ALBERT

Description: Background Type 2 Diabetes Mellitus (T2DM) is a chronic disease closely related to personal life style. Therefore, achieving effective self-management is one of the most important ways to control it. There is evidence that social support can help to improve the self-management ability of patients with T2DM, but which social support is more effective has been rarely explored. The purpose of this study is to construct an integrated model to analyze which social support has more significant impact on self-management of T2DM, and provide reasonable suggestions to health care providers on how to effectively play the role of social support. Methods We established a social support indicator evaluation system and proposed an integrated model that combines ANP (Analytical Network Process) and CRITIC (CRiteria Importance through Intercriteria Correlation) methods to evaluate the impact of social support on T2DM self-management from both subjective and objective perspectives. The weights calculated by the model will serve as the basis for us to judge the importance of different social support indicators. Results Informational support (weighting 49.26%) is the most important criteria, followed by tangible support (weighting 39.24%) and emotional support (weighting 11.51%). Among 11 sub-criteria, guidance (weighting 23.05%) and feedback (weighting 14.68%) are two most relevant with T2DM self-management. This result provides ideas and evidence for health care providers on how to offer more effective social support. Conclusion To our knowledge, this is the first study in which Multi-Criteria Decision Making (MCDM) tools, specifically ANP and CRITIC, are used to evaluate the impact of social support on improving self-management of type 2 diabetes. The study suggests that incorporating two sub-indicators of guidance and feedback into the diabetes care programs may have great potential to improve T2DM self-management and further control patient blood glucose and reduce complications.

Description: Background and Objectives: Chimeric antigen receptor modified T (CAR-T) cell therapy has emerged as a promising strategy for the treatment of relapsed and refractory hematological malignancies recently. CD19 chimeric antigen receptor T (CD19CAR-T) cell therapy is a representative case showing promising results in treating relapsed and refractory B-lineage acute lymphoblastic leukemia (r/r B-ALL). However, challenges remain due to the concurrent severe side-effects such as cytokine release syndrome (CRS) or neurological toxicities which may cause death if they are not properly managed. So, how to safely use the CAR-T cell therapy in patients has drawn a lot of concern and attention worldwide. The objective of this study was to investigate the cytokine patterns to early identify and monitor the severe side-effects of cytokine release syndrome (CRS) and neurotoxicity caused by the therapy so that the therapy can be safely administered. Patients and Method: From December 2015 to March 2017, five patients with r/r B-ALL treated with CD19CAR-T cells were enrolled in this study. The Th1/Th2 cytokines including Interleukin (IL)-2, IL-4, IL6, IL-10, Tumor necrosis factor (TNF) and Interferon-gamma (IFN-γ ) in the serum and cerebral spinal fluid (CSF) were quickly measured by cytometric bead array (CBA) technology which allowed the result being available within 5 hours after the samples taken. The test were repeated more than once a day during the therapy. Results: 5 pediatric patients (2 boys and 3 girls) with r/r B-ALL aged 4 months -12 years old were treated by CD19CAR-T cell therapy. Four patients achieved complete remission (80% of CR rate) with minimal residual diseases (MRD) negative detected by flow cytometry within 2 weeks. One patient did not respond to the therapy due to the poor quality of his T cells. Five to 10 times of cytokine measurements were carried out for the five patients. Two types of cytokine patterns were identified: (1) very high levels of IL-6, IFN-γ with moderately elevated IL-10 indicated the CAR-T therapy effective pattern; (2) IL-6 slightly - severely elevated IL-6 level without concurrent elevation of IFN-γ represented a CAR-T cell therapy ineffective pattern but rather indicating a current infection. All the four responding patients presented the CAR-T therapy effective cytokine pattern, while the non-responding patient presented the CAR-T therapy ineffective cytokine pattern. We also analyzed the relationship between the cytokine levels and the severity of the side-effects and found that they were highly correlated. The cytokine levels in the CSF of two patients with seizure were also measured and we found that the elevation of the cytokine pattern in the CSF was paralleled to those in their serum but CNS-leukemia and CAR-T cells in their CSFs were not detected, indicating that the neurotoxicity concurrently presented in these two patients might be caused by the cytokines in the serum leaked into the CSF through the blood brain barrier. Extremely high level of cytokines occurred at 12 hours after CAR-T cell infusion in a patient was identified immediately and treated timely in onn-ICU setting to avoid the fatal consequence. Acute toxicities including fever, hypotension and other neurological toxicities occurred in responding patients within 2 weeks post infusion and managed properly with tocilizumab and/or steroids according to the "real-time" monitoring of this simple 6-Th1/Th2 cytokine patterns at the non-ICU setting. In conclusion, our study demonstrates that CD19CAR-T cell therapy can be administered safely for patients with relapsed and refractory leukemia under the "real-time" monitoring of a simple 6-cytokine pattern. Disclosures No relevant conflicts of interest to declare.

Description: Intensive chemotherapy has greatly improved the long-term treatment outcome in children with acute lymphoblastic leukemia (ALL), however, children with de novo acute myelogenous leukemia (AML) remain much less favorable prognosis. Most reports were from western countries while data from Chinese children with AML have been very limited. In this study, we reported the long-term outcome and the prognostic factors of childhood AML treated with modified National Protocol of Childhood Leukemia in China 1997 (NPCLC-AML97) during the past 8 years in our institution. From January1997 to December 2005, 185 children younger than 16 years old with de novo AML were enrolled into our hospital. The NPCLC-AML97 protocol included induction therapy either of DA (daunorubicin + cytarabine), HA (homoharringtonine + cytarabine), DAE (daunorubicin + cytarabine + etoposide) or CAG (Clarithromycin + cytarabine + G-CSF). When CR achieved, the same cycle was repeated as consolidation therapy. Intensification therapy consisted of 3 cycles of intermediate or high dose of cytarabin (I/HDAC) every other month. During the intermission, DA, HA, EA (etoposide + cytarabine) were given. Maintenance therapy was given monthly by sequential HA, EA, AT (cytarabine + 6-mercaptopurine) cycles and I/HDAC was administered every 6 months. The total course was about 2.0~2.5 years from CR. Of the 185 patients, 49 were M3 and 136 were other subtypes. Sixty patients abandoned within the first two weeks after diagnosis, 2 died before chemotherapy, and 123 were eligible for protocol evaluation. The 7-year OS and EFS rates for the whole cohort were 33.1±4.1% and 31.2±3.7%, respectively. For eligible patients, 111 patients (90.2%) achieved CR (95.1% for M3 and 87.8% for non-M3, P = 0.334). With a median follow-up time of 69 months, 70 patients (56.9%) developed significant infection during chemotherapy, 31 patients relapsed and the 5-year cumulative relapse rate was 48.2±5.6% with a median relapse time of 12 (range from 3 to 56) months. No CNS relapse was found. Forty-one patients (33.3%) died in this cohort until data censored. Survival curve showed that the 3-year, 5-year and 7-year estimates of OS were 61.0±4.9%, 55.7±5.1% and 50.2±5.5%, whereas the EFS rates were 50.9±4.9%, 46.9±5.1% and 46.9±5.1%, respectively. M3 was more curable than non-M3 (7-year OS: 66.9±8.8% vs. 38.7±6.8%, P = 0.003; 7-year EFS: 63.5±7.9% vs. 35.9±6.3%, P = 0.005). Univariate analysis showed that superior outcome were favored by initial WBC count less than 100×109/L, M3 subtype, good response to therapy (attaining CR after one cycle of induction for non-M3 or within 30 days for M3), high expression of CD13 and CD33, negative expressions of CD14, CD34 and HLA-DR. And multivariate analysis showed that treatment response, initial WBC count and expression status of CD14 on the surface of leukemic cells were independent prognostic factors for long term survival. We conclude that high incidence of APL, high abandonment rate and low incidence of CNS relapse are the features in this cohort. Abandonment, relapse and infection are the main causes of treatment failure. For patients who adhere to the protocol, a relatively good outcome can be achieved.

Description: Introduction and objective: Recent studies from resource-rich countries have showed that minimal residual diseases (MRD) were the most important independent prognostic factor for children with acute lymphoblastic leukemia (ALL). However, experience from Chinese children with this disease has not been reported in the English literature. In this study, we reported our experience in small series of children with ALL based on multi-parameter flow cytometric detection of MRD to study the relationship between MRD levels and the long term survivals in Chinese children with ALL. Methods: Using multi-parameter flow cytometry and at least one patient specific leukemia associated immunophenotype (LAIP) to determine the MRD levels in 71 Chinese children with ALL expressing leukemia associated immunophenotype (LAIP) from January 2002 to December 2003. Bone marrow aspirates were collected on day 15 and the 1st, 3rd, 6th, 12th, 18th, 24th, 30th month after chemotherapy. Leukemia associated Immunophenotype for each patient was identified according to the patients’ initial immunophenotypes determined by multi-parameter flow cytometry using a panel of more than 30 antibodies. Results: The one, two and three year disease free survival (DFS) for patients with a MRD level less than 10−2 on day 15 were (88.3±6.4) %, (84.3±7.2) % and (76.3±8.5) %, respectively, whereas those for patients with MRD levels ≥10−2 on day 15 were 100%, 0% and 0%, respectively (log rank test, P=0.004). The 5-year DFS for patients with MRD levels

Description: Objectives to report the long-term outcome of childhood acute lymphoblastic leukemia (ALL) treated in our department between 1994 and 2004 under the poor coverage of medical insurance. Subjects and Methods A total of 151 pediatric patients aged 1.1 – 16.2 yrs with a median of 6 yrs were enrolled into this study. Gender: 93 males and 58 females with M:F ratio of 1.6:1. Patients were diagnosed based the morphology, immunophenotyping, cytogenetics and molecular biology markers and divided into standard risk (SR) group (104 cases) and high risk (HR) group (47 cases). Chemotherapy protocols consisted of VDLD (VCR 1.5mg/M2 qw on day 1, 8, 15, 22 + DNR 35mg/M2 qd on day 1, 2 (SR) or on day 1, 2, 3 (HR) + L-Asparaginase (6000U/M2 qod for 10 doses started on day 8 + Dexamethason 6mg/M2 orally for 28 days started on day1 with one week of tapering) for 4 weeks of induction followed by one week of CAT (CTX 800mg/M2 on day1 + Ara-C 50mg/M2 q12h on day1 ~ day7 for SR group or 1g/M2 q12h on day1 ~ day3 for HR group + 6-mercaptopurine 75mg/M2 qn on day1~day7) for consolidation. Then 3 courses of high-dose Methotrexate (HD-MTX) 3g/M2 for SR group or 5g/M2 for HR group for extramedullary leukemia prophylaxis were conducted followed by 3 successive courses of VM-26 150mg/M2 + Ara-C 300mg/M2 every two days for early intensification. In addition to HD-MTX, MTX+Ara-C+Dex in triplicate by intratheacal injection was also performed once a week during induction, consolidation and early/late intensification. Then, 2 weeks of VDLD for late intensification with 2–3 courses of HD-MTX and VM26 + Ara-C intensification with 2–3 courses of HD-MTX were alternated every 6 months until a total of 3 yrs for girls or 3.5 yrs for boys were reached. A total of 7~9 and 9~11 courses of HD-MTX were administered for patients with SR and HR groups, respectively for the extramedullary leukemia prevention. No cranial irradiation was used for the prevention of CNS leukemia. The maximum dosage of DNR was limited to 360 mg/M2. Results. All but two patients got complete remission (149/151, 98.68%) after 4 weeks of induction. The overall 5 yrs of event free survival (EFS) for both SR and HR groups was 70.60% with 85.65% for SR group and 61.36% for HR group. The overall relapse rate was 7/151 (4.63%) cases, of which CNS leukemia 2/151(1.32%) were identified. 3 patients went into second remission with a short duration and relapsed again and died shortly. No testicular leukemia relapse was identified. One patient (1/151, 0.66%) was found to have a secondary leukemia. Of all this patients, 58 patients (38.4%) had one year of medical insurance for a total of 80,000 yuan in RMB (about US$10,000) while 93 patients (61.6%) were all on their own finance. An average of 200,000 yuan in RMB (about US$20,000) was spent for each patient during the whole process of treatment. Conclusions Childhood ALL is curable disease even in patients with poor medical insurance and less intensive as compared to Western countries. The results are comparable to those reported in Western countries.

Description: Owing to the intensification of chemotherapy, the complete remission (CR), overall survival (OS), disease free survival (DFS) and event free survival (EFS) rates in childhood AML have been significantly improved during the past two decades in western countries. However, reports on the long-term outcome of this disease in Chinese children remain to be very limited. Objectives The aims of this study were to investigate the outcome and prognostic factors in Chinese childhood AML treated in our hospital during the past 7 years and to provide the basis for further improvement of outcome in children with AML. Methods From April 1998 to August 2005, 96 children (51 boys and 45 girls, aged 1.5 ~ 16.1 yrs with a median age of 9) with de novo AML diagnosed in our hospital based on MICM criteria were enrolled into this study. In total, 57 patients with non-APL AML were treated with the induction therapy of daunorubicin (maximum total cumulative dose 360 mg/M2) + Ara-C (DA) or homoharringtonine + Ara-C (HA), post-remission therapy with high-dose (1~2 g/M2 q12h for 6 doses) Ara-C containing regimens for three-month courses, and low-dose therapy with daunorubicin, homoharringtonine, etoposide (maximum total cumulative dose 1800 mg/M2) and Ara-C for three-month courses, followed by maintenance therapy for a total of 2~2.5 yrs. The 39 patients with APL were treated with all-trans retinoic acid (ATRA) and drugs above. Results Out of 96 patients, 86 children (89.6%) achieved CR. The estimated OS rates at three, five and seven years were (67.2±5.5)%, (58.1±6.4)% and (49.6±8.0)%, respectively, while the EFS rates were (52.3±5.8)%, (47.6±6.2)% and (47.6±6.2)%, and the DFS rates were (55.9±6.0)%, (50.7±6.4)% and (50.7±6.4)%, respectively. Univariant analysis showed that the variables predicted higher CR rates included the WBC counts (93.2% for patients 〈 100 × 109/L vs 50.0% for those ≥ 100 × 109/L, P = 0.004) at diagnosis, and the blasts (100% for patients without blasts vs 85.2% for those with blasts, P = 0.023) in the peripheral blood. The variables predicted longer survival duration included WBC counts ((49.1±6.5)% of 5yr EFS for patients 〈 100 × 109/L vs (33.3±18.0)% for those ≥ 100 × 109/L, P = 0.022) at diagnosis, FAB subtypes ((55.9±9.7)% for M3 vs (40.4±7.7)% for non-M3, P =0.048), course numbers [(76.0±12.2)% of 5-yr ESF for 1 course vs (31.1±9.0)% for more than 2 courses, P = 0.026) for achieving CR, CD38+ ((57.9± 7.3)% for CD38+ vs (16.7%± 10.8)% for CD38−, P = 0.005), CD14− ((49.9± 7.3)% for CD14− vs (21.5%± 14.2)% for CD14+, P = 0.001), CD34− ((54.7± 9.7)% for CD34− vs (32.6%± 8.8)% for CD34+, P = 0.038) and HLA-DR- ((57.7± 17.7)% for HLA-DR- vs (39.9%± 7.4)% for HLA-DR+, P = 0.024). 17 patients lost follow-up. The total cumulative relapse rate was 31.6% (25/79) with all BM relapse. The total treatment related modality rate was 5.3%. No secondary malignancy case was identified. Conclusions DA-based induction and high dose Ara-C-based post-remission treatment are effective to improve the CR rate and long-term survival in Chinese children with AML. The results are comparable to those reported in western countries. Initial WBC counts, early response to chemotherapy, FAB subtypes and some immunological markers are proved to be the significant prognostic factors for childhood AML under our current protocol.

Description: Acute promyelocytic leukemia (APL) is a specific type of hematopoietic malignancy, accounting for ~ 10% of the de novo acute myeloid leukemia (AML). During the old days, severe complications as disseminated intravascular coagulation (DIC) and intracranial hemorrhage were the most common causes of treatment failure after conventional chemotherapy without all-trans retinoic acid (RA). Owing to the application of RA for the induction treatment, the overall survival (OS), the disease free survival (DFS) and the event free survival (EFS) rates have been dramatically improved in adult patients with APL. However, data on long-term outcome of APL in children, especially in Chinese children, have been very limited. Objective The aim of this study was to investigate the clinical biological features, diagnosis, prognosis and long-term survival in childhood APL. Methods 46 children (26 boys and 20 girls, aged 1.5 ~13.8 yrs with a median of 9.3 yrs) with APL from April 1998 to October 2005 were enrolled into this study. Immunophenotyping analysis was carried out in 43 patients using multi-parameter flow cytometry. 32 patients went through PML/RARα fusion gene detection using RT-PCR. Induction treatment consisted of ATRA and daunorubicin(DNR) or pirarubicin (THP) followed by 6 courses of multi-drug chemotherapy consolidation and a long-term maintenance therapy including ATRA, high dose Ara-C (HD-Ara-C), DNR+Ara-C (DA), homoharringtonine+Ara-C (HA) and etoposide+Ara-C (EA). Results Pale, hemorrhage and fever were the most common symptoms in APL patients at the time of presentation. 19 patients (41.3%) were found to have WBC count more than 10.0×109/L at diagnosis. Immunophenotyping analysis showed that CD13, CD33, CD117 and MPO were the most commonly expressed antigens while HLA-DR, CD14 and CD34 were mostly the negative markers on APL cells. 71.9%(23/32) of the patients analyzed were PML/RARα fusion gene positive. Of the 39 patients receiving treatment, 36 children (92.3%) achieved complete remission. 7 children replased during therapy, and 3 relapsed after finishing the entire courses. The 5-year cumulative incidence of relapse (CIR) was 28.6%. The estimated overall survival (OS) rates at one, three and five years were 86.1%, 76.1%and 70.2%, respectively while the event free survival (EFS) rates were 78.4%, 63.6%and 53.1%, respectively. The probability of remaining alive after 5 years for patients with WBC≤10.0×109/L group was 81.4%, significantly higher than those with WBC〉10.0×109/L group (51.6%, P=0.026). 5 children with positive PML/RARα S (short) subtype died eventually although all of them achieved CR, which was significantly different from the group with the L (long) subtype (13/13, P=0.001). Conclusion Induction with ATRA + DNR or THP is an effective and safe therapy for newly diagnosed childhood APL with very high long-term survival rates after 2.5 years of alternative multi-drug chemotherapy and maintenance. High WBC count and S subtype of PML-RARα are the two poor prognostic factors for children with APL.

Description: Acute promyelocytic leukemia is a unique type of disease for which the all-trans retinoic acid is selected as the first line of induction treatment. Conventional AML regimen containing anthracycline + Ara-C with or without etoposide is dangerous to the patients with APL for its induction of disseminated intravascular coagulation (DIC) and intracranial hemorrhage while otherwise those complications would not happen if all-trans RA were used for induction. Furthermore, morphological diagnosis is usually not always informative at the time of early stage when cytogenetic and fusion gene results are usually not available at the first few weeks. Therefore, rapid and confirmative diagnosis of APL is crucial to the initial treatment of choice. Objectives The aims of this study were to investigate the new immunophenotypic marker(s) of APL and the quick diagnostic assays. Patients and Methods 83 cases of patients (45 males and 38 females, age range of 5 – 52 yrs with a median of 24 yrs) with APL were enrolled into this study. Leukemia cells were analyzed by multi-parameter flow cytometry with CD45/SSC gating strategy and 10% or more positive cells were considered positive. Samples from 21 patients with CML, 29 patients with MDS and 11 normal BMs were used as controls. Results Unsurprisingly, myeloperoxidase (MPO), CD13, CD33 were the most frequent expressing markers for APL cells accounting for 100%, 96% and 99% of the APL cases, respectively, while CD34 and HLA-DR were negative in almost all cases of this disease, with the positive rates of only 3.6% and 2.4%, respectively for these two antigens. The phenotype of high SSC, MPO+CD33+CD13+CD34−DR- strongly suggested the diagnosis. Interestingly, 12 APL cases (14.5%) showed positive for CD56, a neurogenic adhesion molecule, which could be used as leukemia associated phenotype for minimal residual disease (MRD) detection. The stem cell factor (SCF) receptor antigen CD117 was expressed in 78% of APL cases while it was not expressed on CML, MDS and normal bone marrows. Only 17% of APL cases expressed CD11b, while 100% of normal bone marrow neutrophils were positive for this antigen. A multi-color flow cytometry analysis revealed that a phenotype of CD117+CD11b− represented 72% of APL cases while no such phenotype existed in CML(29 cases, P 〈 0.01), MDS (21 cases, P 〈 0.01) and normal bone marrows (11 cases, P 〈 0.01) indicating the diagnostic effect of this particular phenotype. Immunophenotypic analysis of mononuclear cells from the APL patients consecutively detected at 1, 2, 3 and 4 months after RA induction showed that a phenotype switch from CD117+CD11b− to CD117−CD11b+ were clearly observed, indicating the gradual differentiation phenomenon during the induction treatment. Co-existence of CD117 expression and PML-RARα fusion gene presented in 14/16 (87.5%) of long(L)-type cases detected while the co-existence of these two markers presented only in 4/9 cases with short(S)-type fusion gene (P = 0.058), indicating the significant tendency of this two markers. Conclusions Immunophenotypic analysis with FCM is able to rapidly diagnose the APL patients. High SSC, MPO+CD33+CD13+CD117+CD11b−CD34−DR- can be considered as the useful phenotype suggesting APL, which may provide a quick diagnosis of APL.