Jiejing Qian

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.

FLT3 and NPM1 mutations in Chinese patients with acute myeloid leukemia and normal cytogenetics

Mutations of fms-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) exon 12 genes are the most common abnormalities in adult acute myeloid leukemia (AML) with normal cytogenetics. To assess the prognostic impact of the two gene mutations in Chinese AML patients, we used multiplex polymerase chain reaction (PCR) and capillary electrophoresis to screen 76 AML patients with normal cytogenetics for mutations in FLT3 internal tandem duplication (FLT3/ITD) and exon 12 of the NPM1 gene. FLT3/ITD mutation was detected in 15 (19.7%) of 76 subjects, and NPM1 mutation in 20 (26.3%) subjects. Seven (9.2%) cases were positive for both FLT3/ITD and NPM1 mutations. Significantly more FLT3/ITD aberration was detected in subjects with French-American-British (FAB) M1 (42.8%). NPM1 mutation was frequently detected in subjects with M5 (47.1%) and infrequently in subjects with M2 (11.1%). FLT3 and NPM1 mutations were significantly associated with a higher white blood cell count in peripheral blood and a lower CD34 antigen expression, but not age, sex, or platelet count. Statistical analysis revealed that the FLT3/ITDpositive group had a lower complete remission (CR) rate (53.3% vs. 83.6%). Survival analysis showed that the FLT3/ITD-positive/NPM1 mutation-negative group had worse overall survival (OS) and relapse-free survival (RFS). The FLT3/ITD-positive/NPM1 mutation-positive group showed a trend towards favorable survival compared with the FLT3/ITD-positive/NPM1 mutation-negative group (P=0.069). Our results indicate that the FLT3/ITD mutation might be a prognostic factor for an unfavorable outcome in Chinese AML subjects with normal cytogenetics, while NPM1 mutation may be a favorable prognostic factor for OS and RFS in the presence of FLT3/ITD.

Homoharringtonine and SAHA synergistically enhance apoptosis in human acute myeloid leukemia cells through upregulation of TRAIL and death receptors

Single‑agent histone deacetylase (HDAC) inhibitors have exhibited marked antileukemic activity in preclinical and clinical studies and have undergone trials in combination with standard chemotherapeutics. However, the mechanisms of action of combination therapies are not completely understood. In the present study, a novel strategy for treatment of acute myeloid leukemia (AML) was identified, in which the chemotherapeutic agent, homoharringtonine (HHT), was combined with suberoylanilide hydroxamic acid (SAHA), a pan‑HDAC inhibitor. A synergistic effect was observed when HHT was added to SAHA to induce apoptosis in Kasumi‑1 and THP‑1 leukemia cells. This combination was found to significantly enhance the activation of caspase‑8 and ‑9 compared with treatment with each drug separately. Notably, while SAHA induced upregulation of death receptor 4 (DR4) and DR5, HHT upregulated tumor necrosis factor‑related apoptosis-inducing ligand (TRAIL) expression in a dose‑dependent manner. In addition, the synergistic effect between HHT and SAHA was blocked partially using a specific anti‑TRAIL antibody. The combination therapy was also found to significantly inhibit the growth of leukemia xenografts in vivo with enhanced apoptosis. These results indicate that, by regulating the induction of TRAIL and activation of the TRAIL apoptotic pathway, it is possible to administer HHT at low concentrations in combination with SAHA as an effective therapeutic approach for the treatment of AML.

β-Catenin and AKT are promising targets for combination therapy in acute myeloid leukemia

In this study, we confirmed that combining HHT with ACR can result in synergistic cytotoxicity to AML cells in vitro and in vivo. Combining HHT and ACR simultaneously inhibited PI3K/AKT and WNT/β-catenin signaling in AML cells. Significant increases in growth inhibition and apoptosis were induced by an AKT inhibitor when the WNT3A gene of THP-1 cells was silenced. HHT+ACR could synergistically induce the apoptosis of CD34(+)/CD38(-) primary AML cells. These results highlight β-catenin and AKT are promising targets for combination therapy for AML.

Analysis of clinical characteristics and prognostic factors of multiple myeloma: a retrospective single-center study of 787 cases

ABSTRACT Objective: This study aims to explore the clinical features of multiple myeloma (MM) and the influence of various prognostic factors on survival. Methods: A retrospective analysis, consisting of clinical characteristics analysis and laboratory examinations, was performed on 787 MM patients. Clinical and laboratory parameters were analyzed by multivariate process and compared across different groups. Results: Of the 787 patients enrolled (median age, 61 years old, range 29–89 years old), 491 (62.4%) were male. Two most common complaints were bone pain (51.2%) and fatigue (48.0%). Anemia (hemoglobin (Hb) ≤100 g/L in female, Hb ≤110 g/L in male) was present initially in 69.4% patients. IgG was the most common type (46.6%). 52.2% of the patients were diagnosed on stage IIIA according to Durie–Salmon (D–S) system, 44.6% are on stage III according to International Staging System (ISS). Multivariate analysis suggested that age, serum calcium, LDH, percentage of abnormal plasma cells in bone marrow were all independent prognostic factors for OS. Conclusion: The MM patients in China are relatively younger, have higher rate on stage III according to D–S system. Older age, high serum calcium, high LDH, high percentage of abnormal plasma cells in bone marrow were highly related to poor prognosis.

Mantle cell lymphoma in a mother and her daughter.

Mantle cell lymphoma (MCL) was reported to be another potential familial lymphoproliferative disease for the first time in 2004 [1]. Since then, no similar cases have been reported. Here we describe a familial MCL first occurring in the pattern of mother and daughter. A 45-year-old female presented with colonic polyposis and was initially diagnosed with inflammatory bowel disease. After 2 months of mesalazine therapy, the related symptoms were not reduced. Subsequently, a right elbow lymph node biopsy showed lymphadenosis positive for MUM-1, Bcl-2, CD79a, p53, Bcl-6, and cyclin D1, and negative for CD3, CD5, CD10, and CD30. Further abdominal computed tomography (CT) evaluation revealed the walls of the stomach, duodenum, distal ileum, and rectum to be significantly thickened. She was diagnosed as having MCL (stage IV), and achieved a partial response after two cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Two years ago, her 66-year-old mother presented with a bulky retroperitoneal mass with a size of 13.26 12.66 9.9 cm. Biopsy showed diffuse infiltration of lymphoid cells with positive CD20, CD79a, CD5, Bcl-2, and cyclin D1, and negative CD3, UCHL-1, CD23, and CD10. Further evaluation revealed bone marrow involvement. She was diagnosed with MCL (stage IV), and achieved stable disease after one cycle of CHOP combined with radiotherapy. After that, she discontinued further therapy for some reason. The pedigree of this family is shown in Figure 1, and no other family members had ever presented with lymphoproliferative neoplasia. Studies have shown that familial risk contributes to the etiology of lymphomas. Recently, a large epidemiological survey in Sweden evaluated the risk of lymphoma subtypes among first-degree relatives of patients with follicular lymphoma, patients with diffuse large-B cell lymphoma, and patients with Hodgkin lymphoma, and the results implied that relatives were at the highest risk of developing the same lymphoma subtype [2]. However, studies of familial aggregation in patients with MCL are rare, which may result from its low incidence. There was no report of familial MCL until Tort et al. reported MCL occurring in the pattern of father and daughter in 2004 [1]. Unfortunately, the father had not been definitively diagnosed with MCL because paraffin blocks were no longer available for cyclin D1 staining or fluorescence in situ hybridization (FISH). In our study, we describe for the first time a familial MCL occurring in the pattern of mother and daughter, with definitive diagnosis. In this case, the mother had a typical MCL diagnosed at the age of 66, whereas the daughter was diagnosed with the same disease at age 45 years, an early age for MCL, the median age of which at diagnosis is usually over 60 years [3]. This phenomenon of earlier onset in successive generations is known as anticipation, and has been described in other familial hematologic neoplasms [4–7]. Early presentation of MCL should raise the question of a familial disposition in either one of the parents. Many familial clusters of neoplasms have been described. However, the molecular and genetic bases of these familial aggregations remain elusive. Previous studies have demonstrated reciprocal familial risks between chronic lymphocytic leukemia (CLL)