2023年 · 第136卷第03期

Integrins are a family of transmembrane receptors that connect the extracellular matrix and actin skeleton, which mediate cell adhesion, migration, signal transduction, and gene transcription. As a bi-directional signaling molecule, integrins can modulate many aspects of tumorigenesis, including tumor growth, invasion, angiogenesis, metastasis, and therapeutic resistance. Therefore, integrins have a great potential as antitumor therapeutic targets. In this review, we summarize the recent reports of integrins in human hepatocellular carcinoma (HCC), focusing on the abnormal expression, activation, and signaling of integrins in cancer cells as well as their roles in other cells in the tumor microenvironment. We also discuss the regulation and functions of integrins in hepatitis B virus-related HCC. Finally, we update the clinical and preclinical studies of integrin-related drugs in the treatment of HCC.

Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells’ productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.

The lungs are one of the most common extra-articular organs involved in rheumatoid arthritis (RA), which is reported to occur in up to 60% to 80% of RA patients. Respiratory complications are the second leading cause of death due to RA. Although there is a wide spectrum of RA-associated respiratory diseases, interstitial lung disease is the most common manifestation and it impacts the prognosis of RA. There has been progress in understanding the management and progression of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and RA-associated respiratory diseases recently, for example, opportunistic pulmonary infectious diseases and toxicity from RA therapies. From a chest physicians’ perspective, we will update the diagnosis and treatment of RA-associated ILD, methotrexate-associated lung disease, and the complication of Pneumocystis jiroveci pneumonia in RA in this review.

In China, the level of ambient fine particulate matter (PM_2.5) pollution far exceeds the air quality standards recommended by the World Health Organization. Moreover, the health effects of PM_2.5 exposure have become a major public health issue. More than half of PM_2.5-related excess deaths are caused by cardiopulmonary disease, which has become a major health risk associated with PM_2.5 pollution. In this review, we discussed the latest epidemiological advances relating to the health effects of PM_2.5 on cardiopulmonary diseases in China, including studies relating to the effects of PM_2.5 on mortality, morbidity, and risk factors for cardiovascular and respiratory diseases. These data provided important evidence to highlight the cardiopulmonary risk associated with PM_2.5 across the world. In the future, further studies need to be carried out to investigate the specific relationship between the constituents and sources of PM_2.5 and cardiopulmonary disease. These studies provided scientific evidence for precise reduction measurement of pollution sources and public health risks. It is also necessary to identify effective biomarkers and elucidate the biological mechanisms and pathways involved; this may help us to take steps to reduce PM_2.5 pollution and reduce the incidence of cardiopulmonary disease.

Estrogen impacts neural development; meanwhile, it has a protective effect on the brain. Bisphenols, primarily bisphenol A (BPA), can exert estrogen-like or estrogen-interfering effects by binding with estrogen receptors. Extensive studies have suggested that neurobehavioral problems, such as anxiety and depression, can be caused by exposure to BPA during neural development. Increasing attention has been paid to the effects on learning and memory of BPA exposure at different developmental stages and in adulthood. Further research is required to elucidate whether BPA increases the risk of neurodegenerative diseases and the underlying mechanisms, as well as to assess whether BPA analogs, such as bisphenol S and bisphenol F, influence the nervous system.

Epilepsy accounts for a significant portion of the global disease burden. However, little is known about the disease burden of epilepsy in China and its provinces.

We assessed the burden of epilepsy in China and its provinces, municipalities, and autonomous regions from 1990 to 2019. Burden was measured as incidence, prevalence, deaths, years lived with disability, years of life lost, and disability-adjusted life years (DALYs), by age, sex, year, and province. We used the Socio-Demographic Index (SDI) to determine the association between the provincial development level and age-standardized DALY rates of epilepsy from 1990 to 2019.

In 2019, epilepsy caused 1367.51 thousand (95% uncertainty interval [UI]: 979.92–1837.61 thousand) DALYs, and the age-standardized DALY rate was 99.77 (95% UI: 71.33–133.52)/100,000. The age-standardized incidence and prevalence rates for epilepsy in China were 24.65/100,000 and 219.69/100,000, increased by 45.00% (95% UI: 8.03–98.74%) and 35.72% (95% UI: 0.47–86.19%) compared with that in 1990, respectively. From 1990 to 2019, the proportion of DALY caused by epilepsy in the age group under 25 years steadily decreased. The proportion of DALYs caused by epilepsy in people aged 50 years and over increased from 9.45% and 10.22% in 1990 to 29.01% and 32.72% for male and female individuals in 2019, respectively. The highest age-standardized mortality rates were seen in Tibet (4.26 [95% UI: 1.43–5.66]/100,000), Qinghai (1.80 [95% UI: 1.15–2.36]/100,000), and Yunnan (1.30 [95% UI: 0.88–1.62]/100,000), and the lowest mortality rates were in Guangdong (0.48 [95% UI: 0.39–0.64]/100,000), Zhejiang (0.56 [95% UI: 0.44–0.70]/100,000), and Shanghai (0.57 [95% UI: 0.41–0.73]/100,000). The age-standardized DALY rates across the country and in provinces, municipalities, and autonomous regions generally decreased as their SDI increased.

The disease burden of epilepsy is still heavy in China, especially in the western provinces. The incidence and prevalence of epilepsy increased between 1990 and 2019, and the burden of epilepsy in the elderly increases gradually. This study provides evidence on epilepsy prevention and care of different regions in China.

China bears the biggest atrial fibrillation (AF) burden in the world. However, little is known about the incidence and predictors of AF. This study aimed to investigate the current incidence of AF and its electrocardiographic (ECG) predictors in general community individuals aged over 60 years in China.

This was a prospective cohort study, recruiting subjects who were aged over 60 years and underwent annual health checkups from April to July 2015 in four community health centers in Songjiang District, Shanghai, China. The subjects were then followed up from 2015 to 2019 annually. Data on sociodemographic characteristics, medical history, and the resting 12-lead ECG were collected. Kaplan–Meier curve was used for showing the trends in AF incidence and calculating the predictors of AF. Associations of ECG abnormalities and AF incidence were examined using Cox proportional hazard models.

This study recruited 18,738 subjects, and 351 (1.87%) developed AF. The overall incidence rate of AF was 5.2/1000 person-years during an observation period of 67,704 person-years. Multivariable Cox regression analysis indicated age (hazard ratio [HR], 1.07; 95% confidence interval [CI]: 1.06–1.09; P < 0.001), male (HR, 1.30; 95% CI: 1.05–1.62; P = 0.018), a history of hypertension (HR, 1.55; 95% CI: 1.23–1.95; P < 0.001), a history of cardiac diseases (HR, 3.23; 95% CI: 2.34–4.45; P < 0.001), atrial premature complex (APC) (HR, 2.82; 95% CI: 2.17–3.68; P < 0.001), atrial flutter (HR, 18.68; 95% CI: 7.37–47.31; P < 0.001), junctional premature complex (JPC) (HR, 3.57; 95% CI: 1.59–8.02; P = 0.002), junctional rhythm (HR, 18.24; 95% CI: 5.83–57.07; P < 0.001), ventricular premature complex (VPC) (HR, 1.76; 95% CI: 1.13–2.75, P= 0.012), short PR interval (HR, 5.49; 95% CI: 1.36–22.19; P = 0.017), right atrial enlargement (HR, 6.22; 95% CI: 1.54–25.14; P = 0.010), and pacing rhythm (HR, 3.99; 95% CI: 1.57–10.14; P = 0.004) were independently associated with the incidence of AF.

The present incidence of AF was 5.2/1000 person-years in the studied population aged over 60 years in China. Among various ECG abnormalities, only APC, atrial flutter, JPC, junctional rhythm, short PR interval, VPC, right atrial enlargement, and pacing rhythm were independently associated with AF incidence.

There are few data comparing clinical outcomes of complex percutaneous coronary intervention (CPCI) when using biodegradable polymer drug-eluting stents (BP-DES) or second-generation durable polymer drug-eluting stents (DP-DES). The purpose of this study was to investigate the safety and efficacy of BP-DES and compare that with DP-DES in patients with and without CPCI during a 5-year follow-up.

Patients who exclusively underwent BP-DES or DP-DES implantation in 2013 at Fuwai Hospital were consecutively enrolled and stratified into two categories based on CPCI presence or absence. CPCI included at least one of the following features: unprotected left main lesion, ≥2 lesions treated, ≥2 stents implanted, total stent length >40 mm, moderate-to-severe calcified lesion, chronic total occlusion, or bifurcated target lesion. The primary endpoint was major adverse cardiac events (MACE) including all-cause death, recurrent myocardial infarction, and total coronary revascularization (target lesion revascularization, target vessel revascularization [TVR], and non-TVR) during the 5-year follow-up. The secondary endpoint was total coronary revascularization.

Among the 7712 patients included, 4882 (63.3%) underwent CPCI. Compared with non-CPCI patients, CPCI patients had higher 2- and 5-year incidences of MACE and total coronary revascularization. Following multivariable adjustment including stent type, CPCI was an independent predictor of MACE (adjusted hazard ratio [aHR]: 1.151; 95% confidence interval [CI]: 1.017–1.303, P = 0.026) and total coronary revascularization (aHR: 1.199; 95% CI: 1.037–1.388, P = 0.014) at 5 years. The results were consistent at the 2-year endpoints. In patients with CPCI, BP-DES use was associated with significantly higher MACE rates at 5 years (aHR: 1.256; 95% CI: 1.078–1.462, P = 0.003) and total coronary revascularization (aHR: 1.257; 95% CI: 1.052–1.502, P = 0.012) compared with that of DP-DES, but there was a similar risk at 2 years. However, BP-DES had comparable safety and efficacy profiles including MACE and total coronary revascularization compared with DP-DES in patients with non-CPCI at 2 and 5 years.

Patients underwent CPCI remained at a higher risk of mid- to long-term adverse events regardless of the stent type. The effect of BP-DES compared with DP-DES on outcomes was similar in CPCI and non-CPCI patients at 2 years but had inconsistent effects at the 5-year clinical endpoints.

Rheumatoid arthritis (RA), a chronic systemic autoimmune disease, is characterized by synovitis and progressive damage to the bone and cartilage of the joints, leading to disability and reduced quality of life. This study was a randomized clinical trial comparing the outcomes between withdrawal and dose reduction of tofacitinib in patients with RA who achieved sustained disease control.

The study was designed as a multicenter, open-label, randomized controlled trial. Eligible patients who were taking tofacitinib (5 mg twice daily) and had achieved sustained RA remission or low disease activity (disease activity score in 28 joints [DAS28] ≤3.2) for at least 3 months were enrolled at six centers in Shanghai, China. Patients were randomly assigned (1:1:1) to one of three treatment groups: continuation of tofacitinib (5 mg twice daily); reduction in tofacitinib dose (5 mg daily); and withdrawal of tofacitinib. Efficacy and safety were assessed up to 6 months.

Overall, 122 eligible patients were enrolled, with 41 in the continuation group, 42 in the dose-reduction group, and 39 in the withdrawal group. After 6 months, the percentage of patients with a DAS28-erythrocyte sedimentation rate (ESR) of <3.2 was significantly lower in the withdrawal group than that in the reduction and continuation groups (20.5%, 64.3%, and 95.1%, respectively; P < 0.0001 for both comparisons). The average flare-free time was 5.8 months for the continuation group, 4.7 months for the dose reduction group, and 2.4 months for the withdrawal group.

Withdrawal of tofacitinib in patients with RA with stable disease control resulted in a rapid and significant loss of efficacy, while standard or reduced doses of tofacitinib maintained a favorable state.

Chictr.org, ChiCTR2000039799.

Liver biopsy for the diagnosis of non-alcoholic steatohepatitis (NASH) is limited by its inherent invasiveness and possible sampling errors. Some studies have shown that cytokeratin-18 (CK-18) concentrations may be useful in diagnosing NASH, but results across studies have been inconsistent. We aimed to identify the utility of CK-18 M30 concentrations as an alternative to liver biopsy for non-invasive identification of NASH.

Individual data were collected from 14 registry centers on patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD), and in all patients, circulating CK-18 M30 levels were measured. Individuals with a NAFLD activity score (NAS) ≥5 with a score of ≥1 for each of steatosis, ballooning, and lobular inflammation were diagnosed as having definite NASH; individuals with a NAS ≤2 and no fibrosis were diagnosed as having non-alcoholic fatty liver (NAFL).

A total of 2571 participants were screened, and 1008 (153 with NAFL and 855 with NASH) were finally enrolled. Median CK-18 M30 levels were higher in patients with NASH than in those with NAFL (mean difference 177 U/L; standardized mean difference [SMD]: 0.87 [0.69–1.04]). There was an interaction between CK-18 M30 levels and serum alanine aminotransferase, body mass index (BMI), and hypertension (P < 0.001, P = 0.026 and P = 0.049, respectively). CK-18 M30 levels were positively associated with histological NAS in most centers. The area under the receiver operating characteristics (AUROC) for NASH was 0.750 (95% confidence intervals: 0.714–0.787), and CK-18 M30 at Youden’s index maximum was 275.7 U/L. Both sensitivity (55% [52%–59%]) and positive predictive value (59%) were not ideal.

This large multicenter registry study shows that CK-18 M30 measurement in isolation is of limited value for non-invasively diagnosing NASH.

To the Editor: Phosphaturic mesenchymal tumor (PMT) is a rare, slowly progressive, histomorphologically distinct entity of tumors that can emerge anywhere in the body.^[1]According to World Health Organization, PMT has two pathological types: benign and malignant.^[2]PMT was discovered due to tumor-induced osteomalacia (TIO) and is increasingly accepted in recent years as the leading cause of TIO.^[1]However, most published reports have focused on the clinicopathological, immunohistochemical, and molecular genetic studies on PMT rather than the radiological work-ups.^[3,4]Hence, the aim of this study was to find the common imaging characteristics of PMT to assist clinical diagnosis.

To the Editor:DL-3-n-butylphthalide (NBP) is a synthetic drug based on a component extracted from seeds ofApium graveolensLinn. (Chinese celery). It reportedly has protective effects in amyotrophic lateral sclerosis (ALS) model mice.^[1]A randomized, double-blind, placebo-controlled trial was performed at 19 ALS clinical centers of the Chinese ALS association. All patients provided written informed consent. The Ethics Committee of Peking Union Medical College Hospital approved the study protocol (No. S621) and all patients signed informed consent. All centers followed the same research protocol.

To the Editor: Compared with non-readmission chronic obstructive pulmonary disease (COPD) patients, the mortality rate of readmission patients is significantly higher (2.3%vs.13.4%),^[1]which undoubtedly causes socio-economic pressures on rehabilitation care and medical resources. The potential factors affecting the risk of readmission are required to be identified. The incidence of malnutrition, occurring frequently in elderly COPD patients, varies from 20% to 45% depending on the screening tools used. As a practical, economical and effective scoring system, the Mini Nutrition Assessment (MNA) is of great value to assessing nutritional status in the elderly. Malnutrition is a state of vulnerability in elder populations and is associated with a poor long-term prognosis. This study aimed to research the impact of nutritional status related risk factors on readmission and assess the value of MNA scoring system and updated sarcopenia diagnostic criteria in predicting readmission risk for elderly COPD patients.

To the Editor: Psoriasis is a common, chronic papulosquamous skin disease occurring worldwide, presenting at any age, and leading to a substantial burden for individuals and society. Interleukin (IL)-17A is considered the key effector cytokine inducing psoriatic inflammation and tissue damage.^[1]Ixekizumab is a humanized monoclonal immunoglobulin G specifically binding to and inhibiting IL-17A. The efficacy and safety of ixekizumab in patients with psoriasis have been clearly demonstrated in several randomized clinical trials, namely UNCOVER-1, UNCOVER-2, UNCOVER-3, and UNCOVER-J.^[2,3]However, the clinical research data on ixekizumab in Chinese psoriasis patients remain limited.

To the Editor:Currently, lung transplantations are typically performed via a transverse thoracosternotomy or a sternotomy for double lung transplantation, or a posteriolateral thoracosternotomy for single lung transplantation. However, these extremely invasive approaches may contribute to early post-operative pain, delay wound healing, and cause chronic post-thoracotomy neuralgia, which can affect patient’s quality of life.^[1,2]Of interest, several minimally invasive surgical methods for lung transplantation were reported.^[3,4]Furthermore, robotic surgical systems are now widely used in the field of thoracic surgery. Herein, we reported a case of performing robot-assisted right single lung transplantation for a patient with end-stage chronic obstructive pulmonary disease (COPD).

Tothe Editor:Biliary atresia (BA) is a rare obliterative cholangiopathy that occurs during infancy in association with destructive liver inflammation and hepatic fibrosis. Although recent studies have shown that transforming growth factor-β (TGF-β)plays an important role in liver fibrosis and inflammation in BA, disease mechanisms remain poorly understood. Circular RNAs (circRNAs) are a recently discovered unique class of regulatory RNA molecules with high specificity. As previous evidence links circRNAs to the regulation of the TGF-β inflammatory signaling pathway, we further investigated the potential regulatory roles of circRNAs in BA and found novel insights into BA pathogenesis. BA is characterized by destructive inflammation and fibrosis in the affected liver, destroying the extrahepatic bile ducts and disrupting bile flow. If not treated in time, BA can rapidly worsen and result in devastating consequences. Surgical intervention, known as Kasai hepatoportoenterostomy, is the most common treatment option for patients with BA. Unfortunately, in 40% to 50% of patients, bile drainage fails to improve following surgery, and the majority eventually requires liver transplantation. As a key regulator and indicator of the inflammatory response, TGF-β is upregulated in infants with BA.^[1]Hence, understanding TGF-β dysregulation could provide a better understanding of the disease mechanism and consequently provide new insights for treatment development.

To the Editor:Pineoblastoma (PB) is a rare embryonal tumor of pineal parenchymal origin, which is a World Health Organization grade IV lesion frequently diagnosed in children and adolescents. A literature-based study revealed that patients aged ≤5 years have a worse prognosis compared with patients aged >5 years (5-year survival rate: 15%vs.57%,P< 0.001).^[1]Thus, younger children and older children with PB should be treated separately. Maximal safe surgical resection followed by craniospinal irradiation and chemotherapy is recommended for the treatment of PB, and treatment protocols are highly age dependent. Abdelbakiet al^[2]reviewed 23 patients aged <6 years in the Head Start I–III trials and found that craniospinal irradiation and high-dose induction chemotherapy followed by marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR) were associated with better survival. Several population-based studies have evaluated the prognostic factors in pediatric and adult patients using data from the Surveillance, Epidemiology, and End Results (SEER) database. Selvanathanet al^[3,4]included pediatric patients and adult patients between 1990 and 2007 from the SEER database; their results showed that older age was the only positive prognostic factor for pediatric patients, and younger age and localized disease were associated with improved survival in adult patients. Given the rarity of PB, the poor prognosis of young children with PB and the paucity of studies specific to young children with PB, we aimed to determine the prognostic factors and survival outcome of PB patients aged ≤5 years using data from the SEER database.

To the Editor:Cerclage reduces the rate of preterm birth and improves perinatal outcomes in patients with cervical insufficiency. However, previous findings on this subject are discordant. Many clinical factors affect the outcome of cerclage. The morbidity rate of neonates born after 32 weeks of gestation is reported to be significantly reduced.^[1]Therefore, the use of a gestational age of <32 weeks at delivery as the main efficacy measure for cerclage is of practical significance.

To the Editor:Retroperitoneal liposarcoma (RLS) pertains to one of the rare malignant tumors originated from the retroperitoneum. It is evaluated as the most common type of retroperitoneal sarcoma. RLS can be divided into four subtypes according to the pathological classification, which includes well-differentiated liposarcoma (WDL), dedifferentiated liposarcoma (DDL), myxoid cell liposarcoma (MLS), and pleomorphic liposarcoma (PLS).^[1]Giant RLS refers to the RLS with long diameter two times larger than the specified length of pathologic tumor stage-4 (pT4) category (≥30 cm) according to the eighth version of theAmerican Joint Committee on Cancer (AJCC) Staging Manual.^[2]Despite relatively low incidence, it brings great health burdens for patients and the standard therapeutic strategies remain to be explored. There are specific features of giant RLS according to clinical experience. For instance, giant RLS can occupy almost the entire abdominal cavity, close to or even wrapping around the inferior vena cava. Due to its location in the deep abdomen, patients usually have untypical symptoms at the early stage. The obvious signs and symptoms can be perceived only when the tumor becomes giant. These features increase difficulties in achieving complete resection during surgery and satisfactory patient outcomes. In addition, there is a lack of comprehensive research on the characteristics of giant RLS, which hinders the further progress of its diagnosis and targeted therapies. Identification of giant RLS characteristics may have great significance in clinical practice. Herein, we conducted a single-center retrospective study to reveal the clinicopathological features and outcomes of patients with giant RLS.

To the Editor:Chronic periodontitis has been defined as a slowly progressive disease. Scaling and root planning (SRP) provides a satisfactory prognosis in most cases. However, due to the complex anatomy under gingiva, non-surgical periodontal treatment alone is difficult to prevent bacterial plaque recolonization and thoroughly eliminate dental calculus in deep pockets.^[1]In recent years, the efficacy of indocyanine green (ICG)-mediated antimicrobial photodynamic therapy (aPDT) as an adjunct to non-surgical therapy has been explored in some research, but there are no consistent results.