bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Two Re-Freezing Methods on Previously Thawed Peripheral Blood Progenitor Cells.
Authors: Israel Donald S. , Rodriguez Federico , Hunt Stephen , Kitchen Kirk , Torloni Sergio , Wiltbank Thomas B.
Published: October 2019

Background: Peripheral Blood Progenitor Cells (PBPC) cryopreserved in DMSO are thawed at the patient’s bedside and infused immediately. Usually the infusions are completed without incident. There are occasions when mild/severe transfusion related reactions occur. When this does occur, the infusion is either slowed or paused for a short period of time. When reactions are severe enough to warrant stoppage of the infusion, transplant facilities maybe faced with discarding any remaining thawed cells. We have explored the question of salvaging the remaining cells by re-cryopreservation using two cryopreservation methods.

Study Design: Twenty PBPC were thawed in a 37C water bath until the internal temperature of the cells was approx 2-6C. The PBPC were not washed and allowed to remain at room temperature for 15 minutes. Ten PBPC were then placed on ice for 45 minutes. This simulated the transfer of cells to an off-site cryopreservation lab. These cells were then transferred to a new cryo bag, no change in the cryoprotectant solutions, and placed into a rate controlled freezer (RCF) bringing their temperature back to <−160C. The remaining 10 PBPC were allowed to remain at room temperature for an additional 10 minutes. The PBPC were then transferred to a −80C mechanical freezer. This simulated the transfer of cells to an internal laboratory without cryopreservation capabilities. All 20 PBPC were thawed after a minimum of 24 hours after return to their respective storage freezer conditions. We measured total nucleated cell count, viability by trypan blue, and CFU after the initial thaw and after the second thaw.

Results: The median viability of all PBPC after the first thaw was 69.5% (n=20; range= 35–83%). The median post thaw viability of the PBPC frozen by the RCF was 55.5% (n=10; range= 18–73%). Whereas, the median post thaw viability of the PBPC frozen in the −80C freezer was 25% (n=10; range 8–37%). Additionally, the median percent of viable cell loss from the initial pre-freeze data to the second thaw data for the RCF PBPC was 66.1% (n=10; range= 0 – 94.6%) and for the −80C PBPC was 94.1% (n=10; range= 91.3–97.8%. CFU growth was present for the RCF PBPC. No growth was demonstrated for the −80C PBPC.

Conclusion: Though neither method provided outstanding results, if faced with the dilemma of losing cells or attempting to save by re-cryopreservation, a transplant facility should consider RCF over −80C freezing.
Post-That Washing Prior to Transplantation of Umbilical Cord Blood (UCB) That Were Depleted of Plasma but Not of Red Blood Cells.
Authors: Chow Robert , Tan Patrick , Jaing Tang-Her , Rosenthal Joseph , Nademanee Auayporn , Karanes Chatchada , Graham Michael , Eames Gretchen , Chan Lee Lee , Wang Brian , Chow Tiffany , Wu Tina , Tan Ah Moy , Tan Poh-Lin , Lin Hai-Peng , Gjertson David , Petz Lawrence
Published: October 2019

Washing after thawing of frozen UCB used for hematopoietic stem cell transplantation (HSCT) is widely practiced for the purpose of removal of the cryoprotectant DMSO and free hemoglobin from lysed red cells. An updated retrospective audited analysis was performed on the outcomes of 208 PD UCB used in 186 patients with known thaw conditions that have engraftment and/or survival data −106 washed (W) and 80 non-washed (NW). When the DMSO dose was kept under the recommended 1 g per kg of recipient weight, the only severe adverse reaction was a seizure and encephalopathy following infusion of a NW PD UCB that resolved without any sequelae. Total nucleated cell recovery after thawing as reported by transplant centers was higher for NW (median 89% vs. 75%). The Kaplan-Meier estimate of 3-month neutrophil (ANC500) engraftment were 91±4% for NW versus 88±4% for W with median time to neutrophil of 21 versus 24 days (p = 0.02). The K-M estimate for 6-month platelet 20K engraftment were 86±6% for NW and 78±5% for W with median time to engraftment at 46 days for NW and 55 days for W (p = 0.002). Acute grade III–IV GvHD were similar at 12% (NW) and 13% (W), but extensive chronic GvHD were 4% (NW) and 19% (W). 1-year TRM were 25±5% for NW and 34±5% for W (p=0.75), with relapse rate at 16±5% for NW and 28±5% for W (p=0.09). K-M estimates of 1-year OS were 63±6% versus 53±5% (p = 0.54), and for 1-year DFS were 62±6% versus 48±5% (p = 0.23) for NW and W respectively. To our knowledge, this was the largest transplant outcome study comparing no post-thaw wash versus wash for UCB, though the conclusions are confined to PD CBU. No clear benefits of post-thaw washing were seen for PD UCB. HSCT with NW PD UCB was at least as efficacious as that using W PD UCB with respect to GvHD, TRM, relapse rate, 1-year OS and DFS. Moreover, washing may have a negative impact on neutrophil and platelet engraftment of PD UCB.
Clinical Features and Risk Factors of Pure Red Cell Aplasia Following Major ABO-Incompatible Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Zhu Kanger , Li Jun-ping , Zhang Tao
Published: October 2019

Objective:To study the incidence, risk factors, clinical outcome, management and prevention of pure red cell aplasia (PRCA) following major ABO-incompatible allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Method:We retrospectively analyzed 11 cases of PRCA from a series of 42 patients undergoing major ABO-incompatible allo-HSCT from April, 1997 to December, 2005.

Results:1. 11 out of the 42 patients developed PRCA (26.1%); 2. All the 11 cases of PRCA were in blood group O recipients of grafts from blood group A donor (n=9) or blood group B donor (n=2). 3. The following factors were associated with an increased risk of PRCA:(1) blood group O recipient;(2) blood group A donor;(3) blood group O/A in recipient/donor pair;4. Only blood group O/A in recipient/donor pair was identified as being significantly associated with the occurrence of PRCA by multivariate analysis (P=0.006); 5. 6 patients who received donor-type plasma exchange did not develop PRCA, and among them, 5 cases were the O blood group recipients. 8 patients obtained spontaneous remission and in the remaining 3 patients, 2 patients with long-lasting PRCA were successfully treated with plasma exchange with donor-type plasma replacement and the other one who was also complicated by EBV-associated lymphoproliferative disorder (EBV-PTLD) responded rapidly to anti-CD20 monoclonal antibody and achieved complete resolution of clinical finding and symptom of both EBV-PTLD and PRCA.

Conclusions:The incidence of PRCA in this series of patients was 26.1%. Only blood group A/O in donor/recipient pair is identified as being significantly associated with the occurrence of PRCA by multivariate analysis. Donor-type plasma exchange is an effective approach for the treatment and prophylaxis of PRCA. Anti-CD20 monoclonal antibody is indicated for patients who are not response to conventional therapy.
Adverse Events after Infusions of Cryopreserved Hematopoietic Stem Cells Depend on Non-Mononuclear Cell in Infused Suspension and on Patient Age.
Authors: Milone Giuseppe , Pinto Valeria , Mercurio Salvatore , Strano Aurora , Coppoletta Stefania , Farsaci Benedetto , Poidomani Massimo , Leotta Salvatore , Giustolisi Rosario
Published: October 2019

We have prospectively collected data on Adverse Events (AE) that occurred in 179 Hemopoietic Progenitor Cell (HPC) infusions performed in patients affected with haematological neoplasm, after high dose chemotherapy. Stem cell source was Hemopoietic Progenitor Cells Aphaeresis (HPC-A) in 157 cases and Hemopoietic Progenitor Cells Bone Marrow (HPC-BM) in 22 cases. In all cases, an endotoxin-free DMSO was used. One or more AE were registered in 51/179 infusions (28.6%). Frequency of AE was higher after HPC-A than after HPC-BM (31.3% versus 4.5%, (chi square test: p=0.008). In univariate logistic regression other factors found important for AE were: Age (p=0.028), Number of Total Nucleated Cells infused/kg (P=0.002), Volume/kg infused (p=0.057), Volume of Packed Red Blood Cells (p=0.019), a content of Non-Mononuclear Cells >0.500 × 108/Kg (
 0.5×108/kg (P=0.0003) remained significant. No cardiovascular events were recorded during infusions. A significant correlation existed between reduction of cardiac frequency both with Volume/Kg infused (r 0.221; p=0.02) and with Actual Time of infusion (r 0.269; p=0.005). In conclusion, while Cardiovascular Changes are influenced by Volume/Kg infused and by Actual Time of infusion, Non-Cardiovascular AE are dependent on patient Age and on contamination by Non-Mononuclear Cells in apheretic harvests.
High Incidence of BK-Virus-Related Hemorrhagic Cystitis after Busulfan/Fludarabine Myeloablative Conditioning in Allogeneic Stem Cell Transplantation Recipients.
Authors: Akpek Gorgun , Badros Ashraf , Rapoport Aaron P. , Ruehle Kathleen , Barton Kristen , Meisenberg Barry , Yanovich Saul
Published: October 2019

Busulfan (BU) and Fludarabine (F) has been reported by de Lima et al. to be a well-tolerated myeloablative conditioning regimen with 3% incidence of hemorrhagic cystitis (Blood2004;104:857). Between 5/2005 and 5/2006, we performed allogeneic stem cell transplantation (SCT) in 29 patients following BU+F (n=17) and other (n=12) myeloablative regimens. Nineteen (66%) patients were in remission and 10 (34%) had active disease at BMT. Twenty patients had AML, 4 ALL and 5 had other malignancies. Busulfan was given at 130mg/M2 over 3 hours on 4 successive days, along with Fludarabine 40mg/M2 on 4 successive days. Eighteen (72%) had matched-related 7 (24%) had matched-unrelated donor (MUD) transplant. GVHD prophylaxis consisted of Tacrolimus and low-dose Methotrexate. Thymoglobulin (n=4) and CAMPATH (n=3) were given along with conditioning in MUD/one-antigen mismatch transplant recipients (5 BU+F and 2 other). As of August 1st, 2006, 19 (65%) patients are alive. Of 26 evaluable patients, the incidence of bacterial (59% vs. 89%), fungal (29% vs. 11%) infections were similar between Bu+F and other group, respectively. CMV reactivation was observed in 78% in other group as compared to 35% in BU+F recipients (p=0.09). Hemorrhagic cystitis (HC) occurred in 6 patients (35%) in BU+F group and in 1 (11%) patient in other group (p=0.35). BK virus was detected by quantitative PCR in all patients with HC. Two BK(+) cases were in BU+F+CAMPATH group. Considering 18 AML patients who received transplant in remission and had at least 2 months of follow-up, 5 patients (38%) in BU+F group relapsed within 6 months of transplant. Two out of 5 patients relapsed in the other group. Our findings suggest that BU+F myeloablative conditioning appears to be associated with high incidence of BK-related hemorrhagic cystitis and may have long-term consequences. Further studies are warranted.
Bone Marrow Transplantation from Alternative Donors in Children Receiving Rabbit ATG for Prophylaxis of Graft-Versus-Host Disease.
Authors: Hama Asahito , Yagasaki Hiroshi , Nishio Nobuhiro , Yoshida Nao , Tanaka Makito , Hidaka Hirokazu , Takahashi Yoshiyuki , Matsumoto Kimikazu , Kato Koji , Kojima Seiji
Published: October 2019

Rabbit antithymocyte globulin (ATG) has been used in allogeneic stem cell transplantation to facilitate engraftment as well as prevent graft-versus-host disease (GVHD). ATG can reduce the incidence of acute and chronic GVHD, but it prolongs the period of immunodeficiency and increases the incidence of infectious complications such as Epstein-Barr virus-related lymphoproliferative disorders (EBV-LPD). To evaluate the advantages and disadvantages of incorporating ATG into the preconditioning regimen, we reviewed records of 70 children with malignant (n=16) or non-malignant disease (n=54) who received unmanipulated bone marrow transplant (BMT) from alternative donors at our hospitals. Eleven patients (15.7%) received BMT from an HLA-mismatched related donor and 59 (84.3%) received BMT from an unrelated voluntary donor. The median age was 9 years (range, 0–21 years). The ratio of boys to girls was 2:1. The serological compatibility of HLA was as follows: 6/6 matched (n=43), 5/6 matched (n=21), 4/6 matched (n=5), and 3/6 matched (n=1). Fifty-one patients (72.9%) received a preconditioning regimen including total body irradiation, 15 (21.4%) received busulfan-based regimens, and 4 (5.7%) received other regimens. ATG (2.5mg/kg/day) was administered for 4 days (day -5, -4, -3, and -2) in all patients. For prophylaxis against GVHD, cyclosporine + methotrexate (MTX) was administered to 34 (48.6%) patients and tacrolimus + MTX to 36 (51.4%). Stable engraftment was not achieved in 2 of 70 (2.9%) patients. Both patients were rescued by second transplants from another donor. Acute GVHD (grade 2–4) developed in 13 of 68 (19.1%) evaluable patients and chronic GVHD in 16 of 62 (25.8%) evaluable patients (limited type, 4; extensive type, 12). Six patients (8.8%) suffered from interstitial pneumonitis and 5 patients (7.4%) developed EBV-LPD. Ten patients died of regimen-related toxicities and 3 died due to relapse of malignant disease. The estimate for 5-year survival from BMT was 88.5% for patients with non-malignant disease and 51.1% for patients with malignant disease. Our dose schedule of ATG appeared to be well tolerated and effective at reducing the incidence of acute and chronic GVHD in high-risk recipients.
Empiric or Presumptive Anti-Aspergillus Treatments for Allogeneic Hematopoietic Stem Cell Transplant Recipients with Sustained Febrile Neutropenia.
Authors: Oshima Kumi , Kanda Yoshinobu , Asano-Mori Yuki , Sato Hiroyuki , Watabane Takuro , Hosoya Noriko , Izutsu Koji , Asai Takashi , Hangaishi Akira , Motokura Toru , Chiba Shigeru , Kurokawa Mineo
Published: October 2019

Background: Although the onset of invasive pulmonary aspergillosis (IPA) after allogeneic hematopoietic stem cell transplantation (HSCT) was bimodal, IPA early after HSCT has become less frequent, partly due to the shortening of neutropenic periods by the use of peripheral blood stem cells or colony-stimulating factors. Therefore, the validity of empiric anti-Aspergillus treatments based on sustained febrile neutropenia according to the IDSA guideline should be re-evaluated.

Patients and Methods: We retrospectively reviewed the clinical records of 114 adult patients who underwent allogeneic HSCT between September 2002 and December 2005 in HEPA-filtered clean rooms at the University of Tokyo Hospital. Fluconazole at 200 mg/day was given as anti-Candida prophylaxis. In general, anti-Aspergillus agents were not started empirically, but presumptively started after the detection of positive Aspergillus antigen, positive beta-D-glucan, halo-sign on chest X-ray or CT-scan, and so on, associated with sustained febrile neutropenia. For the definition of early IPA, we employed proven or probable IPA according to the EORTC/MSG criteria that developed between the day of HSCT and seven days after engraftment.

Results: All but two who experienced early death showed neutrophil engraftment at a median of 16.5 days after HSCT. Although 15 patients developed IPA after HSCT, early IPA was observed only in 2 (1.8 %) patients. Among 73 patients who experienced sustained febrile neutropenia for more than 7 days before engraftment, we empirically started anti-Aspergillus agents in 13 patients a median of 9 days after the development of febrile neutropenia, whereas fluconazole was continued in 60 patients who had febrile neutropenia for 15 days in median. Four of the 60 patients received presumptive anti-Aspergillus therapy, one of whom developed probable IPA after the initiation of treatment. There was another patient who received anti-Aspergillus treatment only after the development of probable IPA because he showed no prior signs for presumptive therapy. There was no difference in the incidence of early IPA between patients who received empiric anti-Aspergillus therapy and those who did not (0% vs. 3.3%, P>0.99). The two patients who developed early probable IPA were successfully treated with anti-Aspergillus agents.

Conclusions: These findings throw doubt on the validity of empiric anti-Aspergillus treatments for allogeneic HSCT recipients with sustained febrile neutropenia, provided that they are treated in clean units with anti-Candida prophylaxis. A randomized controlled trial is warranted to compare empiric and presumptive anti-Aspergillus treatments for allogeneic HSCT recipients with sustained febrile neutropenia.
Prospective Investigation of Hemostatic Parameters in Patients Undergoing Hematopoietic Stem Cell Transplantation.
Authors: Han Yue , Lu Xiaoxu , Wu De Pei , Sun Aining
Published: October 2019

Objective To illustrate the alteration of hemostatic parameters in recipients of hematopoietic stem cell transplantation (HSCT) and then determine its value in transplantation-related complications.

Methods 45 patients receiving HSCT were evaluated prospectively in our institution. Hemostatic parameters were investigated prior to conditioning therapy and then weekly until five weeks after HSCT by enzymimmunoassay.

Results Significant increase was observed in the levels of fibrinogen, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) after transplant, while Protein C decreased significantly. No significant change existed in prothrombin time (PT), activated partial thromboplastin time (APTT) and antithrombin III (ATIII) levels. Six patients with acute grades II–IV graft-versus-host disease (aGVHD) presented with significantly lower level of Protein C compared with those who had grades 0–I aGVHD, PAI-1 level didn’t change apparently as well as fibrinogen and t-PA in the same time. However, three patients with veno-occlusive disease (VOD) extremely showed elevated PAI-1 levels after the clinical onset of VOD by comparison with mean post-HSCT values in the non-VOD patients; similar result was found in the patient who developed thrombotic microangiopathy (TMA).

Conclusion Our results suggest hemostatic imbalance is one important manifestation during HSCT, reflecting prothrombotic states and endothelial damage, which may be caused by the conditioning regimen and/or transplantation-related complications. The extreme elevation of PAI-1 alteration may be useful to recognize the development of VOD and TMA, while Protein C diminution facilitates the early diagnosis of aGVHD.
Selective Embolization of the Vesical Arteries for the Treatment of Severe Hemorrhagic Cystitis after Hematopoietic Stem Cell Transplantation.
Authors: Han Yue , Wu De Pei , Sun Aining , Chang Weirong , Zhu Xiaming
Published: October 2019

Background Hemorrhagic cystitis (HC) is a frequent and sometimes life-threatening complication after hematopoietic stem cell transplantation (HSCT). Many therapeutic approaches have been performed to control HC, but effective treatment for severe HC is still limited. This study investigated the role of selective embolization of the vesical arteries in patients with severe HC following hematopoietic stem cell transplantation (HSCT).

Methods Eight patients with late onset HC receiving HSCT were enrolled in the study, All patients underwent allogeneic transplantation and cyclophosphamide for preconditioning, including grade 3 or 4 HC, no improvement to routine management. A retrograde arterial catheterization of the femoral artery by seldinger’s technique was achieved in order to perform digital angiography of the aorto-iliac sector. Selective catheterization of the hypogastric arteries with a standard angiographic catheter was performed to localize the vesical vessels and confirm their bleeding site. Embolization of these arteries was carried out with gelatin sponge.

Results Eight patients with severe HC were treated with selective embolization of the vesical arteries. Five patients achieved complete response, with hematuria and symptoms ceased after 1–3 days of treatment. Two patients achieved partial response, with diminution of hematuria or presence of microscopic hematuria with no symptoms. One patient obtained no response to treatment.

Conclusion We investigated eight patients, among more than 280 patients treated in our hospital by allogeneic hematopoietic stem cell transplantation, in which HC was severe enough to require embolization. Our study showed that selective embolization of the vesical arteries is an effective treatment option in patients with severe HC following HSCT.
Prophylactic and Preemptive Anti-Fungal Therapy after Cord Blood Transplantation: A Retrospective Analyses of 188 Adult Patients.
Authors: Matsuhashi Yoshiko , Takagi Shinsuke , Yamamoto Hisashi , Kato Daisuke , Matsuno Naofumi , Seo Sachiko , Uchida Naoyuki , Masuoka Kazuhiro , Wake Atsushi , Miyakoshi Shigesaburo , Yoneyama Akiko , Taniguchi Shuichi
Published: October 2019

Background: Therapeutic outcomes for hematological diseases have recently been markedly improved due to the introduction of hematopoietic stem cell transplantation (HSCT), improvement of therapeutic regimens, and advancement of support therapy. Although invasive fungal infections have been one of the major causes of morbidity and mortality after cord blood transplantation(CBT), proper prophylactic and therapeutic approach to them has not been clearly established yet. To address this, we performed retrospective analysis to assess the effectiveness and safety of various antifungal agents for prevention and treatment of invasive fungal infections.

Patients and Methods: Medical records of a total of 188 patients who underwent umbilical CBT at Toranomon hospital between March 2002 and December 2005 were reviewed. The diagnosis included AML (n=53), ML (n=32), MDS (n=25), ALL (n=24), ATL (n=22), CML (n=7), AA (n=5), MM (n=3), and others (n=17). The median age was 54 (range; 17–79). The conditioning regimen consisted of fludarabine (125mg/m2), melphalan (80 mg/m2) and 4 Gy TBI for most of the patients. The incidence of breakthrough invasive fungal infection within 50 days after transplant was analysed.

Results: Forty-eight of the 188 were administered prophylactic anti-fungal agents other than fluconazole (FLCZ) due to prior mold infection, intorelant to FLCZ, and so on, were excluded. Remaining 140 patients who received FLCZ categolized into 2 groups; those who had empirically switched FLCZ to micafungin (MCFG) and/or amphotericin B (AMPH) and/or itraconazole (ITCZ) capsule at the first sign of infection (group A, n=69), and those who had continued FLCZ (group B, n=71). Four breakthrough invasive fungal infections were observed, 3 of them were invasive pulmonary aspergillosis (IPA), and 1 of them was tricosporon sepsis. Interestingly, all of these 4 were in group B, whereas no breakthrough infections were observed in those who were in group A. All 3 diagnosed IPA died of its exacerbation despite MCFG and/or AMPH treatment.

Conclusion: Proper administration of prophylactic anti-fungal agents can reduce the incidence of invasive fungal infection early after CBT. Although FLCZ has less activity to aspergillus, prophylactic FLCZ is effective enough to prevent breakthrough fungal infection. Immediate switch to other agents at the first sign of infection, such as MCFG, AMPH, ITCZ which are active against aspergillus could be recommended to prevent breakthrough infections.
Autologous Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma: Adverse Events Occurring 5 Years and Beyond.
Authors: Bolwell Brian , Sweetenham John William , Rybicki Lisa , Sobecks Ronald , Dean Robert , Andresen Steven , Brown Stacey , Kalaycio Matt , Pohlman Brad
Published: October 2019

Autologous stem cell transplantation (ASCT) is the treatment of choice for patients with relapsed/refractory DLBCL. ASCT is widely quoted as being potentially curative. We queried whether surviving patients free of disease five years after transplant were still at ongoing risk for relapse or other adverse events. We therefore retrospectively reviewed 174 patients with DLBCL receiving an ASCT from 1/1992 through 12/2001 who have been followed for at least 5 years since the date of transplant. Of these, 121 relapsed or died within the first 5 years of transplant; 42 are alive without disease greater than 5 years after transplant; and 11 relapsed or died greater than 5 years post-transplant. The median follow up among survivors is 7.3 years. Among the 11 patients with late events, 3 experienced non-relapse mortality: one died of secondary malignancy 104 months post-transplant; one died in a car accident 62 months post-transplant; one committed suicide 93 months post-transplant. Eight patients relapsed beyond 5 years from transplant: 3 have died and 5 are still alive. The three patients who expired from their relapse did so at 0.4, 2.5 and 23.2 months after relapse. Five patients relapsed between 63 and 102 months post-transplant and remain alive 6–72 months later. Two demographic trends were of interest: patients experiencing late adverse events were more likely to have bone marrow involvement at diagnosis, as 36% of patients with late events had marrow involvement at diagnosis as compared to 19% who remain alive and disease free; and of patients alive and disease free 5+ years post-transplant, 67% are male and 33% are female; of patients with late adverse events, 45% are male and 55% are female. The relapse-free survival curve for the entire patient cohort is shown below:

Figure Figure

We conclude that there is a low, but detectable, risk of disease relapse that continues beyond 5 years after ASCT for DLBCL. However, in this series the majority of patients experiencing delayed relapse remain alive with additional therapy. This underscores the importance of extended ongoing follow up for DLBCL patients treated with ASCT.
Transplant-Associated Thrombotic Microangiopathy (TAM): A Study Comparing Hemopoietic Stem Cells (HSCT) and Solid Organ (SO) Transplant (TX) Recipients.
Authors: Puente Dolores , Tabares Maria , Requejo Alejandro , Cecilia Colorio , Bonini Nicolas , Rossi Andrea , Listello Viviana , Milovic Vera , Jaimovich Gregorio , Pombo Gonzalo , Feldman Leonardo
Published: October 2019

TAM is associated with a poor prognosis and outcome. Reported incidence varies from 0.5 to 76%. Risk factors (RF) include use of calcineurin inhibitors(CNI), infections, conditioning chemotherapy regimen and graft versus host disease. Although treatment (TMT) modalities such as inmunosuppressive drugs withdrawal, plasma exchange or infusion are used to improve the outcome, optimal therapeutic strategies are not clearly defined.

OBJECTIVE: To compare the incidence, RF and outcome of patients (pts) with TAM after HSCT and SOTX.

PATIENTS AND METHODS: In 1172 consecutive pts transplanted between february 2000 and june 2006, 22 TAM episodes were diagnosed. TAM Dg was defined as evidence of hemolysis and schistocytes in blood smear. Thrombocytopenia (TCP), neurological (NRL) or renal (RNL) dysfunction were not included in the diagnostic criteria.

RESULTS: MAT incidence was 5,41% (11/203) in HSCT and 1,13% (11/969) in SOTX pts (p<0,0006). Median follow up of surviving pts was 1144 days (range: 281–2432). Overall mortality was 36,36% (8/22), 4/11 HSCT and 4/11 SOTX.

HSCT m HSCT r SOTX m SOTX r m: media r: range Age (years) 23,6 7–42 54 31–69 Sex (male) (%) 63,6 54,5 Time to Dg (days) 68,2 12–236 111,4 4–1097 TCP at Dg (%) 81,8 100 NRL at Dg (%) 18,2 40 RNL at Dg (%) 18,2 63,6 Hematocrite at Dg/post TMT(%) 26,9/34,3 20–35/25–48 18,5/32,8 18–28/29–37 LDH at Dg/post TMT 1186,4/946,4 607–2247/548–1629 1325,7/522 639–3960/295–630 Platelets at Dg/post TMT (×10 3/ml) 66,9/158 5–30/20–380 48/139 15–90/5–280 Urea/creatinine at Dg 66/1,2 17–95/0,6–2,3 124,8/3,4 41–190/0,9–6,5 Total Bilirrubin/Indirect Bilirrubin at Dg 6,2/2,3 0,7–14/0,4–5,5 3,2/1,9 0,4–13/0,2–7,7 Cyclosporine/FK at Dg (%) 81,8/18,2 9,1/90 TMT response (%) 72,7 80 Days to last evaluation (all/survival pts) 784,8/978,3 26–1584/281–1584 850,6/1310,6 26–2342/374–2237 Days to death since TX 391 26–908 58,7 26–96 Days to death since MAT Dg 361 6–862 12,8 7–20

CONCLUSIONS: In our experience TAM was an uncommon complication and its incidence was higher during the first 3 months after transplantation. It was more frequent among HSCT recipients. At Dg all TAM pts were receiving CNI as part of the immunosuppressive protocol. Drug withdrawal improved laboratory results and pt outcome in both groups. NRL and renal symptoms were more frequently seen in SOTX. Survival after TAM Dg in SOTX was shorter compared to HSCT recipients. Both groups showed similar mortality rate (36,36%).
Impact of 100-Day Survival on Outcome of Myeloablative Unrelated Bone Marrow Transplantation at an Early Stage of Leukemias.
Authors: Hiraoka Akira
Published: October 2019

There is a growing demand for quality improvement in hematopoietic stem cell transplantation as in other fields of patient manegement. Indicators would be necessary for the quality control, which finally lead a continuoous quality improvement process. We analyzed the impact of 100-day survival on the outcome in leukemia patients receiving a myeloablative unrelated BMT at an early stage of leukemias. Data on 1,203 patients who received a myeloablative unrelated BMT at the first CR of acute leukemia or the first chronic phase of CML between 1993–2001 were retrieved from Japan Marrow Donor Program Registry’s database. There were 40 hospitals which performed more than 10 BMTs during this period. A significantly lower 100-day survival than the average of all patients (n=822) was found in six hospitals (group 1). The remaining 36 hospitals were grouped in group 2. Overall survival (OS) at 1-year was 0.56 in group 1 (n=125) and 0.75 in group 2 (n=697) (p<0.001).

Figure Figure

The 100-day survival was 0.66 (83/125) in group 1 and 0.90 (625/697) in group 2 (p<0.001). OS at 1-year for survivors over 100 days was 0.828 in group 1 and 0.832 in group 2 (p=0.9).

Figure Figure

After adjustment for age (~15, 16~39, 40~), type of leukemia (CML, ALL, ANLL), and group (1, 2) by using the Cox regression model, patients in group 1 were found to have a higher risk of death than patients in group 2 (Hazard Ratio 2.14; 95% CI 1.58–2.90). These results indicate that

among hospitals which performed more than 10 BMTs between 1993–2003, 6 hospitals showed a significantly lower 100-day survival than the average of all patients, OS at 1-year for survivors over 100 days in patients in these 6 hospitals was simillar in patients in the remainging 34 hospitals, and after adjustment of age, type of leukemia and hospital group by using Cox regression model, patients in these 6 hospitals were found to have a higher risk of death than patients in the remaining 34 hospitals.

Thus, the 100-day survival might be an indicator for the quality control in leukemia patients who receive a myeloablative unrelated BMT at an early stage of leukemias.
Optimizing Results of Unrelated Donor Hematopoietic Stem Cell Transplantion in Developing Countries: Young Age and Early Disease as Positive Factors for Survival.
Authors: Funke Vaneuza A.M. , Nunes Elenaide C. , Cezario Eliane , Ruiz Jefferson , Setubal Daniela C. , Oliveira Michel M. , Bonfim Carmem M.S. , Bitencourt Marco A. , Pettengil Claudia , Medeiros Larissa , Datamager Heliz Regina A. Neves , Neto Jose Zanis , Medeiros Carlos R. , Pasquini Ricardo
Published: October 2019

Introduction: Unrelated donor hematopoietic stem cell transplantation (HSCT) has been carried out in Brazil since 1995, with an increasing number of procedures among the transplant centers. Evaluating this experience is important to improve the outcomes of this therapeutic modality. The aim of this study is to assess risk factors for survival in 125 patients who underwent unrelated donor HSCT for malignant diseases.

Material and methods: 125 patients with malignant diseases who received unrelated donor HSCT between july/95 and june/2005 in a single institution in Brazil were analyzed. Kaplan-Meier curves were used to estimate overall survival, log-rank test for comparison of continuous variables and Fisher exact test for categorical variables. Cox proportional hazard model was used for analyzing risk factors for survival. Analyzed risk factors: sex, age, acute graft-versus-host-disease (a-GVHD) grades II-IV, extensive chronic (c) GVHD, diagnosis, stage of disease, source of stem cells, number of infused cells/Kg and HLA matching. Median age was 17 years (range 1–55), male (n=78) and female (n=44).

Diseases: CML (n=46), AML/MDS (n=40), ALL (n=34), other (n=5). Source of stem cells: bone marrow (n=95), umbilical cord blood (n=30). ATG or ALG containing regimens were used in 25 patients. Advanced disease was detected in 66 patients (53%) and was defined as CML in advanced phases, AML and ALL ≥ second clinical remission (CR2), relapsed or refractory.

Results: Acute GVHD II-IV was observed in 51 (41%) patients and extensive c-GVHD in 32 (26%). Main death causes: a-GVHD (9%), c-GVHD (13%), infections (41%) and relapse (27%). Estimated overall survival (OS) in 10 years was 40%, with a median survival of 189 days. Sex, diagnosis, stem cell source, type of conditioning, number of infused cells/Kg and HLA matching did not influenced survival. OS in 10 years was higher in patients with early stage disease compared to advanced diseases (55% × 20%; p=.0005) and in patients under 18 years of age compared to those ≥ 18 years-old (60% × 20%; p=.0012). The presence of extensive c-GVHD had a positive influence in OS (OR 0,1758 – 0,9092).

Conclusions:

The OS in 10 years was 40% for this group of patients. Patients in early stage disease and under 18 years of age have a higher OS in 10 years (55% and 60% respectively). Extensive c-GVHD had a positive impact in survival, probably due to graft versus leukemia effect.
Autologous Stem Cell Transplantation for Elderly Patients with Multiple Myeloma.
Authors: Qazilbash Muzaffar H. , Saliba Rima , Hosing Chitra , Mendoza Floralyn , Qureshi Suhail R. , Weber Donna M. , Wang Michael , Flosser Thuy , Couriel Daniel R. , De Lima Marcos , Kebriaei Partow , Popat Uday , Alousi Amin M. , Champlin Richard E. , Giralt Sergio A.
Published: October 2019

Background: Several trials have shown that autologous stem cell transplantation is superior to conventional therapy in terms of complete response (CR) rate, event-free survival (EFS) and overall survival (OS). This treatment, however, is generally limited to patients younger than 65 due to concerns about excessive toxicity and treatment-related mortality (TRM) in older patients. Previous reports have shown that age alone should not exclude patients from high-dose therapy, as long as they fulfill other eligibility criteria. In this report we analyzed the safety and efficacy of high-dose chemotherapy (HDT) and autologous transplant in patients with MM who were ≥ 70 years at the time of autotransplant.

Methods: Twenty-six patients (16 males, 10 females) with a median age of 72 (range 70–79) underwent HDT and an autograft between July 1999 and October 2005. The preparative regimen was melphalan 200 mg/m2 in 19 patients (73%), melphalan 180 mg/m2 in 6 and melphalan140 mg/m2 in 1 patient. Of the 26 patients, 12 were receiving first remission consolidation, 7 had primary refractory disease and 7 had relapsed disease. Clonal cytogenetic abnormalities were present in 5 patients (19%).

Results: Twenty-two of the 26 patients were alive after a median follow up of 15 months (range 2–63). Responses (complete + partial response) were seen in 20 patients (77%), five (19%) of which were complete responses. Median EFS and OS were 19 and 31.6 months, respectively. 100-day TRM was 0%. Median times to absolute neutrophil count of ≥0.5 × 109/l and platelets ≥20 × 109/l were 10 and 10 days, respectively. Three-year EFS and OS were 37% and 49%, respectively. A low serum albumin (<3.5 g/dl) was associated with a shorter EFS (p=0.02), and patients with relapsed disease at transplant had a shorter OS (p=0.002). ISS stage, b2 microglobulin level, lactic dehydrogenase (LDH) level, abnormal cytogenetics, CCI or HCT-CI at the time of transplant did not emerge as significant predictors of PFS or OS in this group of patients.

Conclusions: HDT and autologous transplant is safe and feasible in selected patients ≥70 years of age. The outcome is comparable to younger patients undergoing an autograft, and older patients receiving conventional therapy.
Autologous Stem Cell Transplant Followed by Low Dose Rituxan Maintenance in CR1 Is Effective for the Treatment of Mantle Cell Lymphoma.
Authors: Lim Seah H. , Esler William V. , Beggs David , Burris Colleen , Zhang Yana , Townsend Mary
Published: October 2019

Conventional chemotherapy is non-curative for mantle cell lymphoma (MCL). Although the addition of Rituxan has improved the outcome of these patients, many patients still relapsed and died of their disease. High dose chemotherapy followed by autologous stem cell transplant (ASCT) has been investigated but produced conflicting results, ranging from no demonstrable benefit to a 2-year event-free survival (EFS) of 77%. A recent randomized study compared ASCT with interferon-a maintenance and showed benefits in both the EFS and overall survival for patients in the ASCT study arm. The conflicting results are probably related to the use of different chemotherapeutic agents as conditioning regimens for the transplant and also to different post-transplant therapy.

In this study, we have chosen to induce patients with advanced MCL with R-CHOP and consolidate these patients with high dose single agent melphalan, a cytotoxic that has not been previously tested as a single agent in MCL. Since most patients relapsed within the first two years after transplant, low dose maintenance Rituxan therapy is given three-monthly during the first 2 years after ASCT. Following consent from the patients, 8 consecutive patients with advanced Stage III or IV MCL were treated. There were 5 male and 3 female, with a median age of 642 years (range 46–72 years). One patient had Stage III and the other 7 Stage IV diseases. All eight patients received remission + 2 courses of R-CHOP as induction chemotherapy. Autologous stem cells were harvested upon recovery from the last course of R-CHOP and ASCT carried out within 6 weeks from the last course of R-CHOP. High dose intravenous melphalan (200 mg/m2) was administered followed, 24 hours afterward, by the infusion of a minimum of 2 × 106/kg of CD34+ autologous stem cells. Rituxan maintenance therapy was initiated at a dose of 375 mg/m2 given as a single infusion once every three months starting Day +100.

As of August 2006, with a median follow-up of 45.5 months from diagnosis (range 10–57 months) and 39 months from ASCT (range 4–52 months), seven patients are alive lymphoma-free, as defined by clinical and PET-CT examination. One patient died in CR of a myocardial infarction. Adverse effects were as expected from the high dose melphalan, except that delayed immunoglobulin reconstitution, as reported previously, was observed in all eight patients. Four of these hypogammaglobulinemic patients had recurrent infections (three with recurrent respiratory tract infection and one with a chronic diarrhea that was Vancomycin sensitive) and two required monthly intravenous immunoglobulin replacement. The result presented here is, therefore, extremely encouraging for a group of patients who normally have a very poor clinical outcome and warrants confirmation in larger multicenter study.
Role of High-Dose Chemotherapy with Autologous Haematopoetic Stem Cell Transplantation for Relapsed or Refractory Hodgkin’s Disease.
Authors: Kumar Ambuj , Djulbegovic Benjamin , Soares Heloisa P.
Published: October 2019

Background: Hodgkin disease (HD) is a potentially curable lymphoma with overall survival exceeding 60% at 10 years. However, patients with relapsed Hodgkin’s disease have a dismal prognosis when treated with conventional salvage chemotherapy. The primary objective of our systematic review/meta-analysis was to evaluate the efficacy of high-dose chemotherapy and autologous stem-cell transplant (HSCT) versus conventional chemotherapy in patients with relapsed Hodgkin’s disease which has not been done before.

Methods: Data search of published studies included Medline (1966–2006), Cochrane library and hand search of references. Studies were included if they were randomized controlled trials of HSCT versus conventional chemotherapy only. Data were extracted on benefits as well as harms (overall survival, event-free survival, and treatment related mortality). All data extraction was done in duplicate independently.

Results: Out of 47 identified studies only 2 met the inclusion criteria of the current systematic review. Overall survival was similar for HSCT and conventional chemotherapy arms (see figure 1) with a pooled hazard ratio (HR) of 0.69 (95%CI 0.40, 1.18, p=0.2). However, the event-free survival was better in the HSCT arm than the conventional chemotherapy alone group (HR = 0.59, 95%CI 0.41, 0.85, p=0.005). Treatment related mortality was similar in both groups. (HR = 0.40, 95%CI 0.11, 1.44, p=0.2).

Conclusion: Results from our meta-analysis indicate that treatment with HSCT compared with conventional chemotherapy only improves event free survival without excessive toxicity. However, overall survival was not affected by the HSCT therapy. In summary patients with relapsed Hodgkin’s disease should be offered HSCT therapy.

Role of transplant in relapsed or resistant hodgkin’s disease Role of transplant in relapsed or resistant hodgkin’s disease
Factor Xa Control of the Extrinsic Pathway: A Different View of the Regulation of Coagulation.
Authors: Hathcock James J. , Rusinova Elena , Nemerson Yale
Published: October 2019

The activation of factor X by Tissue Factor(TF):VIIa on a membrane surface is one of the principal events in the initiation of coagulation. We have previously shown and presently confirm that reactions initiated by TF:VIIa do not typically result in the complete activation of substrate, but rather some intermediate level of fX activation. Excess phospholipid has complex effects on the TF:VIIa reaction, resulting in either inhibition, due to substrate depletion, or acceleration, by virtue of binding fXa. This complexity results in unavoidable ambiguities in interpretation of all previous reports. To tease apart these complexities, we have used benzamidine-sepharose that only binds fXa and not fX. We now show that the reaction product, fXa, can impede, and in fact, completely inhibit TF:VIIa activity. We monitored progress curves of fX activation by TF:VIIa in the presence and absence of benzamidine beads, which specifically partition the reaction product away from the TF:VIIa complexes. In the presence of these benzamidine beads, the activation rate of fX increased by 60% confirming that removal of fXa enhances tissue factor activity. Moreover, binding studies of fXa to TF-phospholipid surfaces indicate that the surface occupancy by fXa regulates TF:VIIa activity. Surface occupancy was evaluated by Total Internal Reflectance (on macroscopic lipid bilayers) and Fluorescence Resonance Energy Transfer (phospholipid vesicles). Our measurements of the off-rate of fXa (0.06–0.08 /s) are similar to some literature values, but differ by up to 500-fold from others. Stochastic simulations of TF:VIIa kinetics on phospholipid surfaces confirm that product leaving rates strongly regulate the observed experimental kinetics. Our approach indicates that current models of coagulation need to be altered to accommodate product surface occupancy. Indeed, if fXa occupancy is ignored, as is generally the case, the models simply cannot reflect reality.
Target Marker Gene Expressions and the Possibility of Molecular Therapy for Children’s Brain Tumors.
Authors: Tsuruta Toshihisa , Kanno Hitoshi , Aihara Yasuo , Hamada Takako , Sakauchi Masako , Osawa Makiko , Wada Emiko , Kubo Osami , Hori Tomokatsu , Fujii Hisaichi
Published: October 2019

ErbB2, c-Myc and p53 gene expressions are widely reported for the poor prognostic markers for medulloblastoma (MB) patients. Recently, Wnt pathway and Sonic Hedgehog (SHH) pathways are known to related to the oncogenesis of MB cells, and the PDGF receptor gene and some adhesion molecule gene expressions are also known to the markers of the dissemination or the metastasis of MB cells. For adult malignant brain tumors, the molecular targeted therapy of the antibody (trastuzumab, cetuximab), the tyrosine kinase inhibitor (imatinib, gefinitib) or other signal transduction inhibitor (cyclopamin) are clinically researched. We examined several important marker gene expressions of the molecular therapy in various children’s brain tumors and searched the possible molecular targeted therapy.

[Materials and methods] Fifteen children’s brain tumor (five MB, seven glioma, three ependymoma) and four adult brain tumor (two glioma, two glioblastoma) were examind. The three MB cases were primary metaststic ones. The mRNA expressions of the marker genes (ErbB2, PDGF receptor, PCNA, SPARC, β-catenin, SUFU, c-Myc, p53, TrkC and so on) were examined by quantity polymerase chain (qPCR) reaction with fresh frozen tumor cells. For the normal control, we used the normal cerebellum total RNA samples of the Becton, Dikinson and Company. CYBR green coloring system was used for the qPCR and their primers were designed in the region between two exons. GAPDH gene expression was also examined as an internal control and all of the gene expression were normalized by GAPDH expression.

[Results] ErbB2 gene expression in MB cells were various, but their expression were similar to clinical futures, such as, the higher expressed cases had some high risk factors. In glioma cells, ErbB2 gene expression were almost equal by lower levels. PDGF receptor gene expression were more than five to ten times elevated in all of the glioma cells, even if they were low grade malignancy glioma, and were higher than that in MB cells. PCNA was specially elevated in primary metastatic MB cells.

[Conclusion] Our data shows that the molecular characteristics of the children’s brain tumors were thought to be different by cases, even if they had same histopathological characters. Some special gene tageting therapy, such as anti-ErbB2, PDGFR and/or PCNA therapy can be used for the various children’s brain tumors which are resistant for conventional therapies and are cured by adequate molecular therapy.