Phenome-wide association study (PheWAS) is a reverse genetic analysis method to identify the potential phenotypes associated with genetic variations. With the increasing availability of biomedical databases and electronic medical records (EMR), PheWAS has gradually become an effective tool to unveil the relationships between exposure and a broad range of health phenotypes. The unique advantage of this method is that it can simultaneously explore the associations of a specific exposure with a variety of disease outcomes, thus helping to reveal multiple causal relationships and the shared pathogenic mechanisms among diseases. However, PheWAS has limitations, including selecting instrumental variables and the heavy burden of various corrections. In addition, how to interpret the biological mechanisms underlying significant findings is another crucial issue of PheWAS. This review will focus on the methodology and application of PheWAS to provide meaningful suggestions and insights for future studies.全表型组关联研究（PheWAS）是一种反向遗传学分析方法，旨在研究哪些表型可能与给定的遗传变异相关联。随着生物医疗数据库和电子病历信息的开放获取，PheWAS已逐渐成为探索暴露因素与多种健康结局之间关联的有效方法。这种方法具有同时探索某一种暴露与多种疾病表型之间的统计学关联的独特优势，从而有助于揭示多重因果关联以及各疾病间共同的致病机制。然而，PheWAS目前也面临诸多挑战。该方法本身存在一定的局限性，包括工具变量的选择是否具有代表性以及繁重的多重校正负担。此外，如何应用生物学知识阐释研究结果是PheWAS的另一重点问题。本文将围绕PheWAS方法学进行概述，以期为后续更好地开展PheWAS提供思路和建议。.
The concurrence of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) is rare. Previous reports of such cases have focused mainly on clinical diagnosis and characteristics, so the mechanism remains unclear, and therapy options have been poorly explored.Here, we report two cases of synchronous AML and CLL. Flow cytometry revealed two distinct abnormal cell populations (myeloblasts and lymphoid cells) according to scatter characteristics. CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy. Chemotherapy regimens indicated for both AML and CLL were used in our patients, and our patients achieved complete response after chemotherapy. Next-generation sequencing of 88 genes was performed.We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML. The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.
Abstract Purpose The present study aims to explore the clinical features, imaging manifestations, pathologic characteristics, treatment, and prognosis of aggressive splenic lymphoma (ASL) patients. Methods From January 2001 to March 2021, patients who were histologically proven splenic lymphoma were enrolled in this study. The survival curves of overall survival (OS) and progressive-free survival (PFS) were calculated by the Kaplan–Meier survival analysis and log-rank test. Univariate and multivariate Cox regression analyses were performed to estimate the potential prognostic factors. Results Sixty-nine patients who were histologically proven ASL in this study. The median follow-up time was 76.3 months (95%CI, 60.194-92.406). Patients with ASL underwent the splenectomy had better PFS and OS than that of patients who did not (OS 61% vs 35%, P=0.084; PFS 57% vs 25%, P=0.061), yet the difference was not remarkably significant. In addition, splenic lymphomas of T-cell origin (OS HR, 3.398[95%CI, 1.327-8.704], P=0.011; PFS HR, 2.776[95%CI, 1.107-6.959], P=0.029) and present with B symptoms (OS HR, 2.703[95%CI, 1.219-5.994], P=0.014; PFS HR, 2.890[95%CI, 1.348-6.194], P=0.006) were independent risk factors correlated with OS and PFS. After establishing a risk-stratified model in combination with cell of origin (COO) and B symptom to divide patients into three risk subgroups: 36 were in low-risk group, 28 were in intermediate-risk group, and 5 were in high-risk group. The differences between each group were statistically significant (OS: χ2=41.000, P<0.001; PFS: χ2=47.739, P<0.001). Conclusion Splenic T-cell lymphoma patients with B symptom at initial diagnosis had the worst outcome among aggressive splenic lymphoma.
Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by an infrequent but immune-mediated life-threatening disease, with confusing clinical manifestations, rapidly deteriorating health, high morbidity and mortality and challenging diagnosis. The purpose of this study was to improve the recognition and understanding of HLH. Retrospective observational cross-sectional study. Data were collected for all cases of adult patients diagnosed with HLH in a large cohort managed at a single medical center from January 2011 to December 2015. The median age was 52 years (range 18–90 years) and 123 (60.0%) were male. Over 95% patients manifested fever, hyperferritinemia and elevated lactate dehydrogenase. Underlying triggers of HLH were as follows: 119 (58.0%) malignancies, 83 (40.5%) infections, 14 (6.8%) unknown triggers and 14 (6.8%) autoimmune disorders. The median overall survival was 55 days. And elderly patients (age ≥60 years) had a markedly worse survival compared with young patients (age <60 years) (median overall survival 24 days vs. 159 days, respectively; P <0.001). In a multivariable analysis, platelet <40 × 109/l (HR = 2.534; 95% CI 1.152–5.573; P = 0.021), PT prolonged >3 s (HR = 1.909; 95% CI 1.127–3.234; P = 0.016) and malignancy (HR = 1.614; 95% CI 1.008–2.582; P = 0.046) were correlated with poor survival. HLH adult patients had very complex clinical manifestations as well as underlying diseases. Patients with PLT <40 ×109/l, PT prolonged >3 s and malignancy had inferior survival. It is of great importance to improve our understanding of this syndrome.
Background In China, the combination of homoharringtonine, cytarabine, and G-CSF (HAG) has been extensively applied for treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods We performed a meta-analysis of 2,314 patients (AML, n = 1754; MDS, n = 560) to determine the overall safety and efficacy of this regimen. Results The complete response (CR) rate of AML patients (53%) was significantly higher than that of MDS/transformed-AML patients (45%; P = 0.007). The CR rate of patients with newly diagnosed AML (62%) was significantly higher than in patients with relapsed/refractory AML (50%; P = 0.001). There were no significant difference in CR rates between elderly AML patients (54%) and all AML patients (P = 0.721). When compared with non-HAG regimens for AML/MDS induction therapy, the CR rate of patients treated with HAG was significantly higher than in treated with intensive chemotherapy (P = 0.000). No significant differences in CR rates were observed between patients treated with HAG and those treated with CAG (cytarabine, aclarubicin, G-CSF) regimens (P = 0.073). HAG regimen was well tolerated, with early death (ED) in 2%, grade IV myelosurrpression in 52% and infection in 50%. Reports of ED and rates of myelosuppression were reduced as compared with intensive chemotherapy (P = 0.000 and P = 0.000, respectively). Conclusion The HAG regimen is an effective and safe regimen for the treatment of AML and MDS, and appears to be more effective and better tolerated than intensive chemotherapy. Future randomized controlled trials and further meta-analyses are strongly needed to confirm its efficacy and safety, especially in comparison with intensive chemotherapy.
Abstract Objectives In order to explore the impact of pegylated liposomal doxorubicin (PLD) dose intensity on survival outcomes of newly diagnosed elderly patients with diffuse large B‐cell lymphoma (DLBCL), we performed a retrospective study to compare the efficacy and adverse effects of RCEOP (70 mg/m 2 ), RCdOP (20–30 mg/m 2 ) and RCDOP (30–45 mg/m 2 ). The optimal PLD dose of patients with different clinical characteristics of subgroups was explored to provide a clue for the selection of clinical PLD dose. Methods A total of 335 DLBCL patients (60–85 years old) who were newly diagnosed and completed at least four cycles of RCE(D)OP were selected. The patients were mainly divided into RCEOP (126 cases) (epirubicin 70 mg/m 2 ), RCdOP (151 cases) (PLD 20–30 mg/m 2 ) and RCdOP (58 cases) (PLD 30–45 mg/m 2 ). The effects of different doses of PLD on clinical efficacy, cardiotoxicity and prognosis of patients were retrospectively analyzed. Subgroup analysis was performed to compare the clinical characteristics of different subgroups. Results Our study showed that PLD and epirubicin had similar efficacy (overall survival (OS) p = 0.776; progression‐free survival (PFS) p = 0.959). RCDOP (30–45 mg/m 2 PLD) group had a higher complete remission (CR) rate of 75.9% compared with RCdOP (20–30 mg/m 2 PLD) group (P D vs. d = 0.018). In the overall population, there was no significant difference in survival between RCDOP and RCdOP groups (OS P D vs. d = 0.661; PFS P D vs. d = 0.212). In patients with underlying cardiovascular diseases, the PFS of the RCDOP group was significantly better than the RCdOP group ( p = 0.043). Meanwhile, patients in the RCDOP group tended to have a better prognosis than those in the RCEOP group (OS: RCDOP vs. RCEOP p = 0.054, PFS: RCDOP vs. RCEOP p = 0.053). There was no significant difference in the incidence of cardiotoxicity and other adverse events among the three groups. For the low‐risk (age‐adjusted‐International Prognostic Index = 0/1) old patients without cardiovascular disease, RCdOP was considered a better strategy in OS ( p = 0.020). Conclusion In the general population, the CR rate in the RCDOP group was significantly higher than that in the RCdOP group ( p = 0.018). For elderly DLBCL patients with cardiovascular disease, the effect benefit brought by the PLD dose was more obvious, and the PFS of the RCDOP group was significantly better than that of the RCdOP group ( p = 0.043). Full dose of PLD is an efficient alternative in the treatment of patients with preexisting cardiovascular diseases.
Background: Adult secondary hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome characterized by excessive activation of mononuclear-phagocytic system resulting in hyperinflammatory response. To date, the factors influencing early death of HLH are still not fully elucidated. Patients and Methods: We did a retrospective study of 171 adult patients with newly diagnosed HLH at our institution from January 2012 to April 2018. All patients' clinical features, laboratory findings, treatments and prognosis were reviewed. Results: The median age was 49 years (range, 18-88 years), and 110 (64.3%) were male. The major underlying trigger of HLH was malignancy (88/171, 51.5%), especially non-Hodgkin lymphoma. In a multivariate analysis, age ≥54 years (P = 0.002), platelet ≤39.5 × 109/L (P = 0.028), activated partial thromboplastin time (APTT) ≥54 sec (P = 0.048), triglyceride ≥3.23 mmol/L (P < 0.001), lactate dehydrogenase (LDH) ≥1300 U/L (P = 0.012) and malignancy (P = 0.001) were significantly associated with early death in HLH. Then, patients were classified into four groups according to the number of risk factors at the time of diagnosis: low risk (zero, one or two risk factors), low intermediate risk (three risk factors), high intermediate risk (four risk factors) and high risk (at least five risk factors), with the 30-day overall survival (OS) of 92.4%, 58.8%, 30.0% and 4.8%, respectively (P < 0.001). Conclusions: Patients with old age, thrombocytopenia, prolonged APTT, hypertriglyceridemia, elevated LDH and malignancy had inferior survival. It is important to identify those patients at risk of early death, which may guide treatment and reduce mortality.
Objective: To analyze the prognostic value of CD7 expression in newly diagnosed acute myeloid leukemia (AML) patients, and to further explore the correlation between CD7 expression and CEBPA mutation, and to clarify the prognostic value of CD7(+) in AML patients with wild-type (WT) or mutant-type (MT) CEBPA. Methods: The clinical data of 298 newly diagnosed non-M(3) AML patients between January 2010 and December 2016 were analyzed retrospectively. The clinical characteristics and prognosis of CD7(+) and CD7(-) patients were respectively compared in all patients, and in patients with WT and MT CEBPA. The relationship between CD7 expression and CEBPA mutation was determined by chi-square, and the effects of CEBPA mutation on survival and prognosis in CD7(+) group by Kaplan-Meier method. Results: In CD7(+) group, the frequencies of CEBPA mutation were 10.1% (single site) and 33.9% (double site) , significantly higher than those of the CD7(-) group (5.3% and 4.2%) (P=0.000) . Subgroup prognostic analysis showed a lower CR rate (P=0.001) and a higher RR (P=0.023) in CD7(+) group comparing to those of CD7(-) group in AML patients with wild type CEBPA. There were no statistical difference between CD7(+) group and CD7(-) group in overall survival (OS) and disease free survival (P>0.05) , while in the CEBPA mutant group the CD7(+) group has higher OS (P=0.019) and DFS (P=0.010) . Based on the CD7 expression and CEBPA mutation, 298 cases were divided into 3 subgroups, named as CD7(+)-CEBPA MT group, CD7(-) and CD7(+)-CEBPA WT group. The 3-year OS of the 3 groups were 80.2%, 48.0% and 30.6%, respectively (P<0.001) , and the 3-year DFS were 74.1%, 37.4% and 22.2%, respectively (P<0.001) . Conclusion: The CEBPA mutation rate was higher in CD7(+) AML patients then that of CD7(-) patients. CD7 expression has opposite prognostic significance in AML patients carrying the wild-type or mutant-type CEBPA. Based on CD7 expression and CEBPA mutation, a new risk stratification model can be established, which is helpful to guide the clinical individualized treatment for AML patients.目的： 分析CD7在初治急性髓系白血病（AML）患者中的表达和预后价值，进一步探讨CD7表达情况与CEBPA突变的相关性，明确其在CEBPA野生型和突变型AML患者中与预后的关系。 方法： 回顾性分析2010年1月至2016年12月收治的298例初治AML患者（除外M(3)亚型）的临床资料，在全部患者以及CEBPA野生型和突变型组中，分别比较CD7阳性（CD7(+)）和CD7阴性（CD7(-)）患者的临床特征及预后差异，并联合CD7表达情况和CEBPA突变状态初步建立新的危险分层模型。 结果： 在CD7(+)组中，CEBPA单位点和双位点突变的发生率分别为10.1%和33.9%，显著高于CD7(-)组（5.3%和4.2%），差异具有统计学意义（P=0.000）。在CEBPA野生型患者中，CD7(+)组患者相较CD7(-)组患者完全缓解率低（P=0.001）、复发率高（P=0.023），而两组总生存（OS）期和无病生存（DFS）期差异无统计学意义（P值均>0.05）；在CEBPA突变患者中，CD7(+)组显示有更长的OS期（P=0.019）和DFS期（P=0.010）。根据CD7表达和CEBPA突变与否将AML患者分为三个亚组：CD7(+)伴CEBPA突变组、CD7(-)组和CD7(+)伴CEBPA野生型组。三组患者的3年OS率分别为80.2%、48.0%和30.6%（P<0.001），3年的DFS率分别为74.1%、37.4%和22.2%（P<0.001）。 结论： CD7(+)组中CEBPA突变率显著高于CD7(-)组，CD7(+)在CEBPA野生型组和突变组AML中存在截然相反的预后意义。根据CD7表达情况和CEBPA突变与否建立新的危险分层模型，有助于指导临床个体化治疗。.
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