Jian Huang

Clinical characteristics of T-cell lymphoma associated with hemophagocytic syndrome: Comparison of T-cell lymphoma with and without hemophagocytic syndrome

T-cell lymphoma-associated hemophagocytic syndrome (T-LAHS) has been frequently reported in Asian countries and is considered with extremely poor prognosis. To summarize its clinical characteristics and explore its early diagnosis and treatment, we retrospectively analyzed the records of 113 patients with aggressive T cell lymphoma, of which 28 were associated with LAHS. According to WHO classification (2001), 22 cases were classified into peripheral T-cell lymphoma (unspecified), 2 into extranodal NK/T-cell lymphoma, and 4 into systemic anaplastic large cell lymphoma. The median survivals of the LAHS and no-LAHS groups were 40 days and 8 months, respectively. The elevating rates of serum lactate dehydrogenase (LDH) (100% vs. 55%), ferritin (100% vs. 64%), fasting triglycerides (79% vs. 43%), and hypofibrinogen (43% vs. 14%)levels were higher in the LAHS group than in the no-LAHS group (P < 0.05), so were bone marrow involvement (57% vs. 32%, P < 0.05)and liver dysfunction (40% vs. 13%, P < 0.05). Eleven of the 28 LAHS patients did not receive any chemotherapy, and 14 received CHOP regimen as initial chemotherapy. Three patients in critical conditions were given plasma exchange and gained the chance of initial chemotherapy. We suggest that in patients presenting with fever, hepatosplenomegaly, cytopenia, and constantly increasing levels of serum LDH, CA125, ferritin, transglutaminase, and β2-microglobulin, T-LAHS should be taken into account. Repeating biopsies of multiple parts of bone marrow may help diagnosis. The therapeutic result of chemotherapy alone or combined for T-LAHS was discouraging and the survival time of most cases was no more than 1 year. Plasmapheresis as initial therapy is worth considering in critical cases.

High efficacy of arsenic trioxide plus all-trans retinoic acid based induction and maintenance therapy in newly diagnosed acute promyelocytic leukemia.

We conducted a retrospective study to evaluate the efficacy of combining arsenic trioxide (ATO) with all-trans-retinoic acid (ATRA) based induction therapy, followed by 3 courses of consolidation chemotherapy and 2-year sequential ATO/ATRA maintenance therapy in acute promyelocytic leukemia (APL). 137 patients were enrolled in the study. The complete remission (CR) rate was 93.4%. All the 9 (6.6%) induction failures were due to early death. With a median follow-up of 35 months, 5 relapses (4%) in CR patients were recorded, including 3 isolated CNS relapses. By using the Kaplan-Meier analysis, the 5-year overall survival and relapse-free survival of the low/intermediate risk group and high-risk group was 98.9% versus 97.4% and 98.7% versus 87.9%, respectively. The results indicated that ATO based first-line protocol is highly effective for treatment of newly diagnosed APL.

Long-term efficacy of low-dose all-trans retinoic acid plus minimal chemotherapy induction followed by the addition of intravenous arsenic trioxide post-remission therapy in newly diagnosed acute promyelocytic leukaemia.

We evaluated the efficacy of low‐dose all‐trans retinoic acid (ATRA) plus minimal chemotherapy for induction in newly diagnosed acute promyelocytic leukaemia (APL). Furthermore, we compared its long‐term outcome with or without the addition of intravenous arsenic trioxide (ATO) in post‐remission therapy. From January 2004 to September 2011, a total of 109 patients with a median age of 41u2009years (range 14–73) were enrolled in the study. Two arms were assigned according to post‐remission protocols: ATO group cases were subsequently treated with intravenous ATO, standard chemotherapy, and ATRA. No‐ATO group cases were subsequently treated with chemotherapy and ATRA only. Patients were monitored of minimal residual disease (MRD) by reverse‐transcriptase polymerase chain reaction. The haematologic complete remission (CR) rate was 96.3%. The early death rate was 0.9%. At a median follow‐up of 49u2009months (range 8–102u2009months), the Kaplan–Meier estimates of 5‐year relapse‐free survival were significantly better for patients in the ATO group than in the no‐ATO group, 94.4% vs 54.8% (pu2009=u20090.0001), and the 5‐year overall survival rate was 95.7% vs 64.1%, in the two groups (pu2009=u20090.003). Our data show that low‐dose ATRA plus minimal chemotherapy exhibits efficacy in induction therapy for untreated APL and suggest that the addition of ATO to post‐remission therapy significantly improves the long‐term outcome. Copyright

Outcomes and prognostic factors of first relapsed acute promyelocytic leukemia patients undergoing salvage therapy with intravenous arsenic trioxide and chemotherapy

Arsenic trioxide (ATO) is an effective therapy for relapsed acute promyelocytic leukemia (APL) patients; however, the optimal treatment strategy remains unclear, and knowledge of the prognostic factors is still limited. We retrospectively analyzed the outcomes of 64 consecutive first relapsed APL patients (12 with molecular relapse and 52 with hematologic relapse). Patients received re-induction with intravenous ATO-based regimens. Patients who achieved a CR2 were offered further courses of alternating ATO/conventional chemotherapy with or without stem cell transplantation (SCT). With a median follow-up of 27 months (range, 6–57) in the molecular relapsed subgroup, the 3-year relapse-free survival (RFS) and overall survival (OS) rates were 81.5xa0% and 100xa0%, respectively. With a median follow-up of 38 months (range, 0–129) in the hematologic relapse group, the 3-year RFS and OS rates were 57.1xa0% and 72.1xa0%, respectively. Furthermore, in the hematologic relapse group, we compared the outcome between relapsed patients after previous ATO therapy (nu2009=u200920) with those who did not receive prior ATO therapy (nu2009=u200932). The CR2 rate was 80xa0% (16/20) vs. 93.8xa0% (30/32), (pu2009=u20090.189). However, the relapse rate was 68.8xa0% (11/16) vs. 33.3xa0% (10/30), (pu2009=u20090.03). The 4-year OS rate was 62.4xa0% vs. 71.2xa0%, (pu2009=u20090.816), and the 4-year RFS rate was 29.8xa0% vs. 66.2xa0% (pu2009=u20090.023). The results indicate that, irrespective of frontline therapy with ATO, salvage therapy with an ATO-based regimen remains effective. However, the long-term survival for those patients who received previous ATO-based treatment was inferior compared to those who did not receive prior ATO. In addition, the alternating ATO/chemotherapy strategy can be a post-remission treatment option in a subset of patients.

Human urine extract CDA‐2 induces apoptosis of myelodysplastic syndrome‐derived MUTZ‐1 cells through the PI3K/Akt signaling pathway in a caspase‐3‐dependent manner

AbstractAim:The aim of this study was to investigate the antitumoral activity of human urine extract against myelodysplastic syndrome (MDS)-derived MUTZ-1 cells in vitro and in vivo.Methods:The MDS–refractory anemia with excess of blasts (RAEB)-derived MUTZ-1 cell line was used to examine the effects of a human urine preparation, CDA-2, on the induction of growth arrest and apoptosis. Apoptotic proteins, including caspase family, Bcl-2 family, the inhibitor of apoptosis protein (IAP) family, and the FLICE-like inhibitory protein (FLIP), as well as cell cycle-associated proteins were studied. The phosphoinositide 3 kinase (PI3K)/Akt survival signaling pathway and the NF-κB pathway were also examined. The caspase-3 inhibitor Z-DEVD-fmk was used to examine the involvement of caspase-3 and poly (ADP-ribose) polymerase (PARP). PI3K inhibitor LY294002 was used to examine the involvement of the PI3K/Akt signaling pathway in this apoptosis-inducing effect. MUTZ-1 cell xenografted serious combined immunodeficiency disease mice were used for the in vivo study.Results:We found that CDA-2 could induce growth arrest and apoptosis of MUTZ-1 cells in vitro and in vivo. The main mechanisms were related to the inhibition of PI3Kp110α expression at the transcriptional level, which inactivated the phosphorylation of Akt involving the prevention NF-κB phosphorylation and nuclear translocation, the downregulation of the IAP family and FLIPL protein, and the dephosphorylation of the Bad protein, which then triggered the activation of the caspase cascades. This phenomenon could be inhibited by the PI3K inhibitor LY294002 and caspase-3 inhibitor Z-DEVD-fmk.Conclusion:Our results demonstrate the presence of active components in the human urine extract that can induce the growth arrest and apoptosis of MDS–RAEB-derived MUTZ-1 cells and may involve the PI3K/Akt signaling pathway in a caspase-3-dependent manner. This may provide new insights for the treatment of high-risk MDS.

Characteristics and prognosis analysis of additional chromosome abnormalities in newly diagnosed acute promyelocytic leukemia treated with arsenic trioxide as the front-line therapy

Currently, there are few studies that address the prognostic significance of baseline additional chromosomal abnormalities (ACAs) in newly diagnosed acute promyelocytic leukemia (APL) patients treated with arsenic trioxide (ATO) as the front-line therapy. A series of 271 consecutive APL patients has been cytogenetically investigated between 2004 and 2011 in our institution. The incidence of ACAs was 27% (46/172) in APL cases with t(15;17). Trisomy 8 was the most recurrent abnormality, accounting for 30% (14/46) of patients with ACAs, followed by +21 (7%, 3/46) and -7/7q (7%, 3/46). Nine cases (14.1%) were found to have additional balanced translocation aberrations, most of them are new and non-recurrent. Treatment protocols consisted of all-trans retinoic acid (ATRA) and chemotherapy with or without the ATO therapy. Overall, patients with and without ACAs had similar complete remission (CR) rates (94% and 98%, respectively, P=0.344). With a median follow-up of 41 months, univariate analysis showed that ACAs did not show any prognostic significance in relapse-free survival (RFS) and overall survival (OS). In addition, ATO treatment was an independent favorable predictor for RFS. Thus, this data provides insights into cytogenetic features of APL, and suggests that ATO-based combination therapy improved RFS in de novo APL patients, while ACAs had no impact on prognosis.

Interleukin-6-independent expression of glucocorticoid receptor is upregulated by triptolide in multiple myeloma

Glucocorticoids are widely used chemotherapeutic agents for multiple myeloma. Drug resistance to steroid therapies is associated with the downregulation or loss of glucocorticoid receptor expression in malignant plasma cells. In this study, we examined the constitutive expression of glucocorticoid receptor in dexamethasone-sensitive and dexamethasone-resistant multiple myeloma cell lines. We found that triptolide increased the amount of the phosphorylated glucocorticoid receptor and enhanced the growth inhibitory effect of dexamethasone. Notably, these effects could not be blocked by interleukin-6, one of the most important growth factors in multiple myeloma.

Antitumor activity and drug interactions of proteasome inhibitor Bortezomib in human high-risk myelodysplastic syndrome cells.

The purpose of this study was to investigate the antitumor effects and drug interactions of the proteasome inhibitor Bortezomib against high-risk myelodysplastic syndrome (MDS) cells in vitro and in vivo. The high-risk MDS-derived MUTZ-1 cell line and bone marrow mononuclear cells from primary high-risk MDS patients were used to examine antitumor activity and drug interactions for Bortezomib. Apoptotic proteins, including caspase and Bcl-2 family members, as well as the protein FLIP, were studied. Phosphoinositide 3-kinase (PI3K)/Akt and MAPK signaling pathways were also examined. The PI3K inhibitor LY294002 was used to examine the involvement of the PI3K/Akt signaling pathway in the induction of apoptosis. Cytarabine (AraC) and daunorubicin (DNR) were used to test for synergistic effects between Bortezomib and chemotherapeutic agents. SCID mice xenografted with MUTZ-1 cells were used for in vivo study. We found that Bortezomib could induce growth arrest and apoptosis in high-risk MDS cells in vitro and in vivo. The mechanisms were related to decreased activation of the PI3K/Akt survival signaling pathway, but not the MAPK pathway, and involved inhibition of the NF-κB activity and downregulation of the Bcl-2/Bax and FLIPL/FLIPS ratios, triggering the activation of caspase cascades. This phenomenon was inhibited by the PI3K inhibitor LY294002. Bortezomib also acted synergistically with the chemotherapeutic agents AraC and DNR, which are associated with the inhibition of NF-κB activity. Our results demonstrate that Bortezomib can induce growth arrest and apoptosis of high-risk MDS cells and had a synergistic effect with two chemotherapeutic agents. Our findings provide new insights for the treatment of high-risk MDS, using either Bortezomib alone, or in combination with conventional antineoplastic agents.

CDA-II, a urinary preparation, induces growth arrest and apoptosis of human leukemia cells through inactivation of nuclear factor-kappaB in a caspase-dependent manner

CDA-II (cell differentiation agent II) was a urinary preparation, isolated from healthy human urine. We determined the anticancer activity of CDA-II using human acute myeloid leukemia (AML) cell lines, K562, Kasumi-1 and KG-1. An in vitro cytotoxicity assay showed that CDA-II exhibited growth arrest in leukemic cells, while it did not induce cytotoxicity in normal peripheral blood mononuclear cells (PBMCs). In vivo studies using the Kasumi-1 xenografted SCID mouse model showed tumor inhibition rate were increased and the survival time were prolonged in a dose-dependent manner, without any significant toxicity on mice body. Depolarized mitochondrial membranes and the activation of caspase-3, 9 as well as PARP were found in leukemic cells treated with CDA-II for 6-24h. We further found NF-kappaB nuclear translocation were prevented by CDA-II treatment, which therefore inactivated NF-kappaB and down-regulated its target genes expression, including Bcl-2/Bax ratio, Mcl-1 and XIAP. The caspase-3 inhibitor Z-DEVD-FMK inhibited CDA-II-induced apoptosis and CDA-II combined with NF-kappaB inhibitor PDTC significantly increased the apoptotic rate of leukemic cells. We concluded that CDA-II potently induced caspase-dependent leukemia-specific apoptosis in leukemic cells mediated through inactivation of NF-kappaB, involving in Bcl-2 family and XIAP, which has no cytotoxicity on normal cells.

Hyaline vascular Castleman disease associated with POEMS syndrome and cerebral infarction

Dear Editor, In 2006, a 42-year-old Chinese woman was admitted to the Endocrine Department of our hospital because of diarrhea for 5 months and chilly for 1 month. She was diagnosed of hyperthyroidism 2 months before admission and was treated with antithyroid drugs. Her prior medical history was unremarkable, with no history of diabetes, smoking, alcohol, or HIV. On admission she was suffering from diarrhea, was experiencing progressive fatigue and chill, night sweats, weight loss, and edema. Positive physical examination revealed multiple small peripheral lymph nodes, hepatomegaly, splenomegaly, hyperpigmentation, paraesthesia in four limbs and pitting edema of the lower extremities. Laboratory tests on admission showed HbsAg (+), HbcAb (+), HbeAb (+) and HIVAb (−). The fibrinogen level was 0.35 g/dl (normal 0.2–0.4 g/dl). Blood biochemistry indicated hypoalbuminemia and hyperglobulinemia. Immunoelectrophoresis showed a polyclonal increase in serum immunoglobulin (IgG 22.7 g/l, IgA 48.3 g/l, IgM 0.66 g/l) with a monoclonal IgA kappa. Ultrasonic examination indicated pericardial effusion. Needle electromyogram test was performed. Slow conduction velocity on sensory nerve and motor nerve was confirmed. Blood routine was normal. Cervical lymph node biopsy diagnosed of Castleman disease (hyaline vascular type) (Fig. 1). Then she was admitted to the Hematology Department because of Castleman disease associated with POEMS syndrome. One day after admission, the patient suffered from mental anomaly, gradually occurred left hemiplegia, and coma. Findings of physical examination revealed fever, hyperpigmentation, ascites, dysarthria, tetraparesis, and areflexia of both legs. The fibrinogen level was 0.412 g/dl. Neither polycythemia nor thrombocythemia was detected. The MRI and DWI scans showed a large area of acute cerebral infarction including right frontal lobe and parietal lobe, left frontal lobe, extending to the cortex and subcortex (Fig. 2). After treatment with dexamethasone 10 mg/day, cerebrospinal fluid pressure lowered; after supportive treatment for 7 days, the consciousness of the patient improved. She became drowsy and could respond to our call. Physical examination showed no fever or ascites, no edema or lymphadenectasis; she could raise her right limbs by herself. The fibrinogen level dropped to normal (0.29 g/dl). Ultrasonic examination indicated no pericardial effusion or splenohepatomegalia. Castleman disease is a rare pathologic process of unknown etiology, characterized by reactive proliferation of lymphoid tissue [1]. The clinical features of Castleman disease are classified into two categories, localized and multicentric. The localized form usually presents in young adults with localized masses in the mediastinum, neck, or, less commonly, intra-abdominal masses. Systemic symptoms are rare with localized Castleman disease (LCD). In contrast, multicentric Castleman disease (MCD) presents with polylymphadenopathy and frequently multi-organ involvement and is associated with systemic features. MCD is less common than LCD and follows a more aggressive natural history. The histology of Castleman disease is similarly divided into two subgroups: the hyaline vascular type and the plasma cell type. The former is found in 90% of LCD, but rarely in MCD and associated with systemic clinical manifestations. The latter is found in only Ann Hematol (2007) 86:59–61 DOI 10.1007/s00277-006-0188-z