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Joe Antony Jacob, Jumah Masoud Mohammad Salmani, Baoan Chen Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People’s Republic of China Abstract: Targeted therapy has modernized the treatment of both chronic and acute lymphoblastic leukemia. The introduction of monoclonal antibodies and combinational drugs has increased the survival rate of patients. Preclinical studies with various agents have resulted in positive outputs with Phase III trial drugs and monoclonal antibodies entering clinical trials. Most of the monoclonal antibodies target the CD20 and CD22 receptors. This has led to the approval of a few of these drugs by the US Food and Drug Administration. This review focuses on the drugs under preclinical and clinical study in the ongoing efforts for treatment of acute and chronic lymphoblastic leukemia. Keywords: targeted therapy, monoclonal antibodies, preclinical studies, receptors, lymphoblastic leukemia&nbsp

Xue Wu,1 Haijun Zhang,2 Jumah Masoud Mohammad Salmani,1 Rong Fu,3 Baoan Chen1 1Department of Hematology, 2Department of Oncology, The Affiliated Zhongda Hospital, School of Medicine, Southeast University, 3Department of Physiology, China Pharmaceutical University, Nanjing, People’s Republic of China Abstract: As the major bioactive compound of Scutellaria baicalensis that has been approved to be effective as an anti-inflammatory and antiviral inhibitor in cardiovascular diseases, wogonin (WG) showed potent and promising antitumor effects both in vitro and in vivo. It has been proved that WG has the ability to inhibit the growth of tumor cells, induce apoptosis, and suppress angiogenesis. The molecular mechanisms involve reactive oxygen species, Ca2+, NF-κB, tumor necrosis factor-related apoptosis-inducing ligand, and tumor necrosis factor-alpha. Furthermore, the synergistic effect of WG with 5-fluorouracil, etoposide, and adriamycin to enhance chemotherapy and reverse drug resistance has also been confirmed. In this review, we summarize the advances in recent years on the antitumor effect of WG on multiple tumors; in addition, we also present information regarding the synergistic and chemosensitizing effects of WG with other drugs to illustrate its potential use in the clinic. Keywords: antitumor effect, drug resistance, mechanisms, synergistic effect

Daunorubicin (DNR) has a broad spectrum of anticancer activity, but is limited in clinical application due to its serious side effects. The aim of this study was to explore a novel "smart" pH-responsive drug delivery system (DDS) based on titanium dioxide (TiO(2)) nanoparticles for its potential in enabling more intelligent controlled release and enhancing chemotherapeutic efficiency of DNR. DNR was loaded onto TiO(2) nanoparticles by forming complexes with transition metal titanium to construct DNR-TiO(2) nanocomposites as a DDS. DNR was released from the DDS much more rapidly at pH 5.0 and 6.0 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. DNR-TiO(2) nanocomposites induced remarkable improvement in anticancer activity, as demonstrated by flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and nuclear 4',6-diamidino- 2-phenylindole staining. Furthermore, the possible signaling pathway was explored by western blot. For instance, in human leukemia K562 cells, it was demonstrated that DNR-TiO(2) nanocomposites increase intracellular concentration of DNR and enhance its anticancer efficiency by inducing apoptosis in a caspase-dependent manner, indicating that DNR-TiO(2) nanocomposites could act as an efficient DDS importing DNR into target cancer cells. These findings suggest that "smart" DNR delivery strategy is a promising approach to cancer therapy.

Chengxin Luan,1,* Zixue Yang,2,* Baoan Chen1 1Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, 2State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, People’sRepublic of China *These authors contributed equally to this work Abstract: MicroRNAs (miRNAs), a new class of noncoding RNAs, which can hybridize to target messenger RNAs and regulate their expression posttranscriptionally, express differentially in distinct stages of lymphopoiesis and influence the direction of lymphoid precursor maturation. Hence, there is aberrant expression of miRNAs involved in malignant lymphopoiesis, and these aberrations can be used as signatures of acute lymphoblastic leukemia (ALL) with different subtypes. In addition, changes in the expression of several miRNAs may have functional relevance with leukemogenesis or drug resistance. As a result, the reversal of the expression of these miRNAs may alleviate the disease to some extent and improve clinical outcomes. However, among the studies of miRNAs, there are still some problems that need to be solved to understand the function of miRNAs in ALL more thoroughly. Keywords: ALL, microRNA, lymphopoiesis, molecular diagnosis, lymphoid malignant, molecular therapy

Liting Guo,1,* Haijun Zhang,1,* Weiwei Shao,2 Baoan Chen1 1Department of Hematology and Oncology (Key Department of Jiangsu Medicine), The Affiliated Zhongda Hospital, Medical School of Southeast University, Nanjing, 2Department of Pathology, the First People’s Hospital of Yancheng, Yancheng, Jiangsu, People’s Republic of China *These authors contributed equally tothis work Abstract: Crizotinib, the first clinically designed and synthesized as a tyrosine kinase inhibitor targeting mesenchymal–epithelial transition factor, indicating marked anticancer activity in patients with advanced, anaplastic lymphoma kinase-positive non-small-cell lung cancer, was approved by the US Food and Drug Administration in 2011. In this review, we focus on the efficacy of crizotinib compared with chemotherapy in advanced anaplastic lymphoma kinase-positive lung cancer and present the role of crizotinib as a personalized alternative in previously treated patients with non-small-cell lung cancer. Keywords: crizotinib, anaplastic lymphoma kinase rearrangement, non-small-cell lung cancer&nbsp

Runzhe Chen, Baoan Chen Department of Hematology and Oncology, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic ofChina Abstract: Siltuximab (CNTO 328) is a promising antibody-drug conjugate targeting cytokine interleukin-6 (IL-6). It is highly binding to IL-6 and thus neutralizing IL-6 bioactivity and promoting death of tumor cell. In this review, we mainly focus on the mechanisms, clinical studies, and adverse effect of siltuximab in the treatment of human malignancies. We also provide our recommendations for siltuximab treatment in the future. Keywords: interleukin-6, Castleman’s disease, clinical trials

Chengxin Luan, Runzhe Chen, Baoan Chen, Jiahua Ding, Ming Ni Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of China Abstract: Delayed hematopoietic recovery and increased rate of engraftment failure limit the use of umbilical cord blood transplantation (UCBT). We describe a case of severe aplastic anemia treated by UCBT combined with mesenchymal stem cells. Our case reveals that infusing mesenchymal stem cells early (about 40days) after UCBT may promote hematopoietic recovery. This experience will guide clinical scientists, especially hematologists, to deal with similar situations and encourage them to widen this strategy. Keywords: cord blood transplantation, mesenchymal stem cell, aplastic anemia

Runzhe Chen, Fei Wang, Xiaoping Zhang, Chong Gao, Baoan Chen Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic ofChina Abstract: Dasatinib, a second-generation tyrosine kinase inhibitor, is used for treating patients with Philadelphia chromosome (Ph) positive leukemia, especially for those who are resistant or intolerant to imatinib. The common adverse effects associated to its use include myelosuppression, nausea, diarrhea, and peripheral edema. This study reports a very rare case of a 60-year-old male who suffered from severe thrombocytopenia after dasatinib administration. The platelet count did not increase even after dasatinib had been discontinued for more than 6months. Various means had been tried, but the count of platelet did not increase, and the result was not optimistic. This is the first report of so severe thrombocytopenia after dasatinib treatment, and the pathophysiology underlying this reaction remains unknown. We hope that this case will help remind clinicians to pay more attention to the side effect of thrombocytopenia caused by dasatinib in the future. Keywords: platelet, monoclonal antibody, hematological malignancies

Runzhe Chen, Baoan Chen Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of China Abstract: Brentuximab vedotin is a promising antibody–drug conjugate (ADC) targeting CD30 of tumor cells. It selectively delivers monomethyl auristatin E (MMAE) into CD30-expressing cells and induces tumor cell apoptosis. Various clinical trials have provided evidence that it is effective in relapsed or refractory Hodgkin’s lymphoma (HL), and it has also shown its advantages in other CD30-positive lymphomas. In this review, we focus on the structure, mechanisms, and pharmacokinetics of brentuximab vedotin. We also summarize clinical trials with brentuximab vedotin and make recommendations for brentuximab vedotin in the treatment of relapsed or refractory HL. Keywords: lymphoma, CD30-positive, clinical trials, tumor cells, antitumor effects, monoclonal antibody

Runzhe Chen, Baoan Chen Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic ofChina Abstract: Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) for chronic, blastic, or accelerated phase chronic myeloid leukemia (CML) patients who are resistant or intolerant to previous treatment. It potently inhibits BCR/ABL and SRC-family kinases (SRC, LCK, HCK, YES, FYN, FGR, BLK, LYN, FRK), as well as c-KIT, PDGFR-a and -b, and ephrin receptor kinase. Various clinical trials have provided evidence that it has more durable complete hematologic and cytogenetic responses, as well as more potency in imatinib-resistant or-intolerant CML, and it has also shown its advantages in newly diagnosed CML compared to imatinib. In this review, we mainly focus on the structure, mechanisms, pharmacokinetics, and pharmacogenetics of dasatinib. We also summarize clinical trials with dasatinib on CML and provide our recommendations for dasatinib in the treatment of CML. Keywords: imatinib, tyrosine kinase inhibitor, clinical trials&nbsp

Runzhe Chen, Zhengping Yu, Hongming Zhang, Jiahua Ding, Baoan Chen Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic ofChina Abstract: Primary malignant lymphoma of the uterus and broad ligament is rare. Here, we present a rare case of primary diffuse large B-cell lymphoma (DLBCL) of uterus and broad ligament in a 63-year-old female. The patient presenting with lower abdominal distention was referred to our hospital. Subsequent abdominal and pelvic ultrasound revealed the presence of a large mass, which was highly suspected as subserosal uterine leiomyoma. A large tumor was found with unclear boundary with right posterior wall, broad ligament and bilateral adnexa during surgery. Her uterus and the tumor of a broad ligament and bilateral adnexa were all excised as a result. Postoperative pathological examination showed DLBCL in uterus and broad ligament. Further examinations excluded metastatic diseases, which supported the diagnosis of primary DLBCL of the uterus and broad ligament. The patient received six cycles of R-CHOP (21days) regimen. During the 8months follow-up, no evidence of disease recurrence was identified. As the prevalence of primary extranodal lymphoma is increasing, the details of this rare case may highlight the importance and facilitate treatment of similar diseases. A summary focusing on the presentation and prognosis as well as a review of current management is also discussed. Keywords: diffuse large B-cell lymphoma, primary uterine and broad ligament lymphoma, extranodal lymphoma, diagnosis, therapy

Run-Zhe Chen,* Gang Zhao,* Nan Jin, Bao-An Chen, Jia-Hua Ding Department of Hematology and Oncology, Key Department of Jiangsu Medicine, Zhongda Hospital, Medical School, Southeast University, Nanjing, Jiangsu Province, People’s Republic of China *These authors contributed equally to this work Abstract: Superselective arterial embolization is a common therapeutic procedure for cases of visceral hemorrhage. However, until now, it has not been applied in the treatment of gastrointestinal (GI) hemorrhage caused by acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. We describe a case presenting with persistent GI bleeding associated with acute GVHD successfully treated by superselective arterial embolization of the superior mesenteric artery with gelatin sponge after noneffective conventional management. This case will help guide hematologists to deal with a similar situation in the future. Keywords: gastrointestinal bleeding, acute graft-versus-host disease, allo-hematopoietic stem cell transplantation, arterial embolization