2018年 · 第131卷第15期

Background: Prospective real-life data on the safety and effectiveness of rituximab in Chinese patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) are limited. This real-world study aimed to evaluate long-term safety and effectiveness outcomes of rituximab plus chemotherapy (R-chemo) as first-line treatment in Chinese patients with DLBCL or FL. Hepatitis B virus (HBV) reactivation management was also investigated. Methods: A prospective, multicenter, single-arm, noninterventional study of previously untreated CD20-positive DLBCL or FL patients receiving first-line R-chemo treatment at 24 centers in China was conducted between January 17, 2011 and October 31, 2016. Enrolled patients underwent safety and effectiveness assessments after the last rituximab dose and were followed up for 3 years. Effectiveness endpoints included progression-free survival (PFS) and overall survival (OS). Safety endpoints were adverse events (AEs), serious AEs, drug-related AEs, and AEs of special interest. We also reported data on the incidence of HBV reactivation. Results: In total, 283 previously untreated CD20-positive DLBCL and 31 FL patients from 24 centers were enrolled. Three-year PFS was 59% (95% confidence interval [CI]: 50-67%) for DLBCL patients and 46% (95% CI: 20- 69%) for FL patients. For DLBCL patients, multivariate analyses showed that PFS was not associated with international prognostic index, tumor maximum diameter, HBV infection status, or number of rituximab treatment cycles, and OS was only associated with age >60 years (P < 0.05). R-chemo was well tolerated. The incidence of HBV reactivation in hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative/hepatitis B core antibody-positive patients was 13% (3/24) and 4% (3/69), respectively. Conclusions: R-chemo is effective and safe in real-world clinical practice as first-line treatment for DLBCL and FL in China, and that HBV reactivation during R-chemo is manageable with preventive measures and treatment. Trial Registration: ClinicalTrials.gov, NCT01340443; https://clinicaltrials.gov/ct2/show/NCT01340443.

Background: After the first examination of patients with lymphoma diagnosis, important laboratory tests such as complete blood count; albumin, kidney and liver function tests; uric acid; β2-microglobulin; C-reactive protein (CRP); erythrocyte sedimentation rate (ESR); and lactate dehydrogenase (LDH) examinations are recommended. In this study, our aim was to find the relationship between laboratory parameters and the maximum standard uptake value (SUVmax) of positron emission tomography/computed tomography (PET/CT) in patients with lymphoma at the diagnosis and after treatment. Methods: Thirty-four lymphoma patients treated at Mustafa Kemal University Internal Medicine Clinic between 2014 and 2017 were included in this retrospective study. Results of CRP, ESR, LDH, albumin, and white blood cell (WBC) count were recorded before each PET scan test, and each parameter was analyzed for correlation with SUVmax measurements. Results: Spearman’s correlation test showed that the after-treatment SUVmax values were significantly correlated with the after-treatment LDH, ESR, and CRP values (for LDH, ESR, and CRP, R2: 0.453, 0.426, and 0.351; P= 0.007, 0.012, and 0.042, respectively). On the other hand, albumin and WBC count did not show a significant correlation with the after-treatment SUVmax values (all P> 0.05). Conclusions: CRP, ESR, and LDH values may also be good predictors in patients for whom PET/CT imaging cannot be performed.

Background: Although much attention has been paid to the pharmacokinetics (PKs) of different factor VIII (FVIII) concentrates in persons with hemophilia A (HA), limited information is available in young boys with severe HA. In this study, we aimed to assess the PK parameters of FVIII products in boys with severe HA in China. Methods: A total of 36 boys (plasma-derived [pd]-FVIII, n = 15; recombinant [r] FVIII, n = 21) were enrolled between January 2015 and May 2016 in Beijing Children’s Hospital. PK characteristics of FVIII products were studied according to a reduced 4-sampling time point design (1 h, 9 h, 24 h, and 48 h postinfusion). Results: The mean FVIII half-life (t1/2) was 10.99 ± 3 .45 h (range 5.52- 20.02 h), the mean in vivo recovery (IVR) was 2.01 ± 0.42 IU/dl per IU/kg (range 1.24–3.02 IU/dl per IU/kg) and mean clearance (CL) of FVIII is 4.34 ± 1.58 ml·kg−1·h−1 (range 2.29–7.90 ml·kg−1·h−1). We also analyzed the influence of several parameters that potentially modulate FVIII PK. The age was closely associated with FVIII half-life (R2 = 0.32, P< 0.01). The t1/2 of FVIII increased by 0.59 h per year. Besides age, von Willebrand factor antigen (VWF:Ag) also was associated with FVIII half-life (R2 = 0.52, P< 0.01). Patients with blood Group O had a shorter FVIII half-life than patients with non-O blood group (9.40 ± 0.68 h vs. 12.3 ± 0.79 h, t = 2.70, P= 0.01). The FVIII IVR correlated with age (R2 = 0.21, P< 0.01) and VWF:Ag level (R2 = 0.28, P< 0.01). CL rates were faster in young patients and in those with low-VWF:Ag levels. CL rates of FVIII are higher in blood Group O versus non-blood Group O persons (5.02 ± 0.38 vs. 4.00 ± 0.32 ml·kg−1·h−1, t= 2.53, P= 0.02). Conclusions: Chinese boys with severe HA have similar PK values to other ethnic groups and large differences in FVIII PK between individual patients. Age, blood group, and VWF:Ag levels are important determining factors for FVIII CL.

Background: Central nervous system (CNS) involvement is found in many patients with hemophagocytic lymphohistiocytosis (HLH). In this study, we mainly analyzed neurological symptoms, imaging findings, cerebrospinal fluid (CSF), and their relationship with outcomes of HLH children. Methods: Related data of 179 Chinese pediatric patients with HLH admitted to our center from January 2010 to December 2015 were analyzed retrospectively. Diagnosis and treatment were based on the HLH-2004 protocol. Two-tailed Chi-squared test was used to compare between different groups, and Kaplan-Meier survival curves were used to analyze the overall survival (OS) of patients with HLH. Results: In the present study, 21.2% (38/179) of total patients had neurological symptoms including seizure, irritability, somnolence, and unconsciousness. There were 80 (50.0%, excluding 19 patients without imaging data) patients with cranial imaging abnormalities. There were 14.7% (17/116, excluding 63 patients who did not accept lumbar puncture) of patients with abnormal CSF results. CNS involvement is defined as abnormalities in one or more of CNS symptoms, radiological findings, and CSF. Thus, 60.3% of them had CNS involvement. As for the prognosis, the median follow-up time was 3.2 years (17 lost to follow-up). The probable 3-year OS of children was higher without CNS involvement (86.0% ± 4.6%) than those with CNS involvement (68.9% ± 4.9%, hazard ratio [HR] = 2.286, P= 0.019). Among them, the probable 3-year OS of children without CNS symptoms was 76.0% ± 3.8%, higher than with CNS symptoms (59.5% ± 8.1 %, HR= 2.147, P= 0.047). The 3-year OS of children with abnormal CSF was 64.7% ± 11.6%, compared with normal CSF (85.1% ± 3.7%, HR= 0.255, P= 0.038). Conclusions: HLH patients with CNS involvement might have worse outcomes compared with those without CNS involvement, and CNS symptoms and CSF changes are more important to access the prognosis than imaging abnormality.

Background: Pulmonary Langerhans cell histiocytosis (PLCH) is an interstitial primary pulmonary disease, characterized by Langerhans cell proliferation. It is easily misdiagnosed in children. This study aimed to characterize the clinical manifestations and features of PLCH by retrospective analysis. Methods: A retrospective analysis was performed in 117 PLCH patients out of 338 LCH patients who were admitted in our center from November 2006 to October 2013. Variables between two groups were compared by Mann-Whitney U-test and Chi-square test. Kaplan-Meier curves were constructed to compare the survival rates and Cox regression to evaluate the effect of risk factors. Results: The median age of PLCH group was significantly lower than that of non-PLCH group (18.63 months vs. 43.4 months, P< 0.001). All PLCH children had other organ involvement and only 11 cases (9.4%) had respiratory symptoms. The most common radiologic finding was cystic lesions (29 cases, 24.8%). Pulmonary function abnormalities were dominated by obstructive ventilatory dysfunction (63 cases, 82.9%). The 5-year overall survival (OS) of PLCH children was 93.6% ± 2.3% and the event-free survival (EFS) was 55.7% ± 5.2%. Among the 38 cases with progressed or relapsed disease, five cases (13.2%) were due to progression or recurrence of lung damage. The 5-year OS of PLCH children with "risk organ" involvement was significantly lower than those without "risk organ" involvement (86.0% ± 4.9% vs. 100%, χ2= 8.793, P= 0.003). The difference of EFS between two groups was also significant (43.7% ± 7.7% vs. 66.3% ± 6.5%, χ2 = 5.399, P= 0.020). The "risk organ" involvement had a significant impact on survival (hazard ratio = 1.9, P= 0.039). Conclusions: PLCH mainly occurs in young children, and only a small percentage of patients have respiratory symptoms. They generally have other organ involvement. Most of PLCH children have a good prognosis and most lung lesions could have improved or stabilized. Management of "risk organ" involvement is the key point to improving EFS.

Background: It is known that short sleep duration adversely affects children’s behavior and physical development. This study aimed to investigate the status of sleep duration in 3–14-year-old children in Beijing and explore the related factors of sleep loss with them. Methods: In this study, a cross-sectional study of random stratified cluster sampling was conducted on 3–14-year-old children and adolescents in Beijing. According to the proportion of children in each district and school, the final cohort included a total of 11 kindergartens, 7 primary schools, and 8 junior high schools from 7 districts of Beijing. Children of sampled classes were included, and their parents were invited to fill a series of questionnaires including the simplified Chinese version of Pediatric Sleep Questionnaire, Sleep Questionnaire Scale, and Hong Kong-Children Sleep Questionnaire about the performance of the last 6 months. Results: Out of the total 11,420 questionnaires, 9198 questionnaires were valid and effective with the response rate of 80.54%. The age of the investigated children was 8.8 ± 3.8 years, including 4736 males and 4462 females. The daily sleep duration of children in Beijing was 9.7 ± 0.7 h. The prevalence of sleep loss (<9 h/day) of children in Beijing was 11.8%. The daily sleep duration of children aged <6, 6 ≤ age <11, and ≥11 years was 9.7 ± 0.6 h, 9.6 ± 0.6 h, and 9.5 ± 0.8 h, respectively. The sleep duration reduced significantly in children aged ≥11 years as compared to younger children in Beijing which was mainly contributed by the variation tendency of sleep duration on weekdays. The multivariate logistic regression analysis identified factors associated with sleep loss (P < 0.05): male (odds ratio [OR] = 1.32, 95% confidence interval [CI ]: 1.15–1.51), age ≥11 years (OR = 2.37, 95% CI: 1.92- 2.93), overweight (OR = 1.34, 95% CI: 1.17–1.54), family history of snoring (OR = 1.35, 95% CI: 1.13–1.61) and activities before bedtime with watching TV (OR = 1.24, 95% CI: 1.08–1.43), sports (OR= 1.22, 95% CI: 1.01–1.48), playing cellphone (OR = 1.91, 95% CI: 1.31- 2.73) and surfing the Internet (OR = 1.27, 95% CI: 1.06–1.52) and among them age ≥11 years and playing cellphone before bedtime had greater impact on children’s short sleep duration than that of other factors. Conclusions: Sleep loss was common among 3–14-year-old children in Beijing. Sleep duration decreased with age, especially among children over 11 years old. Factors associated with sleep loss covered sociodemographic characteristics, family sleep habits and routine activities before bedtime, and among those variables, age ≥11 years and playing with cellphones before bedtime had a greater impact on sleep duration, indicating that existing sleep loss in 3–14-year-old children could be, at least partly, improved by paying more attention to children aged of 11 years or entering Grade 5 and Grade 6 and to children with a family history of snoring; by reducing the use of electronic products before bedtime, especially cellphones; by managing weight and keeping fit; and by improving the bedtime routine.

Background: The 47,XYY syndrome could result in fertility problems. However, seldom studies reported comprehensive researches on the embryonic development and pregnancy outcomes of these patients. This study aimed to evaluate the clinical outcomes of nonmosaic 47,XYY patients performed with fluorescent in situ hybridization (FISH) and preimplantation genetic diagnosis (PGD) treatment. Methods: This was a retrospective study. Between January 2012 and May 2017, 51 infertile males with nonmosaic 47,XYY syndrome underwent FISH-PGD were included in the study. According to sex chromosomal FISH results, embryos were classified as normal signal, no nuclei fixed, no signal in fixed nuclei, suspensive signal, and abnormal signal groups, respectively. The incidence of each group, the fixation rate, and hybridization rate were calculated. Embryonic development and pregnancy outcomes were also analyzed. The measurement data were analyzed with Student’s t-test. The comparison of categorical data was analyzed with the Chi-square test and Fisher’s exact test when expected cell count was <5. Results: The 53 PGD cycles with 433 embryos were analyzed. The fixation rate was 89.6%, while the hybridization rate was 96.4%. There were 283 embryos with two sex chromosomal signals with clear diagnosis (65.4%). The numbers of no nuclei fixed, no signal in fixed nuclei, suspensive signal, and abnormal signal groups were 45 (10.4%), 14 (3.2%), 24 (5.5%), and 67 (15.5%), respectively. Embryos with abnormal signals were abandoned. The number of good-quality embryos was 210 (57.4%), including implanted embryos on day 4/day 5 and cryopreserved. The rates of good-quality embryos in the no nuclei fixed (22.2%), no signal in fixed nuclei (28.6%), and suspensive signal groups (33.3%) were comparable (P > 0.05), and were significantly lower than the normal signal group (66.4%, P< 0.001). The clinical pregnancy rates of fresh and frozen embryos transferred cycles were 70.6% and 85.7%, respectively. Conclusions: Among embryos with a clear diagnosis of sex chromosome, about one-fifth showed abnormal signals. Embryos with two sex chromosomal signals are more likely to develop into good-quality ones. The application of the PGD by FISH may help to improve the clinical outcomes.

Background: Cytokines play an important role in occurrence and recovery of hepatitis B virus (HBV) infection. The aim of this study was to investigate the changes of cytokines concentration and its correlation to alanine aminotransferase (ALT), HBV deoxyribonucleic acid (HBV-DNA), hepatitis B envelope antigen (HBeAg), and HBV surface antigen (HBsAg) in the development of chronic hepatitis B (CHB). Methods: Thirteen healthy individuals (HI), 30 chronic HBV-infected patients in immune tolerant (IT) phase, and 55 CHB patients were enrolled between August 2015 and May 2017. The peripheral blood samples were collected from all individuals. The levels of interferon (IFN)-α2, interleukin (IL)-10, transforming growth factor (TGF)-β1, HBV-DNA, HBsAg, and HBeAg and liver function were measured. The quantitative determinations of cytokines levels, including IFN-α2, IL-10, and TGF-β1 were performed using Luminex multiplex technology. The correlation of cytokines to ALT, HBV-DNA, HBsAg, and HBeAg was analyzed by linear regression analysis. Results: IFN-α2 levels were similar between HI and IT groups (15.35 [5.70, 67.65] pg/ml vs. 15.24 [4.07, 30.73] pg/ml, Z= −0.610, P= 0.542), while it elevated significantly in CHB group (35.29 [15.94, 70.15] pg/ml vs. 15.24 [4.07, 30.73] pg/ml; Z= −2.522, P= 0.012). Compared with HI group (3.73 [2.98, 11.92] pg/ml), IL-10 concentrations in IT group (5.02 [2.98, 10.11] pg/ml), and CHB group (7.48 [3.10, 18.00] pg/ml) slightly increased (χ2 = 2.015, P= 0.365), and there was no significant difference between IT and CHB group (Z= −1.419, P= 0.156). The TGF-β1 levels among HI (3.59 ± 0.20 pg/ml), IT (3.62 ± 0.55 pg/ml), and CHB groups (3.64 ± 0.30 pg/ml) were similar (χ2 = 2.739, P= 0.254). In all chronic HBV-infected patients (including patients in IT and CHB groups), the elevation of IFN-α2 level was significantly associated with ALT level (β = 0.389, t = 2.423, P= 0.018), and was also negatively correlated to HBV-DNA load (β= −0.358, t= −2.308, P= 0.024), HBsAg (β= −0.359, t= −2.288, P= 0.025), and HBeAg contents (β= −0.355, t= −2.258, P= 0.027). However, when both ALT level and cytokines were included as independent variable, HBV-DNA load, HBsAg, and HBeAg contents were only correlated to ALT level (β= −0.459, t= −4.225, P= 0.000; β= −0.616, t= −6.334, P= 0.000; and β= −0.290, t= −2.433, P= 0.018; respectively). Conclusions: IFN-α2 elevation was associated with ALT level in patients with chronic HBV infection. However, in CHB patients, only ALT level was correlated to HBV-DNA, HBsAg and HBeAg contents.

Background: Currently, spectral-domain optical coherence tomography (SD-OCT) appears to be a new type of glaucoma diagnostic tool. Thus, this study aimed to evaluate the effectiveness of glaucoma diagnostic parameters from SD-OCT of patients with different severities of myopia. Methods: This was a cross-sectional study. A total of 248 participants (248 eyes) were enrolled, including 51 cases in the early primary open-angle glaucoma group, 79 cases in the control group (0.50 D to −0.50 D, excluding −0.50 D), 47 cases in the low-myopic group (−0.50 to −3.00 D, excluding −3.00 D), 43 cases in the moderate-myopic group (−3.00 to −6.00 D, excluding −6.00 D), and 28 cases in the high-myopic group (≤−6.00 D). All participants were examined using the Humphrey visual field test and SD-OCT. The SD-OCT parameters of the retinal nerve fiber layer (RNFL) and ganglion cell complex were analyzed statistically using the receiver operating characteristic curve and area under the curve (AUC). Results: The AUC showed that the best parameters for the control and low-myopic groups were the inferior and inferior temporal RNFL thicknesses (AUC >0.94), respectively; for the moderate- and high-myopic groups, the best parameter was the temporal low RNFL thickness (AUC, 0.926 and 0.896, respectively). The AUC of the inferior parameters of the moderate-myopic group (0.864) was lower, ranked 15th among all RNFL parameters. When the sensitivity was fixed at 85%, the specificity of the inferior, superior, inferior temporal, and superior temporal quadrants was higher (>80%) in the control and low-myopic groups, while they were lower (20–60%) for the moderate- and high-myopia groups. The green color based on the OCT database was also less for the high-myopic group compared with that of other groups (P < 0.05). Conclusions: Glaucoma diagnostic parameters from SD-OCT were not clinically effective for the moderate- and high-myopic groups. The specificities were low. The moderate- and high-myopic groups require comprehensive analyses for the diagnoses of glaucoma. The SD-OCT database should be improved to better indicate the level of myopia based on the corresponding diopter readings.

Background: Technical aspects of the correct placement of medial support locking screws in the locking plate for proximal humerus fractures remain incompletely understood. This study was to evaluate the clinical relationship between the number of medial support screws and the maintenance of fracture reduction after locked plating of proximal humerus fractures. Methods: We retrospectively evaluated 181 patients who had been surgically treated for proximal humeral fractures (PHFs) with a locking plate between September 2007 and June 2013. All cases were then subdivided into one of four groups as follows: 75 patients in the medial cortical support (MCS) group, 26 patients in the medial multiscrew support (MMSS) group, 29 patients in the medial single screw support (MSSS) group, and 51 patients in the no medial support (NMS) group. Clinical and radiographic evaluations included the Constant-Murley score (CM), visual analogue scale (VAS), complications, and revision surgeries. The neck-shaft angle (NSA) was measured in a true anteroposterior radiograph immediately postoperation and at final follow-up. One-way analysis of variance or Kruskal-Wallis test was used for statistical analysis of measurement data, and Chi-square test or Fisher’s exact test was used for categorical data. Results: The mean postoperative NSAs were 133.46°± 6.01°, 132.39°± 7.77°, 135.17°± 10.15°, and 132.41°± 7.16° in the MCS, MMSS, MSSS, and NMS groups, respectively, and no significant differences were found (F = 1.02, P= 0.387). In the final follow-up, the NSAs were 132.79°± 6.02°, 130.19°± 9.25°, 131.28°± 12.85°, and 127.35°± 8.50° in the MCS, MMSS, MSSS, and NMS groups, respectively (F = 4.40, P= 0.008). There were marked differences in the NSA at the final follow-up between the MCS and NMS groups (P = 0.004). The median (interquartile range [IQR]) NSA losses were 0.0° (0.0–1.0)°, 1.3° (0.0–3.1)°, 1.5° (1.0–5.2)°, and 4.0°(1.2–7.1)° in the MCS, MMSS, MSSS, and NMS groups, respectively (H = 60.66, P< 0.001). There were marked differences in NSA loss between the MCS and the other three groups (MCS vs. MMSS, Z = 3.16, P= 0.002; MCS vs. MSSS, Z = 4.78, P< 0.001; and MCS vs. NMS, Z = 7.34, P< 0.001). There was also significantly less NSA loss observed in the MMSS group compared to the NMS group (Z= −3.16, P= 0.002). However, there were no significant differences between the MMSS and MSSS groups (Z= −1.65, P= 0.225) or the MSSS and NMS groups (Z= −1.21, P= 0.099). The average CM scores were 81.35 ± 9.79, 78.04 ± 8.97, 72.76 ± 10.98, and 67.33 ± 12.31 points in the MCS, MMSS, MSSS, and NMS groups, respectively (F = 18.68, P< 0.001). The rates of excellent and good CM scores were 86.67%, 80.77%, 65.52%, and 43.14% in the MCS, MMSS, MSSS, and NMS groups, respectively (χ2 = 29.25, P< 0.001). The median (IQR) VAS scores were 1 (0- 2), 1 (0- 2), 2 (1–3), and 3 (1–5) points in the MCS, MMSS, MSSS, and NMS groups, respectively (H = 27.80, P< 0.001). Functional recovery was markedly better and VAS values were lower in the MCS and MMSS groups (for CM scores: MCS vs. MSSS, P< 0.001; MCS vs. NMS, P< 0.001; MMSS vs. MSSS, P= 0.031; and MMSS vs. NMS, P< 0.001 and for VAS values: MCS vs. MSSS, Z = 3.31, P= 0.001; MCS vs. NMS, Z = 4.64, P< 0.001; MMSS vs. MSSS, Z= −2.09, P= 0.037; and MMSS vs. NMS, Z= −3.16, P= 0.003). Conclusions: Medial support screws might help enhance mechanical stability and maintain fracture reduction when used to treat PHFs with medial metaphyseal comminution or malreduction.

Background: Estrogen is one of the most important reproductive steroidal hormones and plays a critical role in the maintenance of pregnancy, and its function is mediated by estrogen receptor 1(ESR1 ). The polymorphisms of ESR1 were involved in recurrent spontaneous abortion (RSA); however, the association between ESR1 polymorphisms and RSA remains controversial. The present meta-analysis was aimed to clarify the association between ESR1 PvuII (-397C/T, rs2234693) and XbaI (-351A/G, rs9340799) polymorphisms and the risk of RSA. Methods: All the included articles were retrieved from PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Med Online Database up to January 3, 2018. Data were processed in the Stata 12.0 software. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using fixed-effects models (FEM)/random-effects models (REM). Results: Seven case- control studies with 836 cases and 1164 controls were included in the study. Generally, the ESR1 polymorphisms were not associated with RSA in any of the genetic analysis models. However, it was found that as rs9340799 polymorphism was related to increased risk of RSA in non-Asian group in the homozygous genetic model (OR = 2.40, 95% CI = 1.05–5.50, P= 0.039). Moreover, in Asian group, rs9340799 polymorphism was found to be related to decreased RSA risk in both the heterozygous model (OR = 0.53, 95% CI = 0.33- 0.85, P= 0.009) and the dominant genetic model (OR = 0.55, 95% CI = 0.30- 0.98, P= 0.042). Conclusions: Generally, there was no significant association between the polymorphisms of ESR1 and the risk of RSA. However, subgroup analysis indicated that ESR1 rs9340799 polymorphism was related to increased RSA risk in the non-Asian group while associated with decreased RSA risk in Asian group.