Volume 133 · Issue 04 · 2020

新年伊始，我们为您呈现一期关注血液疾病的特刊。本期收录的部分综述和研究论文介绍并讨论了急性白血病治疗的最新进展、淋巴瘤免疫治疗的最新进展、多发性骨髓瘤（MM）治疗的最新进展等。

Acute myeloid leukemia (AML) is a common type of hematological malignancy in elderly people. Geriatricians have developed comprehensive geriatric assessment (CGA) methods for elderly patients; however, the tools used for CGA in AML are not uniform. Thus, we aimed to validate the instrumental activities of daily living (IADL) scales, age, comorbidities (Charlson Comorbidity Index), and albumin (IACA) index, which is a new tool for CGA, in elderly patients with AML.

As a congenital malformation that results in infertility and an inability to have vaginal intercourse, Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome places a considerable psychological burden on patients, which results in anxiety symptoms. However, only single case studies or a few small to medium-sized cross-sectional studies were identified to focus on anxiety symptoms in MRKH patients. Thus, the aim of this study was to explore the status of anxiety symptoms and the related factors in patients with MRKH syndrome.

This cross-sectional study involving 141 patients with MRKH syndrome and 178 healthy women was conducted from January 2018 to December 2018. All participants were required to complete a demographic questionnaire and the Generalized Anxiety Disorder 7-item scale (GAD-7), Patient Health Questionnaire-9, Eysenck Personality Questionnaire-Revised, Short Scale for Chinese, and Chinese Version of the Female Sexual Function Index. The main outcome was the anxiety symptoms measured by the GAD-7. Main outcome was compared between the MRKH syndrome group and the healthy control group. Then, we explored the related factors by comparing patients with and without anxiety symptoms.

Of the respondents, 24.1% experienced moderate to severe anxiety symptoms. Patients with MRKH syndrome manifested more severe anxiety symptoms than healthy women. Negative self-evaluation of femininity (odds ratio [OR] 2.706, 95% confidence interval [CI] 1.010-7.247), neurotic personality traits (OR 1.100, 95% CI 1.029-1.175), and coexisting depressive symptoms (OR 4.422, 95% CI 1.498-13.049) were more prevalent in anxious patients.

The findings stress the importance of anxiety symptom screening in MRKH patients and identify patients at risk of anxiety symptoms, providing a possible basis for future intervention.

Surgical treatment of both-column acetabular fractures is challenging because of the complex acetabular fracture patterns and the curved surface of the acetabulum. Seldom study has compared the application of three-dimensional (3D) printing technology and traditional methods of contouring plates intra-operatively for the surgical treatment of both-column acetabular fractures. We presented the use of both 3D printing technology and a virtual simulation in pre-operative planning for both-column acetabular fractures. We hypothesized that 3D printing technology will assist orthopedic surgeons in shortening the surgical time and improving the clinical outcomes.

Forty patients with both-column acetabular fractures were recruited in the randomized prospective case-control study from September 2013 to September 2017 for this prospective study (No. ChiCTR1900028230). We allocated the patients to two groups using block randomization (3D printing group, n = 20; conventional method group, n = 20). For the 3D printing group, 1:1 scaled pelvic models were created using 3D printing, and the plates were pre-contoured according to the pelvic models. The plates for the conventional method group were contoured during the operation without 3D printed pelvic models. The operation time, instrumentation time, time of intra-operative fluoroscopy, blood loss, number of times the approach was performed, blood transfusion, post-operative fracture reduction quality, hip joint function, and complications were recorded and compared between the two groups.

The operation and instrumentation times in the 3D printing group were significantly shorter (130.8 ± 29.2 min, t = －7.5, P < 0.001 and 32.1 ± 9.5 min, t = －6.5, P < 0.001, respectively) than those in the conventional method group. The amount of blood loss and blood transfusion in the 3D printing group were significantly lower (500 [400, 800] mL, Mann-Whitney U= 74.5, P < 0.001 and 0 [0,400] mL, Mann-Whitney U = 59.5, P < 0.001, respectively) than those in the conventional method group. The number of the approach performed in the 3D printing group was significantly smaller than that in the conventional method group (pararectus + Kocher-Langenbeck [K-L] approach rate: 35% vs. 85%; x² = 10.4, P < 0.05). The time of intra-operative fluoroscopy in the 3D printing group was significantly shorter than that in the conventional method group (4.2 ± 1.8 vs. 7.7 ± 2.6 s; t = －5.0, P < 0.001). The post-operative fracture reduction quality in the 3D printing group was significantly better than that in the conventional method group (good reduction rate: 80% vs. 30%; x² = 10.1, P < 0.05). The hip joint function (based on the Harris score 1 year after the operation) in the 3D printing group was significantly better than that in the conventional method group (excellent/good rate: 75% vs. 30%; x² = 8.1, P < 0.05). The complication was similar in both groups (5.0% vs. 25%; x² = 3.1, P = 0.182).

The use of a pre-operative virtual simulation and 3D printing technology is a more effective method for treating bothcolumn acetabular fractures. This method can shorten the operation and instrumentation times, reduce blood loss, blood transfusion and the time of intra-operative fluoroscopy, and improve the post-operative fracture reduction quality.

No.ChiCTR1900028230; http://www.chictr.org.cn

The preferred treatment for uncomplicated type B dissection (thoracic endovascular aortic repair [TEVAR] or medical) is still under debate. Since 2001, our center has performed TEVAR for uncomplicated type B dissection. Based on our data, 5- and 10-year survival rates among patients with uncomplicated type B dissection after TEVAR were 96.5% and 83.0%, respectively. We, therefore, believe that TEVAR is preferable for uncomplicated type B dissections. This study analyzed the impact of a pre-operative smoking history on long-term survival after TEVAR in patients with uncomplicated type B dissections.

From May 2001 to December 2013, data from 751 patients with type B dissections were collected and analyzed. Patients were divided into two groups (337 smoking patients and 414 non-smoking patients). The Kaplan-Meier method and log-rank test were used to compare survival curves of the two groups. Multivariable analyses using the Cox proportional hazards model were used to estimate the effects of smoking on survival rates.

The 5- and 10-year survival rates of non-smokers were 97.6% (95% confidence interval [CI], 96.0%-99.2%) and 87.0% (95% CI, 81.6%-92.7%), respectively, and 94.9% (95% CI, 92.2%-97.7%) and 73.8% (95% CI, 62.3%-87.5%) for smokers, respectively (Log-rank test, P = 0.006). Multivariable analyses showed that smoking increased the risk of death during follow-up, 2.1-fold when compared to non-smokers (P = 0.039).

A pre-operative smoking history increases long-term mortality rates after TEVAR in patients with uncomplicated type B dissections.

The diagnosis of contrast-induced nephropathy (CIN) is usually based on changes in serum creatinine (sCr). However, sCr has poor sensitivity as a biomarker of kidney injury. The aim of this study was to investigate the usefulness of serum cystatin C (sCysC) to predict CIN after intra-arterial interventions.

A total of 360 consecutive patients underwent intra-arterial procedures using digital subtraction angiography. SCr, sCysC, and estimated glomerular filtration rate were measured at 1 to 2 days before and at 48, 72 h, and 7 days after the procedure.

Thirty-one patients (8.61%) developed CIN. Receiver operating characteristic (ROC) curve analysis showed that preoperative sCysC levels had good discriminatory power (area under the curve [AUC] = 0.634; 95% confidence interval [CI] = 0.526-0.743) for evaluating the risk of CIN after an endovascular procedure, with a sensitivity of 53.33% and specificity of 73.70%. ROC analysis showed that sCysC at 48 h after contrast medium administration was predictive of CIN after an endovascular procedure (AUC = 0.735; 95% CI = 0.647-0.822) with satisfactory sensitivity of 74.20% and specificity of 63.90%. Diabetes mellitus was an independent risk factor for CIN (odds ratio = 2.778; 95% CI = 1.045-7.382; P = 0.040).

SCysC is an appropriate biomarker to predict the occurrence of CIN. Baseline sCysC before an intervention is useful to obtain a preliminary estimate of the risk of CIN. A 48-h cut-off value of sCysC of 0.99 mg/L after an endovascular procedure may help to rule out patients at lower risk of CIN.

The platelet to lymphocyte ratio (PLR) has recently emerged as a potential inflammatory biomarker and has been shown to be significantly associated with atherosclerotic coronary artery disease (CAD). Therefore, we aimed to explore the association of PLR with in-hospital major adverse cardiovascular events (MACEs) and the severity of CAD assessed by the Gensini score (GS) in patients with acute myocardial infarction (AMI) undergoing coronary angiography.

A total of 502 patients with AMI consecutively treated at the Affiliated Hospital of Qingdao University (Qingdao, China) and underwent coronary angiography from August 2017 to December 2018 were recruited in this study. The demographic, clinical, angiographic characteristics, and laboratory parameters were collected. According to the presence of in-hospital MACEs, the included patients were divided into the MACE group (n = 81) and the non-MACE group (n = 421). Further, according to tertiles of the GS, the patients were classified into three groups: the low GS group (GS ≤32 points, n = 173), medium GS group (32 points < GS ≤ 60 points, n = 169), and high GS group (60 points < GS ≤ 180 points, n = 160). The main statistical methods included Chisquared test, non-parametric Mann-Whitney U test, Kruskal-Wallis H test, logistic regression, and receiver operating characteristic curves.

The PLR in the MACE group was significantly higher than that in the non-MACE group (179.43 [132.84, 239.74] vs. 116.11 [87.98, 145.45], Z = -8.109, P < 0.001). Further, there were significant differences in PLR among the tertiles of GS (110.05[84.57, 139.06] vs. 119.78 [98.44, 157.98] vs. 140.00 [102.27, 191.83], H= 19.524, P < 0.001). PLR was demonstrated to be an independent risk factor of in-hospital MACEs (odds ratio [OR]: 1.012, 95% confidential interval [CI]: 1.006-1.018, P < 0.001) and severe CAD assessed by the GS (OR: 1.004, 95% CI: 1.002-1.009, P= 0.042). The cutoff value of PLR for predicting the development of in-hospital MACEs was 151.28 with a sensitivity of 66.7% and a specificity of 78.1% (area under the curve [AUC]: 0.786, 95% CI: 0.730-0.842, P < 0.001), and a PLR of 139.31 was also identified to be an effective cutoff point for detecting a high GS (<60 points) with a sensitivity of 49.4% and a specificity of 69.6% (AUC: 0.611, 95% CI: 0.556-0.666, P < 0.001).

PLR as a novel inflammatory marker is significantly and independently associated with the occurrence of in-hospital MACEs and the severity of CAD assessed by the GS in patients with AMI. As an easily available and inexpensive inflammatory indicator, PLR could be widely used as an efficient inflammatory biomarker for identifying high-risk patients and for individualizing targeted therapy to improve the prognosis of AMI.

Traditional tissue engineering methods to fabricate urinary tract patch have some drawbacks such as compromised cell viability and uneven cell distribution within scaffold. In this study, we combined three-dimensional (3D) bioprinting and tissue engineering method to form a tissue-engineered urinary tract patch, which could be employed for the application on Beagles urinary tract defect mode to verify its effectiveness on urinary tract reconstruction.

Human adipose-derived stem cells (hADSCs) were dropped into smooth muscle differentiation medium to generate induced microtissues (ID-MTs), flow cytometry was utilized to detect the positive percentage for CD44, CD105, CD45, and CD34 of hADSCs. Expression of vascular endothelial growth factor A (VEGFA) and tumor necrosis factor-stimulated gene-6 (TSG-6) in hADSCs and MTs were identified by Western blotting. Then the ID-MTs were employed for 3D bioprinting. The bioprinted structure was encapsulated by transplantation into the subcutaneous tissue of nude mice for 1 week. After retrieval of the encapsulated structure, hematoxylin and eosin and Masson’s trichrome staining were performed to demonstrate the morphology and reveal collagen and smooth muscle fibers, integral optical density (IOD) and area of interest were calculated for further semiquantitative analysis. Immunofluorescent double staining of CD31 and α-smooth muscle actin (α-SMA) were used to reveal vascularization of the encapsulated structure. Immunohistochemistry was performed to evaluate the expression of interleukin-2 (IL-2), α-SMA, and smoothelin of the MTs in the implanted structure. Afterward, the encapsulated structure was seeded with human urothelial cells. Immunofluorescent staining of cytokeratins AE1/AE3 was applied to inspect the morphology of seeded encapsulated structure.

The semi-quantitative assay showed that the relative protein expression of VEGFA was 0.355 ± 0.038 in the hADSCs vs. 0.649 ± 0.150 in the MTs (t = 3.291, P = 0.030), while TSG-6 expression was 0.492 ± 0.092 in the hADSCs vs. 1.256 ± 0.401 in the MTs (t = 3.216, P = 0.032). The semi-quantitative analysis showed that the mean IOD of IL-2 in the MT group was 7.67 ± 1.26, while 12.6 ± 4.79 in the hADSCs group, but semi-quantitative analysis showed that there was no statistical significance in the difference between the two groups (t = 1.724, P = 0.16). The semi-quantitative analysis showed that IOD was 71.7 ± 14.2 in non-induced MTs (NI-MTs) vs. 35.7 ± 11.4 in ID-MTs for collagen fibers (t = 3.428, P = 0.027) and 12.8 ± 1.9 in NI-MTs vs. 30.6 ± 8.9 in ID-MTs for smooth muscle fibers (t= 3.369, P = 0.028); furthermore, the mean IOD was 0.0613 ± 0.0172 in ID-MTs vs. 0.0017 ± 0.0009 in NI-MTs for α-SMA (t = 5.994, P = 0.027), while 0.0355 ± 0.0128 in ID-MTs vs. 0.0035 ± 0.0022 in NI-MTs for smoothelin (t= 4.268, P = 0.013), which indicate that 3D bioprinted structure containing ID-MTs could mimic the smooth muscle layer of native urinary tract. After encapsulation of the urinary tract patch for additional cell adhesion, urothelial cells were seeded onto the encapsulated structures, and a monolayer urothelial cell was observed.

Through 3D bioprinting and tissue engineering methods, we provided a promising way to fabricate tissue-engineered urinary tract patch for further investigation.

Nipple discharge cytology is a simple non-invasive method that may provide valuable information for detecting underlying malignancy. Several studies have investigated the diagnostic value of cytology in breast cancer patients with pathological nipple discharge, but the results have been highly variable. Herein we presented a systematic review and meta-analysis of published studies pertaining to the diagnostic capacity of nipple discharge cytology in patients with breast cancer.

A systematic literature search was performed (Medline/PubMed, Embase, Cochrane Library databases, and Google Scholar) to identify studies that investigated the diagnostic capacity of cytology with regard to breast cancer in patients with pathologic nipple discharge. Two independent researchers identified articles that assessed the sensitivity and specificity of cytological evaluation for breast cancer detection in patients with pathologic nipple discharge published between January 2000 and October 2018. Articles were only included in the meta-analysis if they met predetermined criteria. The characteristics of each study and the data they yielded were summarized. Quality assessment of all articles included was performed using the Methodological Index for Non-randomized Studies Criteria (MINORS) and the Quality Assessment of Diagnostic Accuracy Study 2 (QUADAS-2). Heterogeneity was tested via Cochran Q test and the I² statistic using Stata 12.0 and Meta-DiSc 1.4 software, and meta-analysis was performed.

A total of 286 articles were identified, of which 12 articles including a total of 1476 patients were deemed eligible for inclusion in the meta-analysis. A random-effects model assessing the capacity of nipple discharge cytology to predict breast cancer yielded pooled sensitivity 63% (95% confidence interval [CI]: 53%-72%), specificity 95% (95% CI: 87%-98%), positive likelihood ratio 12.35 (95% CI: 4.87-31.34), and negative likelihood ratio 0.39 (95% CI: 0.30-0.50). The diagnostic odds ratio was 31.88 (95% CI: 11.30-89.98). The area under the summary receiver operating characteristic curve was 0.79 (95% CI: 0.75-0.82). Conclusion: The current meta-analysis suggests that nipple discharge cytology is a useful diagnostic modality for detection of breast cancer in patients with pathological nipple discharge, with moderate sensitivity and high specificity.

Pioglitazone may be beneficial in the treatment of psoriasis. However, based on the effectiveness and safety considerations, it has not been widely used. To fully evaluate the strength of evidence supporting psoriasis treatment with pioglitazone, we conducted a meta-analysis of existing published studies.

PubMed, Ovid, Cochrane Library, Google Scholar, and Web of Science databases were systematically searched before February 2019. Randomized controlled trials (RCTs) of pioglitazone administration compared with placebo, administered to patients with psoriasis for at least 10 weeks, and published in English were included. Quality of the included RCTs was identified by the modified Jadad scale. The quality of evidence for each outcome was evaluated using the GRADEpro Guideline Development Tool online software. Primary outcomes were proportion of patients showing psoriasis area and severity index (PASI) score improvement (<75%) and the mean percent change in PASI score from baseline to the end of treatment. Dichotomous data were analyzed using odds ratios (ORs) corresponding to the 95% confidence interval (CI), whereas continuous variables, expressed as mean and standard deviation, were analyzed using the mean differences (MD) with the 95% CI.

Six RCTs were analyzed. Meta-analysis showed that pioglitazone reduced the PASI scores in patients with psoriasis compared with the control group when administered at 30 mg per day (P < 0.001, MD = -3.82, 95% CI = -5.70, -1.93) and at 15 mg per day (P = 0.04, MD = -3.53, 95% CI = -6.86, -0.20). The PASI-75 of the pioglitazone group was significantly higher than that of the control group at 30 mg per day (P < 0.001, OR = 8.30, 95% CI = 3.99, 17.27) and at 15 mg per day (P = 0.03, OR = 2.96, 95% CI = 1.08, 8.06). No statistically significant differences in total adverse events were observed between the groups. There were no significant differences in common adverse reactions such as weight gain and elevated liver enzymes between the two pioglitazone groups.

Use of pioglitazone in the current treatment of psoriasis is beneficial. The therapeutic effect of the daily 30 mg dose may be greater than that of the 15 mg dose per day with no significant change in the frequency of adverse reactions.

Clinical features and outcomes of heart failure (HF) with mid-range ejection fraction (HFmrEF) remain controversial. Thus, we systematically reviewed literatures of clinical research to assess and analyze characteristics and prognosis of patients with HFmrEF.

PubMed, Embase, and Web of Science were searched for cohort studies up to April 23, 2019. Clinical features and multivariate adjusted hazard ratios (HRs) of endpoints of short-term all-cause mortality (SAM), long-term all-cause mortality (LAM), long-term cardiovascular death (LCD) and long-term HF rehospitalization (LHR) among patients with HFmrEF and HF with preserved ejection fraction (HFpEF), HF with reduced ejection fraction (HFrEF) were well addressed. The primary outcome was LAM.

Totally 19 studies were included in this study with 164,678 patients enrolled. The follow-up time of LAM was 3.6 ± 2.5 years. HRs of LAM, SAM, LCD, LHR indicated that the risks of patients with HFmrEF were higher than HFpEF patients but lower than HFrEF patients, as for LAM, HFmrEF:HFpEF (reference) HR: 1.07, 95% confidence interval (CI): 1.00-1.15 (I² = 63%, P= 0.0005); HFmrEF:HFrEF (reference) HR: 0.80, 95% CI: 0.73-0.88 (I² = 70%, P < 0.0001). However, HFmrEF patients had the lowest rate in LAM (30.94%), SAM (2.73%), LCD (17.45%), LHR (26.36%) compared with the other two groups.

This systematic review and meta-analysis compared features and prognosis between patients with HFmrEF and HFpEF, HFrEF by HRs. There appeared a special "separation phenomenon" showing rates of endpoints were inconsistent with their hazards in patients with HFmrEF compared with HFpEF patients.

Long noncoding RNAs (lncRNAs) have recently been discovered and are increasingly recognized as vital components of modern molecular biology. Accumulating evidence shows that lncRNAs have emerged as important mediators in diverse biological processes such as cell differentiation, pluripotency, and tumorigenesis, while the function of lncRNAs in the field of normal and malignant hematopoiesis remains to be further elucidated. Here, we widely reviewed recent advances and summarize the characteristics and basic mechanisms of lncRNAs and keep abreast of developments of lncRNAs within the field of normal and malignant hematopoiesis. Based on gene regulatory networks at different levels of lncRNAs participation, lncRNAs have been shown to regulate gene expression from epigenetics, transcription and post transcription. The expression of lncRNAs is highly cell-specific and critical for the development and activation of hematopoiesis. Moreover, we also summarized the role of lncRNAs involved in hematological malignancies in recent years. LncRNAs have been found to play an emerging role in normal and malignant hematopoiesis, which may provide novel ideas for the diagnosis and therapeutic targets of hematological diseases in the foreseeable future.

CD19-targeted chimeric antigen receptor T-cell (CAR-T) therapy is effective in refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL). This review focuses on achievements, current obstacles, and future directions in CAR-T research. A high complete remission rate of 68% to 93% could be achieved after anti-CD19 CAR-T treatment for B-ALL. Cytokine release syndrome and CAR-T-related neurotoxicity could be managed. In view of difficulties collecting autologous lymphocytes, universal CAR-T is a direction to explore. Regarding the high relapse rate after anti-CD19 CAR-T therapy, the main solutions have been developing new targets including CD22 CAR-T, or CD19/CD22 dual CAR-T. Additionally, some studies showed that bridging into transplant post-CAR-T could improve leukemia-free survival. Some patients who did not respond to CAR-T therapy were found to have an abnormal conformation of the CD19 exon or trogocytosis. Anti-CD19 CAR-T therapy for R/R B-ALL is effective. From individual to universal CAR-T, from one target to multi-targets, CAR-T-cell has a chance to be off the shelf in the future.

Etiology of adolescent idiopathic scoliosis (AIS), a complicated three-dimensional spinal deformity with early-onset, receives continuous attention but remains unclear. To gain an insight into AIS pathogenesis, this review searched PubMed database up to June 2019, using key words or medical subject headings terms including "adolescent idiopathic scoliosis," "scoliosis," "pathogenesis," "etiology," "genetics," "mesenchymal stem cells," and their combinations, summarized existing literatures and categorized the theories or hypothesis into nine aspects. These aspects include bone marrow mesenchymal stem cell studies, genetic studies, tissue analysis, spine biomechanics measurements, neurologic analysis, hormone studies, biochemical analysis, environmental factor analysis, and lifestyle explorations. These categories could be a guidance for further etiology or treatment researches to gain inspiration.

肠道微生物群由数万亿个微生物组成，其中大多数被认为是非致病性的，在宿主免疫系统中起防御作用。细菌群落的失衡与多种宿主疾病有关，包括脂肪肝、代谢综合征、炎症性肠病和结肠癌。肝脏在解剖和生理水平上与肠道相连，并通过门静脉暴露于肠道微生物群的产物。因此，肝脏病理生理学受到肠道微生物群的密切影响。

致编辑：慢性粒单核细胞白血病(CMML)的特征是骨髓增生异常综合征(MDS)和骨髓增生性肿瘤(MPN)。^[1]CMML的罕见发病率导致难以建立诊断的标准标准和特定的治疗范式，并且需要准确的预后评分来进行适当的治疗范式。

致编辑：患者女，40岁，左腿外侧出现逐渐增大的红色椭圆形斑块，表面粗糙，持续4年。未见溃疡、结痂、渗出或出血。查体示病变为边界清楚的红色扁平斑块，直径1.5 cm × 1.0 cm，硬度中等，无压痛[图1A].无全身异常，患者无疼痛或瘙痒主诉。皮肤镜检查显示红色背景上有多个棕色小球、点状和球状血管。还可以看到几个毛囊角化塞和多发性粟粒样囊肿。病变有一个边界[图1B和图1C].

致编辑：变异性红斑性角化病（EKV，人类在线孟德尔遗传[OMIM]#133200）是一种罕见的遗传性皮肤病，以游走性红斑和固定性角化过度为特征。病变好发于四肢远端、臀部和躯干。^[1]然而，EKV病变上的异常毛发生长很少被报道。

致编辑：肺癌是全球恶性肿瘤中发病率和死亡率最高的。提高5年生存率的关键是早期诊断和治疗。基于深度学习的人工智能（AI）具有高效自我优化的能力，不仅提升了肺结节的识别能力，也有助于提高早期肺癌的诊断效率。