[The 492nd case: recurrent thrombosis, thrombocytopenia].

A 43-year-old female patient was admitted with recurrent thrombosis for more than 2 years and thrombocytopenia for more than 1 year. Both arterial and venous thromboses developed especially at rare sites even during anticoagulation therapy such as cerebral venous sinus thrombosis. Antinuclear antibody, anti-ENA antibody and antiphospholipid antibody were all negative. Platelet count elevated to normal after high dose glucocorticoid and intravenous immunoglobulin (IVIG). Immune thrombocytopenia was suspected. When 4 grade thrombocytopenia recurred, intravenous heparin, rituximab 600 mg, IVIG and eltrombopag were administrated. After 3 weeks, thrombocytopenia did not improve, and new thrombosis developed instead. Screening of thrombophilia related genes revealed PROS1 gene heterozygous mutation and MTHFR TT genotype. Low amount of serum IgG κ monoclonal protein was detected. Heparin-induced thrombocytopenia was differentiated and excluded. Finally, serum negative antiphospholipid syndrome was considered the most likely diagnosis. Dexamethasone 20 mg/day × 4 days combined with sirolimus 2 mg/day was prescribed. The patient was discharged with low molecular weight heparin. At one month, her headache was greatly relieved. The platelet count raised to 20-30×109/L, and no new thrombosis or bleeding was reported.

[The clinical manifestations and risk factors in primary antiphospholipid syndrome with thrombocytopenia].

Objectives: To cross-sectionally analyze the clinical characteristics of primary antiphospholipid syndrome (PAPS) patients with thrombocytopenia, risk factors associated with thrombocytopenia, and risk of symptom recurrence in these patients. Methods: The inpatients with PAPS were retrospectively analyzed in Peking Union Medical College Hospital from 2009 to 2019. Using the collected clinical and laboratory data, the clinical characteristics and risk of symptom recurrence in the PAPS patients with thrombocytopenia were compared with those in the PAPS patients with normal platelet counts. Univariate and multivariate logistic regression analyses were performed to screen the risk factors for thrombocytopenia. Results: In this study, 127 patients with PAPS were enrolled, of which 36 (28.3% ) had thrombocytopenia, with a median age of 38 years, and 63.9% were female. In the thrombocytopenia group, the average platelet count was (58.9±27.0) ×10(9)/L, and the prevalence of thrombosis and morbid pregnancy was not significantly different from that in the normal platelet group. However, the thrombocytopenia group had higher incidence rate of autoimmune hemolytic anemia (19.4% vs 3.3% ) , livedo reticularis (16.7% vs 3.3% ) , chronic kidney disease (25% vs 8.8% ) and antiphospholipid antibodies triple positiveness (61.1% vs 37.4% ) , lower complement levels (C3 of 0.87 g/L vs 1.07 g/L, C4 of 0.12 g/L vs 0.18 g/L, P<0.05) , and higher adjusted Global APS Score (median score of 13 vs 9, P=0.037) than the normal platelet group. In multivariate logistic regression analysis, hypocomplementemia (OR value 5.032, 95% CI 3.118-22.095) is an independent risk factor for thrombocytopenia. Conclusions: In patients with PAPS, thrombocytopenia is mostly mild to moderate. Hypocomplementemia may be the independent risk factor for thrombocytopenia in PAPS patients. The PAPS patients with thrombocytopenia may have a higher risk of symptom recurrence.

[A pediatric-inspired regimen for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: results from a single center].

Objective: To investigate the efficacy of using a pediatric-inspired regimen for adolescents and young adults (AYA) with Philadelphia chromosome-negative (Ph(-)) acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL) at a single center in China. Methods: Clinical data of 71 consecutive newly diagnosed AYA patients with Ph(-) ALL/LBL on a pediatric-inspired regimen in Peking Union Medical College Hospital from January 2012 to November 2018 were retrospectively analyzed. Results: Median age at diagnosis was 20 years (range: 15-38) , and 46 patients (64.8%) were male. Forty-nine (69.0%) had B-ALL/LBL. Among 62 ALL patients, 22 (35.5%) were high-risk. Complete remission rate was 93.0%. At follow-up with a median time of 44 months, the estimated 5-year disease-free survival (DFS) and overall survival (OS) was 56.3% and 64.3%, respectively. There was no significant difference in 5-year OS between allogeneic hematopoietic stem cell transplantation group and the continuous chemotherapy group after completion of 4 courses of chemotherapy. The 5-year DFS and OS for the non-high-risk group was 63.1% and 73.7%, respectively, which were significantly higher than 32.0% and 44.4% for the high-risk group, respectively (P<0.001) . Conclusions: The use of pediatric-inspired regimen for AYAs with Ph(-) ALL/LBL was feasible and effective.

[Posaconazole as primary prevention of fungal infection in intensive immunosuppressive therapy for severe aplastic anemia].

Objective: To Evaluate the efficacy and safety of posaconazole as primary prevention of invasive fungal disease (IFD) in patients with severe aplastic anemia (SAA) treated with anti-thymus/lymphocyte immunoglobulin (ATG/ALG) combined with cyclosporine intensive immunosuppressive therapy (IST). Methods: A retrospective analysis of clinical data of 58 SAA patients who received IST of anti-thymocyte immunoglobulin combining cyclosporine and antifungal prophylaxis during April 2013 to May 2017 in Peking Union Medical College Hospital was performed. The patients were divided into posaconazole prophylaxis group and the control group (itraconazole or fluconazole). The disease characteristics, IFD prevention effect and adverse drug reaction, curative effect and prognosis of the two groups were compared. Results: Posaconazole was used to prevent fungal infection in 20 patients. The other 38 patients were used as the control group. Retrospective analysis showed comparable characteristics (gender, age, disease severity, etiology, interval between the onset of disease to treatment, ATG/ALG type) of both groups. The incidence of IFD were 0 and 15.8% in posaconazole prophylaxis group and the control group, respectively (P=0.084). In the control group, there were 6 cases diagnosed as IFD. Of them, 2 were confirmed, 2 suspected and 2 not identified. Five of the 6 cases were pulmonary infection, 1 bloodstream infections. Of the 6 IFD cases, 5 were very severe aplastic anemia (VSAA). There was no obvious adverse reaction in posaconazole prophylaxis group. Conclusion: Posaconazole is safe and effective for primary prevention of fungal infection of SAA patients receiving IST, especially for the VSAA.

[A prospective study of the efficacy and safety of maintenance therapy with recombinant human thrombopoietin in patients with primary immune thrombocytopenia: a multicenter study].

Objective: To evaluate the efficacy and safety of maintenance therapy with reduced dose of rhTPO in the patients with primary immune thrombocytopenia (ITP) who attained stable platelet (PLT) counts after daily administration of rhTPO. Methods: Treatment was started with a daily administration of rhTPO (300 U/kg) for 2 consecutive weeks. Patients who attained stable PLT≥50×10(9)/L were enrolled to maintenance therapy starting with every other day administration of rhTPO, then adjusted dose interval to maintain platelet count (30-100) ×10(9)/L. Results: A total of 91 eligible patients were enrolled. Fourteen patients discontinued the study due to noncompliance (12/14) and investigator decision (2/14) . Among 77 patients who completed the study, 38 patients with the administration of rhTPO at every other day or less could maintain PLT≥30×10(9)/L for 12 weeks. The percentage of patients with a platelet response (PLT≥30×10(9)/L) at 4(th) week, 8(th) week and 12(th) week of maintain therapy was 92.6% (63/68) , 82.7% (43/52) and 85.0% (34/40) , respectively. Median platelet counts remained in the range of (70-124) ×10(9)/L. The overall incidence of rhTPO-related adverse events was 7.7%. All the adverse events were generally mild. Conclusion: Extending the dose interval of rhTPO is feasible to maintain stable platelet count in the patients with ITP, but the optimal dose interval is uncertain and might vary with individuals.

[Evaluation of clinical characteristics, MYD88(L265P) mutation, CXCR4(WHIM) mutation and prognosis in Waldenström macroglobulinemia: A single center retrospective study of 93 patients].

Objective: To evaluate the clinical characteristics, MYD88(L265P) mutation, CXCR4(W)HIM mutation and prognosis in patients with Waldenström macroglobulinemia (WM). Methods: The clinical characteristics, International Prognostic Scoring System for symptomatic WM (WPSS) , and overall survival (OS) were retrospectively assayed in 93 patients with newly diagnosed WM at Peking Union Medical College Hospital during January 2000 to August 2016. The MYD88(L265P) mutation and CXCR4(W)HIM mutation were tested among 34 patients. Results: The median age of the 93 patients was 64 years (range, 33-85 years) with a male-to-female ratio of 2.44. According to WPSS, we included 16 (17.2%) low-risk, 44 (47.3%) intermediate-risk and 33 (35.5%) high-risk patients. Eight patients had secondary amyloidosis. With a median follow-up of 44 (1-201) months, the median OS was 84 months. Cox regression multifactor analysis showed WPSS risk group (HR=2.342, 95% CI 1.111-4.950, P=0.025) , whether patients had secondary amyloidosis (HR=5.538, 95% CI 1.958-15.662, P=0.001) and whether patients received new drugs (HR=3.392, 95% CI 1.531-7.513, P=0.003) were independent factors associated with OS. We have investigated the presence of the MYD88(L265P) and CXCR4(WHIM) mutation in 34 patients and found that MYD88(L265P) mutation was occurred in 32 patients (94.1%) and CXCR4(WHIM) mutation was occurred in 8 patients (23.5%). Seven of 8 patients who harbored CXCR4(WHIM)-mutated also exhibited the MYD88(L)265P mutation. Patients with MYD88(L265P)CXCR4(WHIM) vs MYD88(L265P)CXCR4(WT) presented with more severe anemia, lower platelet level, higher M protein level and more hyper-viscosity syndrome. Conclusion: WPSS risk group, whether patients had secondary amyloidosis or received new drugs are independent factors for OS in WM. MYD88(L265P) and CXCR4(WHIM) mutation, the most common somatic variants in WM, often occur together and impact the clinical presentation.

Impact of pretransplant induction therapy on autologous stem cell transplantation for patients with newly diagnosed POEMS syndrome.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) is a rare plasma cell dyscrasia sometimes treated with a haematopoietic cell autotransplant. We analyzed data from 138 subjects with newly diagnosed POEMS syndrome receiving a autotransplant at our center. Thirty-two subjects with severe end-organ dysfunction ineligible for immediate autotransplant received pretransplant therapy, which made a subsequent autotransplant feasible. Pretransplant therapy resulted in vascular endothelial growth factor (VEGF) remissions in 15 (47%). Thirty-three transplant recipients (24%) had early posttransplant complications. Risk factors for these complications identified through multivariate analysis included age >50 years (odds ratio (OR) 2.79, 95% confidence interval (CI) 1.09-7.14; P=0.033), time from symptom onset to transplant >5 years (OR 4.71, 95% CI 1.10-20.18; P=0.037) and pleural effusion (OR 3.39, 95% CI 1.26-9.12; P=0.016). Subjects receiving pretransplant therapy had fewer early complications than those who did not (OR 0.17, 95% CI 0.04-0.71; P=0.015), especially in subjects with a VEGF remission (OR 0.05, 95% CI 0.01-0.49; P=0.010). Autotransplants resulted in hematological remission in 60 (50%), VEGF remissions in 76 (72%) and improvements in other organ functions (65-90%). The 5-year progression-free survival (PFS) and overall survival were 76% (95% CI 64-84%) and 94% (95% CI 87-97%), respectively. Hematological (5-year PFS 83 vs 66%, P=0.008), VEGF (5-year PFS 79 vs 57%, P=0.021) remissions and especially both (5-year PFS 95 vs 61%, P=0.004) were associated with better PFS.

Relative contributions of testosterone deficiency and metabolism syndrome at the risk of reduced quality of life: A cross-sectional study among Chinese mid-aged and elderly men.

Testosterone deficiency and metabolism syndrome (MetS) are universal among ageing males, and they have been suggested responsible for poorer quality of life (QoL). We aimed to evaluate the relative contributions of reproductive hormones and components of MetS at the risk of reduced QoL among Chinese mid-aged and elderly men. A cross-sectional study recruited 2,364 males aged 40-79 years, and 2,165 was included for analysis eventually. The Chinese version of ageing male symptoms scale, 36-item Short Form and Beck Depression Inventory were applied to assess QoL. Bivariate correlation analysis and multiple linear regression analysis were used to assess the relative contributions of reproductive hormones and components of MetS at the risk of reduced QoL. Testosterone deficiency and MetS contributed to poorer QoL, of which higher fasting blood glucose made the primary contribution, lower total testosterone mainly contributed to poorer physical functioning.

[Analysis of the safety and efficacy of 60 mg·m-2·d-1daunorubicin combined with standard dose of cytarabine as induction therapy in acute myeloid leukemia patients under 65 years old].

Objective: To evaluate the long- term safety and efficacy of high- dose daunorubicin(DNR)(60 mg·m-2·d-1)combined with standard dose of cytarabine(DA)as induction therapy in patients under 65 years old with newly diagnosed acute myeloid leukemia(AML). Methods: The complete remission(CR)rate, disease free survival(DFS), overall survival(OS)and side effects of therapy were retrospectively assayed in 116 patients with newly diagnosed AML who were younger than 65 years old and received daunorubicin(60 mg · m-2·d-1)combined with cytarabine(Ara- C 200 mg ·m-2·d-1)as induction therapy at Peking Union Medical College Hospital during July 2012 to February 2016. Results: Of 116 patients, 78 cases(67.2%)achieved CR after first course of induction treatment, 94(81.0%)achieved CR after two courses of induction, and early death occurred in only 3 patients(2.6%)during the first course of induction treatment. Only 1 patient had asymptomatic decreased ejection fraction after 6 months of induction treatment. Eighty nine patients received 1 to 4 courses of consolidation. With a median follow-up of 24(1-46)months, the median DFS was 25 months and median OS was not achieved yet. Cox regression multifactor analysis showed genetics risk groups was the only risk factor for DFS(HR=0.258, 95% CI 0.100- 0.664, P=0.005), while genetics risk groups(HR=0.309, 95% CI 0.126- 0.756, P=0.010)and whether patients received more than one cycle of high dose of Ara-C as consolidation therapy(HR= 0.370, 95% CI 0.179- 0.765, P=0.007)were independent factors associated with OS. Conclusions: In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin(60 mg/m2)could improve the rate of complete remission without obvious side effects.

[Autologous peripheral blood hematopoietic stem cell transplantation for patients with primary light chain amyloidosis: experience of 31 cases in a single center].

OBJECTIVE: To evaluate the efficacy and safety of autologous peripheral blood hematopoietic stem cell transplantation (ASCT) for patients with primary light chain (AL) amyloidosis. METHODS: Clinical data, hematological and organ response, safety and survival status of 31 patients with AL amyloidosis who had received ASCT from January 2009 to June 2015 were retrospectively analyzed. RESULTS: Among 31 patients, there were 18 males and 13 females with the median age of 55 (range, 43-66) years old. Involvement of 1 organ was presented in 20 patients. 80.6% patients were defined as Mayo stage 1. The median time from diagnosis to ASCT was 3 (range, 0.5-26) months. The median time to neutrophil and platelet engraftment was 11 (range, 9-12) days and 11 (range, 8-14) days, respectively. No one patient had transplantation related death. Among 27 evaluable patients, overall best hematological response was 85.2% with complete response of 63.0% and very good partial response of 7.4%. The median time to the best hematological response was 4 (range, 1-21) months. 59.2% patients archived organ response and the median time to organ response was 8 (range, 3-18) months. After the median follow up time of 21 months, one patient had died and three patients had progressed. Therefore, the estimated 3 years progress free survival and overall survival was 92.8% and 96.4%, respectively. CONCLUSIONS: ASCT was an effective and safe treatment for patients with primary AL amyloidosis in early stage.

Comparison of vindesine and prednisone and cyclophosphamide, etoposide, vindesine, and prednisone as first-line treatment for adult Langerhans cell histiocytosis: A single-center retrospective study.

OBJECTIVE: We compared the efficacy and clinical outcomes of vindesine and prednisone (VP) and cyclophosphamide, etoposide, vindesine, and prednisone (CEVP) regimens as first-line treatment for multisystem (MS) or multifocal single system (SS-m) adult Langerhans cell histiocytosis (LCH). METHOD: Clinical features, treatment response, and survival of adults with Langerhans cell histiocytosis treated at our center from January 2001 to January 2015 were reviewed retrospectively. RESULTS: Forty-five adult MS or SS-m LCH patients were treated (N=31, CEVP group; N=14, VP group). Both treatment groups had similar gender distributions, patient ages, and extent of disease. The non-active disease rate for both groups was 70.0% and 64.3% (P=0.775), respectively. Median follow-up was 74.9 (range: 2.8-183.6) months and recurrence rates were 71.0% and 78.6% (P=0.593), respectively. The need for second-line therapy was 64.5% and 71.4% (P=0.649), respectively, and mortality rates were 9.7% and 15.4% (P=0.586), respectively. Neutropenia occurred in 48.4% of CEVP-treated patients and 7.1% of VP-treated patients (P=0.008). CONCLUSIONS: CEVP or VP regimens for the treatment of adult SS-m or MS LCH showed similar efficacies, and both regimens were associated with high disease recurrence and the need for second-line therapy.

Changes in cyclin dependent kinase expression and activity accompanying lens fiber cell differentiation.

Previous studies from this laboratory have shown that differentiating lens fiber cells contain two active cyclin dependent kinases (Cdks), Cdk1 and Cdk5. The present study was undertaken to explore the expression and regulation of six additional members of the Cdk family (Cdk2, Cdk3, Cdk4, Cdk6, Cdk7 and Cdk8) during lens differentiation. Differentiating lens fiber cells were separated from lens epithelial cells by microdissection of developing rat lenses [embryonic day 16 (E16) to postnatal day 8 (P8)] and Cdk expression was assessed by RT-PCR and immunoblotting. Two Cdks (Cdk3 and Cdk6) were not expressed in lens fiber cells or epithelial cells during this developmental period. In the lens epithelium, we detected proteins and mRNAs corresponding to all other Cdks examined (Cdk2, Cdk4, Cdk7, Cdk8) throughout this developmental period. Epithelial cells showed significant Cdk2 activity, which decreased with developmental age, but no significant activity was detected for Cdk4, Cdk7, or Cdk8. Fiber cells contained all four Cdk proteins and the corresponding Cdk mRNAs except for Cdk2 mRNA. None of the Cdks examined showed significant kinase activity in fiber cells. Immunoprecipitates of Cdk2 and Cdk4 from fiber cells contained p57(kip2), supporting the view that this Cdk inhibitor blocks the activity of these Cdks in lens fibers. In contrast, p57(kip2)did not co-immunoprecipitate with Cdk5 from lens fibers. These findings suggest that the differential affinity of p57(kip2)for members of the Cdk family may provide a mechanism for specific regulation of individual Cdks during fiber cell differentiation.