Surgical management of monomorphic epitheliotropic intestinal Tcell lymphoma followed by chemotherapy and stem-cell transplant:A case report and review of the literature

BACKGROUND Monomorphic epitheliotropic intestinal T-cell lymphoma(MEITL)is a rare and rapidly progressive intestinal T-cell non-Hodgkin lymphoma associated with a very poor prognosis and a median survival of 7 mo.Advances in the identification of MEITL over the last two decades have led to its recognition as a separate entity.MEITL patients,predominantly male,typically present with vague and nonspecific symptoms and diagnosis is predominantly confirmed at laparotomy.Currently,there are no standardized treatment protocols,and the optimal therapy remains unclear.CASE SUMMARY We report a case of MEITL that was initially considered to be gastrointestinal stromal tumor(GIST)and Imatinib was administered for one cycle.The 62-yearold man presented with abdominal pain,abdominal distension,and weight loss of 20 pounds.Within 2 wk,the size of the mass considerably increased on computed tomography scans.The patient underwent surgery followed by chemotherapy with CHOP(cyclophosphamide,doxorubicin,vincristine,and prednisone)and stem-cell transplant.A correct diagnosis of MEITL was established based on postoperative pathology.Immunophenotypically,the neoplastic cells fulfilled the diagnostic criteria for MEITL as they were CD3+,CD4+,CD8+,CD56+,and TIA-1+.CONCLUSION Given that MEITL has no predisposing factor and presents with vague symptoms with rapid progression,the concomitant presence of abdominal symptoms and B symptoms(weight loss,fever,and night sweats)with hypoalbuminemia,anemia,low lymphocytic count and endoscopic findings of diffuse infiltrating type lesions should alert physicians to this rare disease,especially when it comes to Asian patients.Immediate laparotomy should then be carried out followed by chemotherapy and stem-cell transplant.

Haploidentical hematopoietic stem-cell transplantation for acute myeloid leukemia in first relapse after complete remission by standard induction chemotherapy

Objective To investigate the therapeutic effects of haploidentical hematopoietic stem - cell transplantation ( Haplo - PBSCT) for acute myeloid leukemia in first relapse after complete remission by standard induction chemotherapy. Methods Eighty - nine cases of AML in first relapse after complete remission by standard DA

Is there a place for cellular therapy in depression?

Although efforts have been made to improve the pharmacological treatment of depression,approximately one-third of patients with depression do not respond to conventional therapy using antidepressants.Other potential non-pharmacological therapies have been studied in the last years,including the use of mesenchymal stem cell therapies to treat depression.These therapies are reviewed here since it is clinically relevant to develop innovative therapeutics to treat psychiatric patients.Experimental data corroborate that mesenchymal stem cell therapy could be considered a potential treatment for depression based on its antiinflammatory and neurotrophic properties.However,some clinical trials involving treatment of depression with stem cells are in progress,but with no published results.These studies and other future clinical investigations will be crucial to define how much mesenchymal stem cells can effectively be used in psychiatric clinics as a strategy for supporting depression treatment.

Fulminant gastrointestinal graft-versus-host disease concomitant with cytomegalovirus infection:Case report and literature review

Here,we report a case of fulminant gastrointestinal graft-versus-host disease(GI-GVHD) with cytomegalovirus(CMV) infection in 44-year-old woman.Despite the difficulties associated with the treatment of GIGVHD and GI-CMV disease,the mucosal findings and the clinical course showed marked improvements during long-term clinical observation.The endoscopic findings were remarkable,with diffuse sloughing mucosa in the stomach and highly active inflammation and deep discrete ulcers throughout the colon.Changes in the CMV quantitative polymerase chain reaction results were correlated with the endoscopic mucosal findings and were useful for assessing the efficacy of the treatment.Although a definite diagnosis of GI-GVHD is generally made by endoscopy with biopsy,the gross appearance of this disease can vary depending on the endoscopy.In this paper,we also conduct a literature review of patients with GI-GVHD.

Hemophagocytic lymphohistiocytosis: Recent progress in the pathogenesis, diagnosis and treatment

Hemophagocytic lymphohistiocytosis(HLH) is a hyperinflammatory syndrome that develops as a primary(familial/hereditary) or secondary(non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell(CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH(familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of(signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome(XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis(e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease(especially EBVHLH).

AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR LYMPHOMA: AN EVALUATION OF GRAFTS SOURCE AND MINIMAL RESIDUAL DISEASE

Objective： To determine whether the source of autologous hematopoietic stem cells altered the clinical outcomes of patients undergoing high dose chemotherapy and autologous hematopoietic stem cell transplantation （AHSCT） for aggressive lymphoma and to study the problem of minimal residual disease （MRD）. Methods： 14 lymphoma patients who had lymphoma with high risk factors, relapsed lymphoma or refractory lymphoma received autologous bone marrow transplantation （ABMT）. 14 lymphoma patients who were similar to ABMT group received autologous peripheral blood stem cells transplantation （APBSCT）. Regimen of CBV （cyclophos phamide 50-60 mg/kg/d×2 d, carmustine 15 mg/kg/d×1 d, etoposide 45-60 mg/kg/d×1 d） was received by all the patients as conditioning regimen in the transplant pretreatment followed by ABMT or APBSCT. Autologous peripheral blood stem cell （APBSC） was mobilized by CTX 2g-3g/m^2/d×2 d iv and G-CSF 5 μg/kg/d for five to seven days. MRD was continually supervised by PCR in bone marrow before and after transplantation. Cellular immunocyte function, such as natural killer cell （NK）, CD3, CD4, CD8 and slL-2R was tested before and twenty days after transplantation. Results： In ABMT group, the median time for hematopoietic recovery of absolute neutrophilia counts ≥0.5×10^9/L and platelet counts ≥20×10^9/L. was ＋18 days and ＋20 days respectively. In contrast, the APBSCT group was both at 12 days. Patients who have undergone ABMT all got complete remission （CR）, while 81.8% patients in APBSCT group got CR. The 3-year disease free survival （DFS） in APBSCT and ABMT group was 75% and 72.7% respectively （P〉0.05）. The mean days of immunity recovering in APBSCT was ＋20 days. After transplantation, MRD in 11 patients were positive, in whom 6 patients died. Conclusion： Aggressive lymphoma patients＇ hemapoiesis recovered more rapidly in APBSCT group than that in ABMT group, but 3-year DFS had no statistical difference. Patients positive for IgH/TCR-γ by molecular PCR analysis had poor DFS. Molecur monitoring of MRD using PCR techniques seems to represent a reliable prognostic indicator. Immunotherapy in the patients whose bone morrow was positive for MRD post-AHSCT may intensify remission and reduce relapse rates.

Novel insights in the management of sickle cell disease in childhood

Sickle cell disease(SCD) is a life-threatening genetic disorder characterized by chronic hemolytic anemia, vascular injury and multiorgan dysfunctions. Over the last few decades, there have been significant improvements in SCD management in Western countries, especially in pediatric population. An early onset of prophylaxis with Penicillin and a proper treatment of the infections have increased the overall survival in childhood. Nevertheless,management of painful episodes and prevention of organ damage are still challenging and more efforts are needed to better understand the mechanisms behind the development of chronic organ damages. Hydroxyurea(Hydroxycarbamide, HU), the only medication approved as a disease-modifying agent by the United States Food and Drug Administration and the European Medicines Agency,is usually under-used, especially in developing countries.Currently, hematopoietic stem-cell transplantation is considered the only curative option, although its use is limited by lack of donors and transplant-related toxicity.SCD symptoms are similar in children and adults, but complications and systemic organ damages increase with age, leading to early mortality worldwide. Experts in comprehensive care of young patients with SCD, especially those approaching the transition age to adulthood,are missing, leading people to rely on urgent care,increasing health care utilization costs and inappropriate treatments. It would be important to establish programs of comprehensive healthcare for patients with SCD from birth to adulthood, to improve their quality and expectancy of life.

Granulocyte Colony-stimulating Factor-primed Bone Marrow： An Excellent Stem-cell Source for Transplantation in Acute Myelocytic Leukemia and Chronic Myelocytic Leukemia

Background：Steady-state bone marrow （SS-BM） and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell （G-BM/G-PBSC） are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation.Here,we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen （HLA）-identical sibling transplantation.Methods：A total of 226 patients （acute myelogenous leukemia-complete remission 1,chronic myelogenous leukemia-chronic phase 1） received SS-BM,G-BM,or G-PBSC from an HLA-identical sibling.Clinical outcomes （graft-versus-host disease [GVHD],overall survival,transplant-related mortality [TRM],and leukemia-free survival [LFS]） were analyzed.Results：When compared to SS-BM,G-BM gave faster recovery time to neutrophil or platelet （P 〈 0.05）.Incidence of grade Ⅲ-Ⅳ acute GVHD and extensive chronic GVHD （cGVHD） was lower than seen with SS-BM （P 〈 0.05） and similar to G-PBSC.Although the incidence of cGVHD in the G-BM group was similar to SS-BM,both were lower than G-PBSC （P 〈 0.05）.G-BM and G-PBSC exhibited similar survival,LFS,and TRM,but were significantly different from SS-BM （P 〈 0.05）.There were no significant differences in leukemia relapse rates among the groups （P 〉 0.05）.Conclusions：G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM.We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

Comparison of outcomes after human leukocyte antigen-matched and haploidentical hematopoietic stem-cell transplantation for multiple myeloma

Background:Allogeneic stem-cell transplantation (SCT) is a well-established immunotherapeutic strategy for multiple myeloma (MM) with a potent and often sustained graft-vs.-myeloma effect.This multicenter investigation aimed to analyze the complications and survival of haploidentical SCT in patients with MM,and compare the main outcomes with matched-related donors (MRDs).Methods:Haploidentical and MRD SCT was identified from a cohort of 97 patients with MM who received a myeloablative transplantation in 13 hospitals from May 2001 to December 2017.A matched-pair analysis was designed.For each haplo recipient,the recipients were randomly selected from the MRD group and were matched according to the following criteria:year of the hematopoietic SCT (±2 years),disease status at transplantation,and the length of follow-up.ults:Seventy cases received MRD and 27 received haploidendcal transplantation.The two groups showed no significant ifferences regarding age,gender,cytogenetic risk,and diagnostic stage.The cumulative incidences of non-relapse mortality (NRM) at1 and 3 years based on donor type were 20.5%(95% confidence interval [CI],10.90-30.10%) and 24.2%(95% CI,13.81-34.59%) for the MRD group and 16.80%(95% CI,1.71-31.89%) and 28.70%(95% CI,8.71-48.69%) for the haplo group,respectively.Cumulative incidence of NRM did not differ significantly between the two groups (x2 =0.031,P =0.861).The cumulative incidences of progression-free survival (PFS) and 1 year and 3 years by type of donors were 59.8 %(95 % CI,48.24-71.36 %) and 45.4 %(95 % CI,33.44-57.36%),and 65.6%(95% CI,47.18-84.02%) and 26.8%(95% CI,7.59-46.01%) for MRD and haploidentical donor,respectively.Cumulative incidence of PFS did not differ significantly between the two groups (x2 =0.182,P =0.670).In multivariate analyses,no statistically significant differences were observed between haploidentical and MRD for relapse,NRM,PFS,and overall survival.There were no statistically differences on main outcomes after haploidentical and MRD.Conclusion:Haploidentical SCT could be performed safely and feasibly for patients with MM in need.

Toward Understanding the Stem-Cell Origin and Molecular Regulation of Rice Tillering

Rice tiller is a specialized grain-bearing branch that contrib- utes greatly to grain production. Therefore, rice tillering is an important agronomic trait and provides a model system for the study of branching in monocots. Owing its importance both to agriculture and to fundamental science, much attention has been given to understand the molecular mechanisms under- lying rice tillering.

Intestinal organoid as an in vitro model in studying host-microbial interactions

BACKGROUND： Organoid is an in vitro three-dimensional organ-bud that shows realistic microanatomy and physiological relevance. The progress in generating organoids that faithfully recapitulate human in vivo tissue composition has extended organoid applications from being just a basic research tool to a translational platform with a wide range of uses. Study of host- microbial interactions relies on model systems to mimic the in vivo infection. Researchers have developed various experimental models in vitro and in vivo to examine the dynamic host-microbial interactions. For some infectious pathogens, model systems are lacking whereas some of the used systems are far from optimal. OBJECTIVE： In the present work, we will review the brief history and recent findings using organoids for studying host- microbial interactions. METHODS： A systematic literature search was performed using the PubMed search engine. We also shared our data and research contribution to the field. RESULTS： we summarize the brief history of 3D organoids. We discuss the feasibility of using organoids in studying host- microbial interactions, focusing on the development of intestinal organoids and gastric organoids. We highlight the advantage and challenges of the new experimental models. Further, we discuss the future direction in using organoids in studying host- microbial interactions and its potential application in biomedical studies. CONCLUSION： In combination with genetic, transcriptome and proteomic profiling, both murine- and human-derived organoids have revealed crucial aspects of development, homeostasis and diseases. Specifically, human organoids from susceptible host will be used to test their responses to pathogens, probiotics, and drugs. Organoid system is an exciting tool for studying infectious disease, microbiome, and therapy.

Tetrahedral framework nucleic acids regulate osteogenic differentiation potential of osteoporotic adipose-derived stem cells

Osteoporosis(OP)is a noncommunicable bone disease caused by a shift in the balance between os-teoblasts and osteoclasts,and can severely affect the health of elderly persons.Autologous stem-cell transplantation can improve reduced bone density and weakened fracture healing abilities in patients with OP.However,OP can adversely affect the osteogenesis and proliferation abilities of autologous adipose-derived stem cells(ASCs).Therefore,an effective drug is required to facilitate autologous ASCs to recover their osteogenic and proliferative potential.Tetrahedral framework nucleic acid(tFNA)is a new type of nanomaterial that has ability to regulate the biological behavior of cells effectively and en-hance the bioactivity of stem cells.In this study,we examine the effects of tFNAs on the osteogenic differentiation and proliferation abilities of ASCs in rats with OP.The results indicate that the 250 nmol/L tFNAs can considerably increase the expression of osteogenesis-related markers,effectively promote the proliferation and osteogenic differentiation of osteoporotic ASCs(OP-ASCs),and help them to regain their osteogenic and proliferative potential.In short,tFNAs can enable OP-ACSs to recover their osteogenic po-tential and promote their proliferation and,therefore,can play a key regulatory role in autologous ASC transplantation.

STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function

Stimulator of interferon genes(STING)-mediated innate immune activation plays a key role in tumor-and self-DNA-elicited antitumor immunity and autoimmunity.However,STING can also suppress tumor immunity and autoimmunity.STING signaling In host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease(GVHD),a major complication of allogeneic hematopoietic cell transplantation(allo-HCT).Host hematopoietic antigen-presenting cells(APCs)play key roles in donor T-cell priming during GVHD initiation.However,how STING regulates host hematopoietic APCs after allo-HCT remains unknown.We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs.STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT.Using bone marrow chimeras,we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease.Furthermore,STING on host CD11c+cells played a dominant role in suppressing allogeneic T-cell responses.Mechanistically,STING deficiency resulted in increased survival,activation,and function of APCs,including macrophages and dendritic cells.Consistently,constitutive activation of STING attenuated the survival,activation,and function of APCs isolated from STING V154M knock-in mice.STING-deficient APCs augmented donor T-cell expansion,chemokine receptor expression,and migration into intestinal tissues,resulting in accelerated/exacerbated GVHD.Using pharmacologic approaches,we demonstrated that systemic administration of a STING agonist(bis-(3'-5')-cyclic dimeric guanosine monophosphate)to recipient mice before transplantation significantly reduced GVHD mortality.In conclusion,we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.

Higher efficacy of oral etoposide for mobilization of peripheral blood stem cells in patients with multiple myeloma

This study compares the efficacy,toxicity,hematopoietic recovery,and cost of stem-cell mobilization using intermediate-dose cyclophosphamide(IDCy)plus granulocyte colony-stimulating factor(G-CSF)compared with etoposide(VP-16)plus pegylated granulocyte colony-stimulating factor(PEG-rhG-CSF)in multiple myeloma(MM)patients.Two hundred forty-four consecutive patients undergoing mobilization with IDCy(3-3.5g/m^(2))plus G-CSF(n=155)were compared with patients receiving VP-16 plus PEG-rhG-CSF(n=89),including oral etoposide(n=65)and intravenous etoposide(n=24).Compared with IDCy,VP-16 use was associated with significantly higher median peak peripheral blood CD34+cell count(8.20[range:1.84-84]×10^(6)/kg vs 4.58[range:0.1-27.9]×10^(6)/kg,P=.000),and ideal CD34+cell yield of more than 6×10^(6)/kg(56.8%vs 35.1%,P=.001),notably with a higher efficacy in oral VP-16 use compared with IDCy use(CD 34+cell counts:median peak peripheral blood 5.87 vs 4.58?106/kg and≥6×10^(6)/kg[48.4%vs 35.1%]).The median number of apheresis courses was reduced from two in the IDCy group to one in the VP-16 group(P=.000).IDCy use was associated with significantly more frequent episodes of neutropenia(70.2%vs 35.2%;P=.000),intravenous antibiotic use(13.2%vs 11.4%;P=.672),and hospitalization(P=.000).The recoveries of neutrophils and platelets after autologous stem-cell transplantation were significantly faster in the VP-16 group compared with the IDCy group(P=.000).Our data indicate robust stem-cell mobilization in MM patients with VP-16 delivered either orally or intravenously.When compared with intravenous VP-16,oral VP-16 mobilization was associated with significantly more convenient,lower average total costs,and especially decreased the risk of hospital visits and exposure.