bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful Treatment with Imatinib Mesylate Significantly Decreases Plasma Levels of Vascular Endothelial Growth Factor (VEGF) and Soluble Endoglin (sCD105) but Not Basic Fibroblast Growth Factor (bFGF) or Angiopoietin-2 (Ang-2) in Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase
Authors: Smolej Lukas , Andrys Ctirad , Voglova Jaroslava , Belohlavkova Petra , Rabasova Jana , Beranek Martin , Maly Jaroslav
Published: April 2020

Introduction: Angiogenesis is an essential process in the biology of solid tumors as well as hematological malignancies. Several studies have recently reported increased markers of angiogenesis in chronic myeloid leukemia (CML). However, much less is known on the possible impact of tyrosine kinase inhibitor imatinib mesylate (IM), the current cornerstone of CML treatment, on angiogenic signaling.

Aims: To analyze peripheral blood levels of angiogenic cytokines in patients with newly diagnosed CML and during imatinib treatment. Methods: Peripheral blood plasma concentrations of key angiogenic activators, namely vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), soluble endoglin (sCD105), and angiopoietin-2 (Ang-2) were quantified using commercially available sandwich enzyme-linked immunosorbent assay (ELISA) in 27 patients with chronic-phase CML and 80 healthy blood donors; furthemore, repeated samples during the therapy with IM were analyzed.

Results: We detected significantly elevated levels of VEGF (p<0.0001), bFGF (p=0.026), and sCD105 (n=25, p<0.0001) in comparison to the control group. Elevation of Ang-2 was of borderline significance (n=14, p=0.051). Levels of VEGF and sCD105 significantly decreased in patients who achieved complete cytogenetic response (p<0.0001 and p=0.01) whereas bFGF or Ang-2 did not change significantly (p=0.978 and p=0.625, respectively). VEGF and sCD105 remained low in repeated samples taken during IM treatment. Interestingly, there was a trend towards higher VEGF in patients who did not achieve complete cytogenetic response (p=0.058).

Conclusions: Peripheral blood levels of angiogenic activators VEGF, bFGF and sCD105 (and borderline Ang-2) were elevated in CML patients. Successful treatment with IM resulted in significant and durable suppression of circulating VEGF and sCD105 but not bFGF and Ang-2. Our results point to the potential significance of angiogenic signaling (especially VEGF pathway) in CML biology. Further research in this field is therefore highly desirable.
A Retrospective Evaluation of Clonal Cytogenetic Abnormalities in Ph Negative Clones in Patients with CP-CML on Therapy
Authors: Hartley Monique A , Shah Bijal D. , Armada Sady , Tinsley Sara , Pinilla Javier
Published: April 2020

Cytogenetic clonal aberrations in CML are a well recognized indicator of transition to blast phase. However, it is unclear how to interpret such changes when they occur in cells not harboring a Philadelphia Chromosome (Ph-), considering that some of these changes are often seen in patients with MDS/AML. In this retrospective review of 208 cases, we sought to determine the frequency, onset, character, and general course among CML patients harboring clonal chromosomal abnormalities (ChA) in Ph- cells during treatment with tyrosine kinase inhibitors (TKI’s). In this cohort, we were able to identify 13 ChA among 11 patients (5% of initial cohort), with most cases demonstrating trisomy 8 (31%), monosomy 7 (23%), and loss/gain of chromosome Y (38%). The median number of treatments per patient was 2 (1–3), with a median followup of 77.5 months (18–196 mo) among these 11 patients. Of the 13 ChA, 9 occurred during Imatinib therapy, and 5 of these 9 resolved without a change in medication. Of the remaining 4 patients, 2 presented with ChA prior to therapy, and 2 developed ChA while on a second generation TKI (Nilotinib, Dasatinib). The ChA persisted in the patient taking Nilotinib and resolved in the Dasatinib treated patient without change in therapy. Among those with ChA prior to therapy, the ChA resolved in one after the addition of INNO-406 (a lyn-abl inhibitor), and in the other despite going untreated between interval marrow specimens (this patient later went on to receive Imatinib with no ChA over an 18 month followup). CML disease course in patients with ChA in Ph- clones does not appear to be more severe, with only one patient having gone on to receive bone marrow transplantation for accelerated phase disease, and one other not currently in cytogenetic remission. Ten patients have attained complete (6) and major (4) molecular responses. Seven patients demonstrated cytopenias at last followup. Accompanying marrow dysplasia was seen among 4 of these patients. Interestingly, cytopenias are most pronounced in those with persistence of the ChA, including one patient with 5q deletion and another with chromosome 7 deletion. In summary, while clonal cytogenetic changes in Philadelphia Chromosome positive cells are a well recognized marker of disease progression, their presence in cells lacking this translocation does not seem to reflect a similar disposition. However while cytopenias of varying severity are noted in the patients reported, there is no evidence of transformation to MDS/AML nor a more resistant disease course. Long term follow up still is needed to confirm these data.
Survival Outcome of Hematopoietic Stem Cell Transplant Recipients Admitted to the Intensive Care Unit: A Single-Center Report of 53 Patients
Authors: Jaswal Jasbir K , Narayanan Sujaatha , Song Kevin W , Chittock Dean R , Griesdale Donald E.G.
Published: April 2020

BACKGROUND: Intensive care unit (ICU) admission following hematopoietic stem cell transplantation (HSCT) has traditionally been associated with a poor prognosis; particularly for those patients requiring mechanical ventilation.

OBJECTIVE: To determine 28-day and 1-year survival of patients admitted to the ICU following autologous or allogeneic HSCT. Data was collected from a single transplant center.

STUDY DESIGN: Retrospective cohort study of all adult patients who received a HSCT at Vancouver General Hospital from April 1st, 2000 to July 31st, 2006.

RESULTS: During the 6 year period of the study, a total of 862 hematopoietic stem cell transplants were performed (367 allogeneic, 486 autologous). Overall 28-day and 1-year survival for those receiving an allogeneic transplant was 97.6% and 68.4%. Patients receiving an autologous transplant had a 28-day and 1-year survival of 98.4% and 78.0% respectively. Fifty-three (6%) of our cohort were admitted to the ICU (34 allogeneic, 19 autologous), of which 43 (81%) required mechanical ventilation. The 28-day and 1-year survival of those patients admitted to the ICU was 42/53 (79.3%) and 18/53 (34.0%), respectively. Recipients of allogeneic stem cell transplants had a 28-day and 1-year survival of 26/34 (76.5%) and 9/34 (26.5%). This is in comparison to 28-day and 1-year survival of 16/19 (84.2%) and 9/19 (47.4%) for those receiving autologous stem cell transplants.

CONCLUSION: These data indicate that the survival of HSCT patients who require ICU admission is better than what has been previously reported in the literature. Limitations of this study include potential selection bias in those patients admitted to the intensive care unit. Future research will be directed at finding prognostic factors for ICU admission. However, based on these results, patients who receive hematopoietic stem cell transplantation should be offered admission to the ICU.
Administration of Rituximab 375 Mg/m2 on Days +1 and +8 after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HCT) Regimens for Patients with Advanced CD20+ Lymphoid Malignancies
Authors: Kharfan-Dabaja Mohamed A , Tate Cheryl , Perkins Janelle , Field Teresa , Fernandez Hugo F. , Alsina Melissa , Ayala Ernesto , Raychaudhuri Jyotishankar , Perez Lia , Ochoa-Bayona J. Leonel , Brand Linda , Pinilla-Ibarz Javier , Sotomayor Eduardo , Sullivan Dan , Anasetti Claudio
Published: April 2020

We evaluated the safety of adding rituximab 375 mg/m2 only on days +1 and +8 following allo-HCT in 18 patients (M=12, F=6), median age 56 (41–66) years, with advanced CD20+ lymphoid malignancies [CLL=9 (CR2=3, PR2=3; ≥PR3=3); Mantle cell lymphoma (MCL)= 5 (CR1=1, PR2=2, ≥PR3=2); follicular (FL)=3 (CR3=2, ≥PR3=1); DLBC NHL=1 (≥PR3=1). Source of stem cells consisted of matched-related (MRD)=11 (61%), matched-unrelated (MUD)=5 (28%), or mismatched-unrelated (MMUD)=2 (11%) donors. Conditioning regimens consisted of fludarabine plus targeted doses of IV busulfan (FLU-BU) (N=11) or 200 cGy TBI (N=4), or cyclophosphamide (FLU-CY) (N=1). ATG was administered on days −3 and −1 in 2 MMUD cases (FLU-BU-ATG). Fifteen patients received rituximab on day +1 (±3) and all on day +8 (±3). GVHD prophylaxis was tacrolimus plus mycophenolate mofetil (N=11) or methotrexate (N=7). Non-relapse mortality at 100 days was 6%. Median time to neutrophils and platelets engraftment was 15 (6–27) days and 12.5 (9–18) days, respectively. Eight patients never dropped platelets below 20,000/uL. Median CD3 and CD33 chimerisms at day +90 (±10) were 89% (50%–100%) and 100% (15%–100%), respectively. DLI was required in 2 patients (FLU-BU=1, FLU-TBI=1) due to poor CD3 engraftment. Response rates after 90 days post allo-HCT, according to diagnosis, were as follows: CLL (evaluable=8/9; CR=7/8; PR=1/8); MCL (evaluable=4/5; CR=4/4); FL (CR=3/3); DLBC (PD=1/1). Twelve (67%) patients remain alive in remission at a median follow up of 9.4 (2.3–42.3) months. The incidence of grade 0,I, II, and III–IV acute GVHD (aGVHD) was 6%, 33%, 50%, and 11%, respectively. Time to onset of aGVHD was 29 (16–77) days. The incidence of chronic GVHD (cGVHD), per NIH consensus criteria, was as follows in 15 evaluable patients: no cGVHD= 27%, mild= 33%, moderate= 13%, and severe=27%. These findings suggest that administration of rituximab 375 mg/m2 only on days +1 and +8 is safe. Response rates are encouraging; but controlled studies will be needed to conclusively determine the effect of post-transplant rituximab on efficacy.
Alternative Schedule of Filgrastim after Autologous Transplantation: Less Dosing, Same Efficacy
Authors: Sousa Aida B. , Costa Fatima , Ferreira Gilda
Published: April 2020

Administration of colony-stimulating factors (CSF) after autologous peripheral-blood progenitor cell transplantation is the current standard of care, and G-CSF is usually given from day +5 or +7 until engraftment. Recent preliminary data in a non-transplant setting suggest that 2 doses of G-CSF may be equivalent to the standard schedule. In this pilot study, we evaluated the safety and efficacy of giving only 2 doses of filgrastim post-transplant (days +7 and +9) in non-myeloma pts; exclusion criteria were re-transplants and clinical instability at day +7. From July 07 to June 08, 19 consecutive pts were included (16 lymphomas, 3 acute leukaemias) and their outcome was compared to a historical control group of 42 similar pts transplanted from Jan 06 to Jun 07, who received filgrastim from d+7 until 1000 neutrophils/ul (4–18 days, median 9). There were no significant differences in primary endpoints: median time to neutrophil engraftment (500/ul reached on day +12 vs +11) rate of documented infections (with bacteremia in 23% of transplants in the study group vs 36% in the control group) and median length of hospitalisation (both 22 days). Median duration of intravenous antibiotics (11 vs 12 days) median time to platelet engraftment (20,000/ul reached on day +13 vs +14) incidence of grade 3/4 mucositis and transfusion requirements were also similar. There were no deaths at day +30 in the study group. In 2 of the 19 pts a secondary prescription of filgrastim was made (for 2 and 4 days). In this pilot study, reducing filgrastim administration to 2 doses seems possible without undue risks. If confirmed in a randomized trial, these findings could have a significant impact on the cost of transplantation.
Hypocalcemia during Autologous Stem Cell Transplant with Concurrent Biphosphonate Use in Patients with Multiple Myeloma
Authors: Wudhikarn Kitsada , Vercellotti Gregory M. , Arora Mukta
Published: April 2020

Autologous hematopoietic stem cell transplantation (HSCT) is one of the treatment options which has been shown to enhance remission rate and survival in patients with multiple myeloma. Biphosphonates are used in conjunction with standard therapy and can ameliorate and prevent bony complications, i.e. bone pain, hypercalcemia or fracture, via direct inhibition of osteoclasts and possible anti-tumor effects on malignant plasma cells. With more frequent use of biphosphonates, there are increasing reports of noticeable adverse effects such as osteonecrosis of the mandible, renal failure and hypocalcemia. In this study we report three patients with multiple myeloma who received autologous HSCT accompanied with monthly administration of bisphosphonates and developed significant hypocalcemia post HSCT. All three patients had normal serum calcium levels at diagnosis and prior to transplant. The maximum drop in serum calcium was noted four to ten days post HSCT, and corrected by five to 13 days post HSCT. All three patients received biphosphonates eight to 20 days prior to the episode of hypocalcemia. All patients noted resolution of hypocalcemia with oral and intravenous calcium supplementation over three to ten days. Two patients required ongoing oral calcium supplementation for approximately one month after resolution of hypocalcemia. Multiple potential mechanisms can be postulated for the hypocalcemia in these patients undergoing HSCT such as chronic nutritional deficiency, GI losses, renal losses, vitamin D deficiency in addition to bisphosphonate use. Potentially melphalan, IV fluids, and furosemide may also play roles. Osteoclasts, bone marrow stromal cells and myeloma cells all can modulate calcium levels directly or indirectly through cytokine production. Future laboratory and clinical studies will focus on biochemical marker of complication and attention is needed while using bisphosphonates during autologous HSCT in myeloma patients.
Investigation of Polyomavirus BK in the Late-Onset Hemorrhagic Cystitis Following Hematopoietic Stem Cell Transplantation
Authors: Han Yue , Xie Ying , Sun Aining , Cen Jian nong , Zhu Zi ling , Gao Haili , Depei Wu
Published: April 2020

Background Late-onset hemorrhagic cystitis (LOHC) is a frequent and sometimes life-threatening complication after hematopoietic stem cell transplantation (HSCT). Our aim in this study is to analyze the risk fators for LOHC after HSCT, then determine the role of polyomavirus BK in the development of LOHC following HSCT.

Methodology 113 patients undergoing HSCT and 30 normal subjects were enrolled in this study. BK virus DNA were detected with PCR in the plasma and urine samples, while cytomegalovirus (CMV) antigen in peripheral blood was identified by immunofluorescence histochemical examination. All patients with LOHC were classified into three groups as grade 1, grade 2 and grade 3–4 by the severity of HC.

Results 22 patients developed LOHC (19.47%), all of them were allogenetic transplants recipients, with a median time of 44 days after HSCT. BK viruria was detected in 50 of all 113 patients following HSCT (44.2%), and no positive BK virema was found at the same time, while CMV virema was detected in 21 patients (18.5%). Of the 22 LOHC patients, 21 were detected BK viruria (95.5%), which was much more than that of non-HC patients (31.9%, P©‚0.01). The first time of BK viruria detection is earlier than the onset time of HC (25.09±16.63 days vs 47.42±29.02 days, P©‚0.01), accompanied with a longer median persistence time than that of HC (6 weeks vs 11 days), no difference was found in the onset and persistence time of HC among all the HC groups of three grades. Both CMV and BKV detection were negative in the control subjects. The occurrences of severe infection (45.5%), CMV reactivation (40.9%) and grade II-IV aGVHD development are much higher in HC group than that of non-HC group(P©‚0.01). Cox’s proportional hazard regression analysis showed that CMV reactivation and the development of grade II-IV acute graft-versus-host disease (GVHD) were associated with the occurrence of BK viruria, while BKV viruria and aGVHD of grade II-IV were independent risk factors of LOHC.

Conclusion BK polyomavirus may contribute to the pathogenesis of LOHC after HSCT, manifested as BK viruria. CMV infection and GVHD could be involved in the occurrence of BKV-related HC.
The Relative Percentage of Recipient T (CD3+) and Activated Lymphocytes (CD25+) Allows to Predict the Dynamics of Chimerism and the Risk of Complications after Allogeneic Stem Cell Transplantation
Authors: Borde Ismael Buno , Manzano Cintia , Balsalobre Pascual , Serrano David , Macias Gabriela Rodriguez , Gomez-Pineda Alfonso , Diez-Martin Jose L.
Published: April 2020

Introduction : The success of allogeneic stem cell transplantation (SCT) is conditioned by the dynamics and the result of the bidirectional interaction of immune reactions exerted by donor and recipient (alloreactivity/tolerance). Quantitative chimerism monitoring after SCT, mainly if performed on leukocyte lineages such as T lymphocytes (TL, CD3+), allows assessment of the immune interaction between donor and recipient.

Objective : To evaluate the usefulness of chimerism quantification in activated lymphocytes (AL, CD25+) for the early detection of complications (graft failure/rejection, GVHD, relapse, etc.) which, eventually, would improve the efficacy of current therapeutic strategies.

Material and methods: Chimerism quantification was done by microsatellite PCR (short tandem repeat, STR-PCR) on peripheral blood (PB) samples obtained every other week from 20 transplanted patients, as well as on leukocyte lineages, TL and AL, purified by immunomagnetic means (autoMACS, Miltenyi Biotec, purity>95%).

Results : Three different patterns of chimerism dynamics were observed:

10 patients showed complete chimerism (CC) in all samples analyzed post-SCT. 6 patients showed mixed chimerism (MC) with lower percentage of recipient cells in AL than in TL. All this 6 patients spontaneously evolved to CC. 4 patients showed MC with higher percentage of recipient cells in AL than in TL.

All these 4 patients showed decreasing MC (increasing percentage of recipient cells) in PB, TL and AL. Moreover, 3 of them showed complications involving the graft:

graft failure (not recovered after two succesive transplants) and graft rejections (1 incipient), which recovered and achieved CC after donor leukocyte infusions.

Concerning disease relapse, 1 case was observed in each of groups A and B, and three cases were observed in group C.

Conclusions: Our results suggest that higher percentages of recipient cells in AL than in TL are associated with stronger host-versus-graft immune reactions and, therefore, with decreasing mixed chimerism and subsequently with various complications after SCT. On the contrary, lower percentages of recipient cells in AL than in TL predict the achievement of CC. Quantitative follow up of chimerism in AL (CD25+) increases the usefulness of the analysis of PB and TL (CD3+) samples, allowing to predict the dynamics of chimerism after SCT and favouring the early establishment of the appropriate therapeutic option in each transplanted patient.
Phosphoinositide-3-Kinase Plays a Vital Role in Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cells Transplantation
Authors: Xing Haizhou , Du Xin , Weng Jianyu , Lu Zesheng
Published: April 2020

Phosphoinositide-3 kinase (PI3K) plays a vital role in T-cell signaling pathway including cell proliferation, differentiation, migration and so on. Scholars have found that PI3K expression is limited to cells related with transplant rejection activation of the immune cells. PI3K plays a crucial role in GVHD occurrence: 1 crucial, PI3K are located in main areas in T-cell activation signal, resulting in affecting GVHD significantly; 2 selective, PI3K expression is limited to the participation of activated cells with immune rejection. But the expression of PI3K in GVHD patients has been not clear. In order to give the more experimental evidence for prophylaxis and treatment of GVHD, PI3K gene expression in patients with different state of GVHD was detected. This research collected the peripheral blood lymphocytes in 32 patients after allogeneic hematopoietic stem cell transplantation from January 2007 to January 2008. The cases include 15 male and 17 female cases, the median age was 27.9 (14–43) years. In accord with the classification of GVHD, all cases were divided into ALL (12), AML (7), CML (10), CMML (2), MDS (1). After one year after transplantation, the number of patients with no-GVHD is 9, simply aGVHD is 8, single-cGVHD is 8, aGVHD and cGVHD is 7. The total sample number is 122(state of blood reconstruction 32, no GVHD 37, aGVHD 27, cGVHD 26). By real-time PCR, PI3K expression were determined of patients at normal blood reconstruction, and at the 30th day, the 60th day, the 90th day, the 180th day, the 270th day, the 360th day after allogeneic hematopoietic stem cell transplantation. Matching with own blood reconstruction, PI3K expression in acute or chronic GVHD patients is statistical difference significantly. At the state of No-GVHD, aGVHD and cGVHD, it was 2.51 ± 1.16, 7.15 ± 5.92, 4.35 ± 3.14 respectively. Results suggest that, comparing with no-GVHD, PI3K expression with aGVHD increase significantly. And PI3K expression increase significantly when occuring cGVHD, but it is less than with aGVHD. In the experiment we also found, PI3K expressed in lymphocytes correlated with the increasing degree of GVHD. Particularly in the cGVHD, PI3K expression increased significantly when GVHD becoming more serious; with access to stable cGVHD, PI3K expression gradually become flat. We can draw the conclusions from this study: PI3K gene expression increased significantly in patients with GVHD than that of patients with no-GVHD, and related to different stages of GVHD. PI3K expression increased in cGVHD patients than that of patients with normal hematopoietic reconstruction, but the amplitude is not significant than that of aGVHD.
Minoriting Cvtomegalovirus after Hematopoietic Stem Cell Transplantation for Seven Years-a Single Center Study
Authors: Wu Xiaojin , Depei Wu , Sun Aining , Tang Xiaowen , Fu Zhengzheng , MA Xiao
Published: April 2020

Objective: To investigate the incidence, risk factor and management of CMV reactivation in patients revived hematopoietic stem cell transplantation(HSCT).

Methods: 374 patients including 275 consecutive allogeneic and 99 autologous patients after bone marrow/stem cell transplantation from May 2001 to December 2007 were studied at our institution with nest-PCR and pp65 antigen assay. Anticoagulant blood samples were obtained from the recipients once weekly after days 14. After three months the CMV monitoring was performed every one month or every three months. If the patients catch CMV again after three year, the CMV monitoring was performed again.

Results:

The incidence of CMV positive in autologous patients was 3.03% and was 54.91% in allogeneic patients with a median onset of 48 days post transplants during 1 to 81 months. The difference between them is significant; The infection rate in the nonmyeloablative allogeneic peripheral stem cell transplantation (NST) group was 61.76%, in the group of HLA—identical sibling donor HSCT(sib-HSCT) was 47.10%, in haploidentical hematopoietic stem cell transplantation (Hi-HSCT) group was 75.00% and in the group of unrelated bone marrow transplantation (UR-BMT) was 57.45%. The infection rate of CMV in the Hi-HSCT group was higher than that in the group of sib-HSCT with significant difference (P<0.05); The incidence rate of CMV infection in patients with regimen including ATG was higher than that without ATG ((65%&47.1%, P<0.05); The incidence rate of CMV infection in patients with III–IV grade aGVHD and patients without III–IV aGVHD had not significant difference (P>0.05).

There was not significant difference in the occurance of aGVHD between the patients with and without CMV infection (P>0.05).5.87.8% patients are effective on antiviral therapy, incidence of CMV disease is very low, 0.65% patients catch CMV more than once.

Conclusion FCMV infection is common in our study, Minoriting CMV for long time is necessary, which benefit to antiviral therapy and judging of prognosis.
The Influence of Disease-Specific Prognostic Factors on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Myeloma
Authors: Singhal S. , Vickrey E. , Allen S. , Krishnamurthy J. , Duffey S. , Williams S. , Mehta J.
Published: April 2020

Although allogeneic HSCT is potentially curative in myeloma, series reporting encouraging results with submyeloablative regimens suffer from limited follow-up and incomplete information on prognostic factors known to be relevant in myeloma. The outcome of 24 myeloma patients (50–66 years, median 52) undergoing reduced-intensity allogeneic HSCT after 100 mg/m2 melphalan from related (n=21) or unrelated (n=3) donors. The 9 patients who had not relapsed after preceding autotransplantation received 50 mg/kg cyclophosphamide in addition. No patient underwent a planned sequential autograft-allograft procedure.

Complete prognostic factor information was available on each patient. High-risk disease (n=16) was defined by one or more of the following: del(13) on conventional karyotyping, t(4;14), del(17p), plasma cell labeling index >1%, elevated LDH, plasmablastic morphology. The disease was refractory to therapy in 16 patients. Three patients (13%) had disease that was neither high-risk nor progressive, 10 had disease that was either high-risk or refractory, and 11 had refractory, high-risk disease.

Four patients died of toxicity (3 GVHD, 1 multiorgan failure) and 19 relapsed. 18 of 19 relapsing patients died of progressive disease and 1 is alive in CR after a second allograft. High-risk (RR 0.11, P=0.0007) disease and refractoriness to therapy (RR=0.10, P=0.0006) were associated with poorer event-free survival. High-risk (RR 0.16, P=0.002) disease and refractoriness to therapy (RR=0.23, P=0.007) were associated with poorer event-free survival.

The combination of the two factors resulted in the identification of 3 categories of patients with highly disparate outcomes as shown in Figure 2.

Figure 1 shows the effect of the biological nature of the disease on EFS and OS. Figure 1. shows the effect of the biological nature of the disease on EFS and OS. Figure Figure

Our data suggest that the outcome of allogeneic HSCT in myeloma is disappointing unless the disease is sensitive to therapy and biologically low-risk. However, such disease responds exceedingly well to autotransplantation–and is associated with prolonged survival that can rival that seen after allogeneic HSCT. Alternative strategies are needed to improve the outcome of patients with refractory or high-risk disease–and may include elective post-allograft maintenance therapy with novel agents such as thalidomide, lenalidomide or bortezomib.
Reduced-Intensity Unrelated Cord Blood Transplantation for Adult Patients with Severe Aplastic Anemia
Authors: Yamamoto Hisashi , Kato Daisuke , Uchida Naoyuki , Ishiwata Kazuya , Takagi Shinsuke , Tsuji Masanori , Araoka Hideki , Yoshimi Mayumi , Narita Madoka , Sagawa Kimiko , Matsuno Naofumi , Masuoka Kazuhiro , Wake Atsushi , Yoneyama Akiko , Makino Shigeyoshi , Taniguchi Shuichi
Published: April 2020

Although unrelated cord blood transplantation (UCBT) has become a viable therapeutic option widely applicable for adult patients with hematological diseases, UCBT for severe aplastic anemia (SAA) remains to be controversial due to higher incidence of graft failure (GF) relative to the other stem cell sources. To evaluate the feasibility of UCBT for SAA, we retrospectively analyzed results for 11 adult patients with SAA who received first UCBT after reduced-intensity conditioning regimen (RI-UCBT) in Toranomon Hospital. Median age was 49 years (range, 20–70). Nine of them were non-responders to intensive immunosuppressive therapy and were multiply transfused, and two patients were fulminant type with no neutrophils in peripheral blood at diagnosis. The conditioning regimen consisted of fludarabine 125mg/m2, melphalan 80mg/m2, and 4 Gy of total body irradiation. Graft-versus-host disease prophylaxis was composed of cyclosporine alone (n=2), tacrolimus alone (n=2), and tacrolimus plus mycophenolate mofetil (n=7). Median total nucleated cell number and median CD34+ cell number were 2.65 × 107/kg (range, 1.83–4.39) and 0.70 × 105/kg (range, 0.27–1.52), respectively. Serological HLA disparities were as follows; 6/6 (n=3), 5/6 (n=2), and 4/6 (n=6). Ten of the 11 patients achieved primary neutrophil and platelet engraftment. Median time to an absolute neutrophil count > 0.5×109/liter and an unsupported platelet count > 20×109/liter were 18 days (range, 12–28) and 42.5 days (range, 26–64) respectively. All patients who achieved engraftment resulted in complete hematological recovery with complete donor chimerism, except for one patient who developed late GF at three years after UCBT. All 2 who experienced GF (1: primary GF, 1: late GF) were rescued by second RI-UCBT. Two of the 11 patients died from IPS (n=2), and remaining 9 patients are alive, having survived for 18.7 months (range, 2–71 months). Six out of 7 patients who survived more than 6 months were free from immunosuppressant. The probabilities of overall survival and event-free survival at 2 years after UCBT were 77.8% and 68.2%, respectively. Our results here strongly indicated feasibility and effectiveness of RI-UCBT for adult SAA patients with high engraftment rate and low treatment-related mortality. RI-UCBT could be considered as a viable therapeutic option for those who lack suitable HLA-matched sibling donors and failed immunosuppressive therapy.
Detection of Pre-Transplant Clonal Cytogenetic Abnormalities in Stem Cells Used for Autologous Stem Cell Transplant in Relapsed Non-Hodgkin Lymphoma Is a Predictor of Relapse
Authors: Rojas Ana Maria , Pinter-Brown Lauren , De Vos Sven , Paquette Ronald , Schiller Gary J , Territo Mary Carol
Published: April 2020

Autologous stem cell transplant is used for chemotherapy sensitive relapsed Non-Hodgkin Lymphoma (NHL). Patients who receive an autologous stem cell transplant after high dose chemotherapy for relapsed NHL have significantly superior survival compared to those receiving conventional chemotherapy. Relapsed patients who achieve a second remission are treated with myeloablative chemotherapy followed by autologous stem cell transplant. These patients can achieve 5-year event free survival close to 50% and 5-year overall survival of greater than 50%. We performed a retrospective analysis of our center’s transplant data and reviewed pre-transplant cytogenetic analysis on the patient’s collected stem cells. 259 patients underwent autologous stem cell transplant from 1998 through 2007 for relapsed NHL. Cytogenetic evaluations of the patient’s pre-transplant stem cells had been done to look for evidence of MDS or characteristics of their lymphoma. Clonal cytogenetic abnormalities were found in 12 of the 259 patients. Two of these patients died within 45 days of transplant without evidence of relapse. One from infection and a second from non-treatment related causes. Nine of the remaining 11 (81%) patients with clonal cytogenetic abnormalities have relapsed and died. All patients relapsed with their original lymphoma. The cytogenetic abnormalities were varied. Out of the 9 relapses, 3 had cytogenetic abnormalities in the stem cells that are associated with lymphoma, 2 that are associated with AML, 1 that is associated with MDS, and 2 were abnormalities whose significance was unknown. In one patient cytogenetic changes of the original lymphoma were identified. The patients that had clonal cytogenetic abnormalities in their collected stem cells had an 81% relapse rate as opposed to 30% in the patients whose stem cells had a normal karyotype. Our findings show that cytogenetic changes in the collected stem cells are associated with a higher rate of lymphoma relapse.
Role of Brain-Type Natriuretic Peptide and Cardiac Troponins as Predictors of Outcome in Multiple Myeloma
Authors: Koca Ebru , Parikh Gaurav , Amjad Ali Imran , Mendoza Floralyn L , Hosing Chitra M , Popat Uday , Champlin Richard E , Giralt Sergio , Qazilbash Muzaffar H.
Published: April 2020

BACKGROUND: High circulating levels of cardiac troponins, T and I (cTnT and cTnI) and brain-type natriuretic peptide (BNP) are associated with shorter overall survival and increased transplant-related mortality (TRM) in patients with amyloidosis undergoing high-dose chemotherapy and autologous stem cell transplantation (auto SCT). Their role as prognostic markers in myeloma is not clearly defined. We evaluated the utility of BNP, cTnT and cTnI as prognostic markers in patients undergoing auto SCT for myeloma.

METHODS: We retrospectively analyzed patients who received high-dose chemotherapy followed by auto SCT at MD Anderson Cancer Center between January 1 and December 31, 2006. Pre auto SCT levels of BNP, cTnT and cTnI were available in all patients. The upper limit of BNP was 100 ng/L, cTnT 0.01 ng/ml and cTnI 0.03 ng/ml.

RESULTS: A total of 105 patients (68 male and 37 female) with a median age of 57 (31–73) received auto SCT during the study period. Seventy-seven patients received high-dose melphalan 200 mg/m2 as preparative regimen, while 28 patients received a combination of melphalan 140 mg/m2 + busulfan 130 mg/m2 × 4 days. Median follow up of surviving patients was 21 months (1–30). Twenty-four (23%) patients had a high BNP level (>100 ng/L) prior to transplantation, 7 patients had a high cTnT level (>0.01ng/ml) and 12 patients had a high cTnI level (>0.03 ng/ml). In 101 evaluable patients, responses (complete 22 + partial 53) were seen in 75 (74%) patients. Overall survival (OS) and progression-free survival (PFS) at 24 months was 86 and 58%, respectively. There was no significant difference in 24-month OS in the high BNP group (p=0.7). Eight patients died of non-relapse causes, with only one death in patients with high BNP (p=0.67). Grade 3–4 cardiac adverse events were reported in 2 patients only, one of whom had elevated BNP (p=0.54). An increase in either BNP, cTnT or cTNI was seen in 30 patients. These patients did not have a significant increase in TRM (p=0.68) or cardiac toxicity, or a decrease in OS.

CONCLUSION: High pretransplant levels of BNP, cTnT or cTnI levels, either individually or together, did not adversely impact cardiac events, TRM or OS.
The Cation Transporter SLC22A16 Is Expressed in Pediatric Acute Lymphoblastic Leukemia
Authors: Moscow Jeffrey A. , Horton Terzah M. , Daily Abigail , Su Xiaoping
Published: April 2020

Hydrophilic drugs require transport proteins to traverse the cell membrane, and the selective expression of these membrane transporters can confer selective sensitivity to their toxic substrates. Therefore, identification of a transport gene with restricted expression on tumor cells represents an opportunity to target that transporter with a selective, toxic substrate. We previously have demonstrated that the organic cation transport gene SLC22A16 (OCT6) is highly expressed in the leukemia cell line HL-60, and its RNA levels were at least 2 orders of magnitude higher in 25 unique specimens of adult leukemic blasts than in liver, placenta and kidney, the tissues that usually have high expression of SLC22 transporters (Gong, S. et al. Experimental Hematology, 30, 1–8, 2002). To determine the relevance of SLC22A16 gene expression in pediatric acute lymphoblastic leukemia (ALL), we examined its expression using an Affymetrix U133B gene expression microarray in 132 primary pediatric ALL specimens. SLC22A16 was broadly and highly expressed in these pediatric ALL primary specimens. The gene was represented by 2 probesets, with average expression levels of 922 ± 344 in one probeset and 1715 ± 857 in the other. Analysis of subgroups revealed that overall expression was highest in hyperdiploid (>50) ALL specimens (n=17), and lowest in T cell ALL (n=14). The gene with highest correlation with SLC22A16 on the U133B array was ERG (Pearson p=2.4 × 10−8; False Discovery Rate (FDR) =5.2 × 10−5), a member of the Ets family of transcription factors that are implicated in leukemogenesis. MLL gene expression correlated with SLC22A16 expression with a Pearson p=3.3 × 10−5 and FDR=0.005. Other genes of special interest in leukemia biology with significant expression correlation to SLC22A16 included LIMD1, a member of the ZYXIN family (Pearson p=2.3 × 10−6, FDR=0.001), PPAR-alpha (Pearson p=4.5 × 10−7, FDR=0.0004), and STS-1 (Pearson p=7 × 10−7, FDR=0.0005). To examine protein expression of SLC22A16 in pediatric ALL, a polyclonal antibody to SLC22A16, that recognizes a protein of expected size in HL-60 cells, demonstrated expression of this protein at a level comparable to HL-60 cells in 3 of 6 primary pediatric B-precursor ALL specimens. These results suggest that an SLC22A16 substrate plays a physiologic role in pediatric ALL, and that SLC22A16 is a new therapeutic target for pediatric ALL that could be exploited by SLC22A16-specific toxins and antibodies.
BAFF-R Receptor Functions in Transcription Regulation in Genes Critical to Survival and Proliferation in Normal and Neoplastic Human B Lymphocytes
Authors: Fu Lingchen , Lin-Lee Yen-Chiu , Pham Lan , Tamayo Archie , Ford Richard J.
Published: April 2020

B-lymphocyte stimulator (BLyS also called BAFF), is a potent cell survival factor expressed in many hematopoietic cells. However, many aspects of BLyS signaling pathway remain unclear. In order to investigate BLyS signaling pathway, we studied the function of BAFF-R (also called BR3), a major BLyS receptor, in normal and neoplastic B cell survival and proliferation. In our initial study, we found that BAFF-R was also present in nucleus, in addition to its presence in the plasma membrane of B cells. A candidate nuclear localization sequence was identified in the BAFF-R protein sequence. We also found BAFF-R mediated transcriptional activity, that could be increased through over expression of a NF-κB family member c-rel. Further study showed that BAFF-R co-localized with, c-rel in the nucleus and bound to the NF-κB binding site on the promoters of NF-κB target genes such as BLyS, CD154, Bcl-xL, Bfl-1/A1 and IL-8. The IκB kinase (IKK) protein complex is critical for regulating NF-κB pathway activation. The IKK complex includes three important subunits: the catalytic subunits IKKα and IKKβ (also known as IKK1 and IKK2) and the regulatory subunit IKKγ (also known as NEMO). In the cytoplasm, activation of the IKK complex induces processing of precursors p105 and p100 into p50 and p52 respectively, resulting in NF-κB subunit dimeric partners that migrate from the cytoplasm into the nucleus. In recent studies, IKKα has also been identified in the cell nucleus, functioning in histone H3 phosphorylation. Although IKKβ was also previously observed in the cell nucleus, its nuclear function has been obscure. Besides functioning as a transcriptional co-factor with c-rel, we also found BAFF-R interacted with IKKβ in the nucleus of normal and neoplastic (lymphoma) B cells, enhancing histone H3 phosphorylation through IKKβ by immuno precipitation experiments and in vitro kinase assays. Inhibition of BAFF-R entry into the nucleus by BAFF-R NLS mutant transfection, decreased the level of phosphorylated histone H3 compared to the controls in NHL-B cells. These findings not only demonstrate a novel nuclear function of IKKβ, but also determine a new mechanism of how BAFF-R promotes survival and proliferation of normal B cells and NHL-B cells. In addition to activating NF-κB pathways in the plasma membrane, BAFF-R also functions as a transcriptional regulator binding to NF-κB targeted gene promoters possibly through a chromatin remodeling mechanism(s).
Inverse Correlation of NM23 Expression with Lysophosphatidic Acid Receptor EDG2/lpa1 Expression of Human Leukemia Cells during Myeloid Differentiation Induced by All-Trans Retinoic Acid
Authors: Okabe-Kado Junko , Kasukabe Takashi , Honma Yoshio , Kaneko Yasuhiko
Published: April 2020

Overexpression of the nm23 gene is found in many hematological malignancies, and predicts poor treatment outcome. Because the amount of intracellular NM23-H1 protein is inversely correlated with differentiation and exogenous over expression of the nm23-H1 in myeloid leukemia cells reduced the sensitivity to induction of myeloid differentiation, nm23-overexpression is considered to function as a differentiation-suppressor. However, the molecular mechanism of this phenomenon is unknown. Recently, lysophosphatidic acid (LPA) receptor EDG2/lpa1 was identified as a gene down-regulated by nm23-H1 and associated with cell motility/metastasis suppressor functions in breast cancer cells. Although the clinical significance of nm23-H1 overexpression in leukemia is completely opposite to that in breast cancer, there might be a common molecular mechanism between the metastasis-suppressing activity and differentiation-inhibiting activity of nm23-H1 overexpression, because many functional characteristics of macrophages/neutrophils are similar to those of motile and metastatic tumor cells. Here, we examined the EDG2/lpa1 expression level and its association with NM23 expression level and myeloid differentiation of leukemia cells. EDG2 and NM23 proteins were expressed at different levels in all leukemia cells tested (HL-60, NB4, THP-1, U937, K562, HEL, BALM-1, BALM-3, MOLT4, Jurkat). During all-trans retinoic acid (ATRA)-induced myeloid differentiation of HL-60 cells, the NM23 expression decreased and EDG2 expression inversely increased. Similar effects of ATRA were observed in myeloid differentiation of NB4 and THP-1 cells. NM23 expression levels and EDG2 expression levels modulated by ATRA treatment were inversely correlated (Spearman’s correlation coefficient, rs = −0.7538, p = 0.0237). However, these correlations were not found in the erythroid differentiation of ATRA-treated HEL and K562 cells. Cell motility is required for myeloid differentiation; therefore, there might be a common mechanism, the inhibition of cell motility thorough EDG2 down-regulation by NM23-H1 overexpression, between differentiation-inhibiting activity in leukemia cells and motility-inhibiting activity in breast cancer cells. The discrepancy in the clinical significance of NM23-H1 overexpression between leukemia and breast cancer might be resolved.
Absence of FLT3 and JAK2 (V617F) Mutations in Langerhans Cell Histiocytosis
Authors: Abedalthagafi Malak , Guo Huimin , Hartmann Dan-Paul , Ozdemirli Metin
Published: April 2020

Langerhans cell histocytosis (LCH) is a neoplasm of histiocytic cells believed to be derived from cells of the dendritic system, but the disease pathogenesis is unknown. FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that is expressed on the surface of hematopoietic stem cells and plays an important role in normal hematopoiesis. Recently, FLT3 has been shown to play a role in regulating dendritic cell development and elevated levels FLT3-ligand was found in the serum of LCH patients. Therefore we evaluated 14 cases of LCH for FLT3 mutations by PCR analysis of genomic DNA, obtained from formalin-fixed paraffin-embedded tissue samples, followed by PAGE for deletions or internal tandem duplications using a commercially available kit (InVivoScrib Technologies, San Diego, CA). There were 7 males and 7 females with a mean age of 25.1. The tissues involved included bones, lymph nodes, bone marrow, breast, lungs and various soft tissues. No mutations in FLT3 were identified in any of the 14 patient samples. In the same patient population we also looked at the JAK2 (V617F) mutation, which has been found in patients with myeloproliferative disorders other than chronic myeloid leukemia and which has not yet been evaluated in LCH by a single strand conformation polymorphism assay using a commercially available kit (Ipsogen, New Haven, CT). There was no JAK2 V617F mutation in any of the 14 cases. These results suggest that FLT3 and JAK2 V617F mutations do not play a role in the pathogenesis of LCH.
Quantitate Detect of the Methylation of Three Hematopathy Patients’ P16 Gene
Authors: Chen Bao-An , Shou Bei-ming , Zhou Dong-rui , Liu De-long , Ding Jia-hua , Gao Chong , Sun Yun-Yu , Wang Jun , Cheng Jian , Zhao Gang , Song Hui-hui , Bao Wen , Wang Jue-qiong , Yuan Peng , Pei Xiao-ping , Chen Ning-na , Ma Xu-dong , Lu Zu-hong
Published: April 2020

Objective: The changes of methylation of CpG Island are the frequent changes in epigenetic. Nowadays, there are many methods to detect the changes of methylation, but all these method are hard to quantitate precisely. In our experiment, we will establish a new precise method.

Methods: Use hydrosulfite to handle the DNA, and then do PCR. The cytosine will change to thymine, if it hasn’t been methylation. On the other side, the cytosine will maintain its state if it has been methylation. Design a pair of probe, which contain one methylation probe and one un methylation probe. This pair of probe will detect three consecutive sites of CpG island in P16. Our experiment will use gene chip. Mix the the DNA of methylation and unmethylation with different ratio, then build the standard curve. Contrast the patient sample with standard curve will get the quantitate result.

Results: We detected three patients, the methylation degree of the patients is 84.3%, 0%, 17.7%.

Conclusion: The method we used can detect methylation degree of three consecutive sites of P16 quantitate precisely. Solve the problem of quantitate precisely.
The Use of Recombinant Activated Factor VII in the Management of Life-Threatening Post Partum Bleeding
Authors: Herrada Juan , Jobe Jeff T. , Long Kristin , Alvarade Jobee , Galvan Carmen
Published: April 2020

Background: Recombinant activated factor VII (rFVIIa) is a novel hemostatic agent, originally developed for the treatment of hemorrhage in hemophiliacs with inhibitors, which has been successfully used recently in an increasing number of nonhemophilic bleeding conditions. We report on the use of this hemostatic agent in a case of severe postpartum bleeding, associated with disseminated intravascular coagulation, and unresponsive to standard treatment.

Case report: A healthy 39-year-old female presented with vaginal bleed and underwent emergency cesarean delivery of a full term baby. During the surgical procedure she was found to have an abruptio placentae, complicated with uncontrollable uterine bleeding that required a total hysterectomy. During the immediate post operative period the patient continued with profuse bleeding from the surgical wound. The diagnosis of clinical disseminated intravascular coagulopathy (DIC) was confirmed by the presence of thrombocytopenia, and a marked elevation of both prothrombin time (PT) and partial thromboplastin time (PTT) levels (both more than 100 seconds). During the first two postoperative days the patient required multiple transfusions of platelets, packed red blood cells (about 30 units), fresh frozen plasma, and cryoprecipitate. On the third postoperative day, she was taken to the operative room and a massive retroperitoneal clot was evacuated, although no specific bleeding site was found during the surgical exploration. After the procedure, and in addition to the usual hemostatic interventions, the patient was given three doses of rFVIIa (each dose consisted of 4.8 mg given intravenously over 2 minutes) over an eight-hour period. During the four subsequent days, the patient’s coagulopathy gradually improved, and eventually corrected. Although the clinical course was complicated with sepsis, renal failure, and respiratory failure, the patient was finally discharged home on stable condition twenty-six days after delivery. She is currently without any sequelae.

Conclusion: Severe post partum bleeding unresponsive to standard hemostatic therapy is associated with a high mortality. This case suggests a potential role of rFVIIa in the management of this complex medical condition.