterogeneous group of inherited neuropathies, characterized by progressive distal muscle weakness and atrophy, sensory deficits, impaired tendon reflexes, and foot deformities.^[1]To date, more than 80 causative genes have been identified in CMT patients, associated with either autosomal dominant or recessive inheritance, or X-linked transmission. The traditional classification of CMT was based on peripheral neuropathy type, as determined by nerve conduction velocity. As more causative genes were identified and the overlap of neuropathy phenotypes became apparent, the traditional classification system proved unwieldy and inadequate. Moreover, CMT needs to be distinguished from several entities including systemic disorders with neuropathy and other types of hereditary neuropathy. In clinical practice, overlap of phenotypes can present a major challenge in reaching the correct diagnosis. This study aimed to investigate the genetic profile in a cohort of Chinese CMT patients and evaluate the role of genetic testing in the diagnosis and subtyping of CMT.

To the Editor: Wake-up stroke (WUS) is the name given to an ischemic stroke that occurs primarily during night-time sleep and accounts for approximately 20% of all cases of acute ischemic stroke (AIS). Epidemiological studies have demonstrated a circadian distribution of AIS, with a higher frequency in the morning and a lower frequency during sleep.^[1]It remains unclear whether WUS is a stochastic event or if a distinct pathophysiologic process, such as circadian rhythm disorder, differentiates WUS from daytime stroke (non-WUS).

To the Editor:Many well-studied sonographic features have been used clinically to evaluate thyroid nodules for malignancies. Sonographic grayscale features proposed by the American College of Radiology Thyroid Imaging, Reporting and Data System (TI-RADS) include composition, echogenicity, shape, margin, and echogenic foci.^[1]Other features, such as vascularity imaging, have gradually been recognized by sonographers. Sustained angiogenesis results in tumor-specific vasculature compared to normal tissues in the context of architecture and biological behavior.^[2]Tumor neovascularization shows abnormal maturation, manifesting irregular sprouting, and branching of angiogenic vessels with disordered coverage of pericytes. Therefore, vascularity is critical for the evaluation of malignancy in thyroid nodules.

To the Editor:Anterior cervical discectomy and fusion (ACDF) is a "gold standard" for patients with spondylotic myelopathy when conservative treatments fail.^[1]A zeroprofile, standalone device (Zero P; Synthes GmbH, Zuchwil, Switzerland) is more popular than the traditional plate and cage for ACDF.^[2]Yunet al^[3]showed that the insertion point of Zero-P in the intervertebral disc space might be an important factor for maintenance of anterior disc height. However, no consensus exists regarding the position related to better clinical and radiological results.

To the Editor:Atrial fibrillation (AF) is one of the most common cardiac arrhythmias observed in the general population. The main cause of stroke associated with AF is the formation of thrombosis in the left atrial appendage (LAA) and falling off from it. More than 90% of cardiogenic thromboses originated from the LAA because the saccate and complex morphology of the LAA induces stasis of blood flow.^[1]In the present study, we aimed to evaluate the feasibility and efficacy of mini-invasive thoracotomy implantation of a modified LAA clip (LAAC) in a canine model by general observation, biochemical and histological studies, and echocardiography.