Publications by authors named "Paul Castillo"

21 Publications

  • Page 1 of 1

Impact of depth of clinical response on outcomes of acute myeloid leukemia patients in first complete remission who undergo allogeneic hematopoietic cell transplantation.

Bone Marrow Transplant 2021 Apr 16. Epub 2021 Apr 16.

Division of Medical Oncology, University of Washington and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13-1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR.
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http://dx.doi.org/10.1038/s41409-021-01261-6DOI Listing
April 2021

Post-Transplant Cyclophosphamide (PTCy) is Associated with Increased Cytomegalovirus Infection: A CIBMTR Analysis.

Blood 2021 Mar 3. Epub 2021 Mar 3.

CIBMTR, United States.

Prior studies suggest increased CMV infection following haploidentical donor transplantation with post-transplant cyclophosphamide (HaploCy). The role of allograft source and PTCy in CMV infection and disease is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection as well as transplant outcomes as it relates to CMV serostatus and occurrence of CMV infection by d180. We examined patients reported to CIBMTR between 2012-2017 who had received HaploCy (n = 757), Sib with PTCy (SibCy, n=403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605) for AML/ALL/MDS. Cumulative incidences of CMV infection by d180 were 42% (99% CI, 37-46), 37% (31 - 43), and 23% (20 - 26), respectively [p<0.001]. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3 (14.4 - 175.2); SibCy (n=279): HR 47.7 (13.3 - 171.4); SibCNI (n=1065): HR 24.4 (7.2 - 83.1); p<0.001]. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD (p=0.006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy. This study supports aggressive prevention strategies in all patients receiving PTCy.
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http://dx.doi.org/10.1182/blood.2020009362DOI Listing
March 2021

Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.

Nat Commun 2021 02 26;12(1):1334. Epub 2021 Feb 26.

Department of Medical Oncology, Division of Hematological Malignancies Dana-Farber Cancer Institute, Boston, MA, USA.

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
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http://dx.doi.org/10.1038/s41467-021-21588-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910481PMC
February 2021

Primary spread of caudal blockade in children: the possible limiting role of the lumbar spinal cord enlargement (tumenescence) in combination with the cerebrospinal fluid rebound mechanism.

Paediatr Anaesth 2021 Feb 10. Epub 2021 Feb 10.

Paediatric Anesthesia, Karolinska University Hospital, Stockholm, Sweden.

Background: Despite being the most frequently used pediatric nerve block, certain aspects of the initial intraspinal spread of local anesthetics when performing a caudal block need further elucidation. The fact that injected volumes of 0.7-1.3 mL kg initially only reach the thoraco-lumbar junction, with only a few vertebral segments difference despite the huge difference in injected volume, still has no apparent explanation. We hypothesize that the narrowing of the epidural space caused by the lumbar spinal enlargement may provide an anatomical barrier causing this restriction of initial spread, alone or in combination with increased intrathecal pressure caused by the "cerebrospinal fluid rebound mechanism." The aim of this observational study was to find support for or refute this hypothesis.

Methods: Twenty nine MRI scans of the vertebral column, performed in children 0-6 years of age, was identified from the radiographic imaging computer system and analyzed for the vertebral level of the maximum of the lumbar spinal enlargement (Associated anatomical data related to the spinal canal, the dura mater, and the spinal cord were also recorded.

Results: The maximum of the lumbar spinal enlargement was found at a median vertebral level of Th 11 (IQR 11-11).

Conclusion: The maximum of the lumbar spinal enlargement is located at the Th 11 vertebral level. Although not entirely conclusive, the findings of the present study do support the notion that the lumbar spinal enlargement, in combination with the CSF rebound mechanism, may be the factors limiting the initial spread of a caudal block to the thoraco-lumbar junction.
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http://dx.doi.org/10.1111/pan.14157DOI Listing
February 2021

Pediatric HCT in Florida (2014 -2016): A report from the FPBCC.

Pediatr Transplant 2020 Nov 27:e13931. Epub 2020 Nov 27.

University of Florida, Gainesville, FL, USA.

FPBCC was formed in 2018 by five pediatric transplant programs in Florida. One of the key objectives of the consortium is to provide outcome analyses by combining HCT data from all the participating centers in order to identify areas for improvement. In this first FPBCC landscape report we describe the patient and transplant characteristics of pediatric patients undergoing first allo and auto HCT between 2014 and 2016 in Florida. The source of data was eDBtC of the CIBMTR. Over the span of 3 years, a total of 230 pediatric patients underwent allo-HCT and 104 underwent auto-HCT at the participating centers. The most significant predictor of survival in allo-HCT recipients with malignant disorders was the degree of HLA- match, while in the recipients of allo-HCT with non-malignant disorders the predictors of survival included age, donor relationship and degree of HLA match. Our analyses identified the need to improve reporting of primary cause of death and improve on donor selection process given that the degree of HLA match remains the most important predictor of survival. This first FPBCC-wide review describes the trends in pediatric HCT activity between 2014 and 2016 among the participating centers in Florida and confirms feasibility of using eDBtC data platform and collaborative approach in order to identify areas for improvement in outcomes.
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http://dx.doi.org/10.1111/petr.13931DOI Listing
November 2020

Specific Class I HLA Supertypes but Not HLA Zygosity or Expression Are Associated with Outcomes following HLA-Matched Allogeneic Hematopoietic Cell Transplant: HLA Supertypes Impact Allogeneic HCT Outcomes.

Transplant Cell Ther 2021 Feb 11;27(2):142.e1-142.e11. Epub 2020 Oct 11.

Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Maximizing the probability of antigen presentation to T cells through diversity in HLAs can enhance immune responsiveness and translate into improved clinical outcomes, as evidenced by the association of heterozygosity and supertypes at HLA class I loci with improved survival in patients with advanced solid tumors treated with immune checkpoint inhibitors. We investigated the impact of HLA heterozygosity, supertypes, and surface expression on outcomes in adult and pediatric patients with acute myeloid leukemia (AML), myelodysplastic syndrome, acute lymphoblastic leukemia, and non-Hodgkin lymphoma who underwent 8/8 HLA-matched, T cell replete, unrelated, allogeneic hematopoietic cell transplant (HCT) from 2000 to 2015 using patient data reported to the Center for International Blood and Marrow Transplant Research. HLA class I heterozygosity and HLA expression were not associated with overall survival, relapse, transplant-related mortality (TRM), disease-free survival (DFS), and acute graft-versus-host disease following HCT. The HLA-B62 supertype was associated with decreased TRM in the entire patient cohort (hazard ratio [HR], 0.79; 95% CI, 0.69 to 0.90; P = .00053). The HLA-B27 supertype was associated with worse DFS in patients with AML (HR = 1.21; 95% CI, 1.10 to 1.32; P = .00005). These findings suggest that the survival benefit of HLA heterozygosity seen in solid tumor patients receiving immune checkpoint inhibitors does not extend to patients undergoing allogeneic HCT. Certain HLA supertypes, however, are associated with TRM and DFS, suggesting that similarities in peptide presentation between supertype members play a role in these outcomes. Beyond implications for prognosis following HCT, these findings support the further investigation of these HLA supertypes and the specific immune peptides important for transplant outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015676PMC
February 2021

Cerebral blood flow alterations associated with high volume caudal block in infants.

Br J Anaesth 2020 Dec 2;125(6):1064-1069. Epub 2020 Oct 2.

Paediatric Perioperative Medicine and Intensive Care, Karolinska University Hospital Stockholm, Sweden; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

Background: High-volume (1.5 ml kg) caudal block in infants results in major reductions of cerebral blood flow velocity (CBFV) and cerebral oxygenation, caused by rostral CSF movement which increases intracranial pressure. The primary aim of this study was to determine the relationship between injected volume and CBFV changes. We hypothesised that this volume-blood flow relationship would have a similar albeit inverted shape to the well-known intracranial pressure volume-pressure curve.

Methods: Fifteen subjects, age 0-6 months, mean (range) weight 4.9 (2.1-6.4) kg, were studied. A 1.5 ml kg caudal injection of 0.2% ropivacaine was administered in three phases separated by two pauses. Subjects were randomised into five groups, in whom the pauses were implemented at different pre-set proportions of the total injected volume. Middle cerebral artery Doppler ultrasonography was used for CBFV measurements (V, peak CBF velocity; V, lowest CBF velocity; velocity time index). Mean flow velocity, pulsatility index, and resistivity index were calculated, and haemodynamic parameters were recorded.

Results: CBFV parameters decreased in all patients. The most affected parameter, V, was reduced by ∼50% (range 15-68%) compared with baseline. There was a nonlinear relationship between the volume of the first phase injection and the CBFV measurement during the first pause. Across all time points, there was a linear relationship between volume administered and CBFV. Systemic haemodynamic parameters remained stable throughout the study.

Conclusions: Injection pauses appear to attenuate adverse CBFV increases during administration of a high-volume caudal block.
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http://dx.doi.org/10.1016/j.bja.2020.08.055DOI Listing
December 2020

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Biol Blood Marrow Transplant 2020 08 17;26(8):1459-1468. Epub 2020 May 17.

Blood & Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio. Electronic address:

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
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http://dx.doi.org/10.1016/j.bbmt.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391266PMC
August 2020

Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study.

Lancet Haematol 2020 Mar 23;7(3):e238-e246. Epub 2019 Dec 23.

Pediatric Hematology-Oncology, Boston Children's Hospital, Boston, MA, USA; Dana Farber Cancer Institute, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA. Electronic address:

Background: Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies.

Methods: We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients.

Findings: We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts.

Interpretation: Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome.

Funding: National Institute of Health.
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http://dx.doi.org/10.1016/S2352-3026(19)30206-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984274PMC
March 2020

A genomics-informed computational biology platform prospectively predicts treatment responses in AML and MDS patients.

Blood Adv 2019 06;3(12):1837-1847

Division of Hematology Oncology, Department of Medicine, University of Florida, Gainesville, FL.

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) are generally older and have more comorbidities. Therefore, identifying personalized treatment options for each patient early and accurately is essential. To address this, we developed a computational biology modeling (CBM) and digital drug simulation platform that relies on somatic gene mutations and gene CNVs found in malignant cells of individual patients. Drug treatment simulations based on unique patient-specific disease networks were used to generate treatment predictions. To evaluate the accuracy of the genomics-informed computational platform, we conducted a pilot prospective clinical study (NCT02435550) enrolling confirmed MDS and AML patients. Blinded to the empirically prescribed treatment regimen for each patient, genomic data from 50 evaluable patients were analyzed by CBM to predict patient-specific treatment responses. CBM accurately predicted treatment responses in 55 of 61 (90%) simulations, with 33 of 61 true positives, 22 of 61 true negatives, 3 of 61 false positives, and 3 of 61 false negatives, resulting in a sensitivity of 94%, a specificity of 88%, and an accuracy of 90%. Laboratory validation further confirmed the accuracy of CBM-predicted activated protein networks in 17 of 19 (89%) samples from 11 patients. Somatic mutations in the , , , and genes were discovered to be highly informative of MDS response to hypomethylating agents. In sum, analyses of patient cancer genomics using the CBM platform can be used to predict precision treatment responses in MDS and AML patients.
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http://dx.doi.org/10.1182/bloodadvances.2018028316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595252PMC
June 2019

Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation.

Biol Blood Marrow Transplant 2019 09 11;25(9):1875-1883. Epub 2019 May 11.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3 T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3 T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3 T cell dose cutoff of 14 × 10 cells/kg identified MSD/low CD3 (n = 223) and MSD/high CD3 (n = 1214), and a dose of 15 × 10 cells/kg identified MUD/low CD3 (n = 197) and MUD/high CD3 (n = 1102). On univariate analysis, the MSD/high CD3 group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3 group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3 group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3 group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3 T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4 T cells, CD8 T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3 T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4 and CD8 T cell doses were not possible given our small sample size.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071947PMC
September 2019

Immunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study.

Haematologica 2019 10 4;104(10):1974-1983. Epub 2019 Apr 4.

Boston Children's Hospital and Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×10L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; =0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.
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http://dx.doi.org/10.3324/haematol.2018.206540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886407PMC
October 2019

Purtscher-like retinopathy: A rare presentation of hematopoietic stem cell transplant-associated thrombotic microangiopathy.

Pediatr Transplant 2019 03 20;23(2):e13344. Epub 2019 Jan 20.

Division of Pediatric Hematology Oncology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas.

Hematopoietic stem cell transplant (HSCT)-associated (TA) thrombotic microangiopathy (TMA) is an acquired disorder and a potentially life-threatening complication after allogeneic HSCT. TA-TMA causes endothelial damage and results in micro-thrombi in capillaries and arterioles. Early detection and treatment of complications associated with TA-TMA might improve outcomes. Purtscher-like retinopathy (PLR) is associated with micro-thrombi that occlude the retinal arteries and cause retinal injury. PLR has been associated with multiple entities, including HUS and TTP, but has not previously been described in the setting of TA-TMA. Here, we describe an 18-year-old male who underwent a mismatched unrelated donor HSCT for relapsed acute lymphoblastic leukemia. The patient was diagnosed with TA-TMA based on standard defined criteria. He presented with acute onset of blurred vision with findings of multiple white retinal patches, retinal hemorrhages, and macular edema, thought initially to be hypertensive retinopathy. However, on further evaluation using fluorescein angiography and optical coherence tomography, the diagnosis was determined to be PLR. The patient was treated with intravitreal steroid injections (triamcinolone acetonide) with dramatic improvement of vision. The aim of this report is to make clinicians aware of PLR as a potential ocular complication associated with TA-TMA and that prompt intervention might reverse visual impairment.
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http://dx.doi.org/10.1111/petr.13344DOI Listing
March 2019

Chimeric Antigen Receptor Signaling Domains Differentially Regulate Proliferation and Native T Cell Receptor Function in Virus-Specific T Cells.

Front Med (Lausanne) 2018 11;5:343. Epub 2018 Dec 11.

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Texas Children's Hospital, Houston, TX, United States.

The efficacy of T cells expressing chimeric antigen receptors (CARs) for solid tumors has been limited by insufficient CAR T cell expansion and persistence. The use of virus-specific T cells (VSTs) as carriers for CARs may overcome this limitation since CAR-VSTs can be boosted by viral vaccines or oncolytic viruses. However, there is limited understanding of the optimal combination of endodomains and their influence on the native T cell receptor (TCR) in VSTs. We therefore compared the function of GD2.CARs expressing the TCR zeta chain (ζ) alone or combined with endodomains from CD28 and 4-1BB in varicella zoster virus-specific (VZV) T cells. VZVSTs expressing GD2-CARs recognized VZV-derived peptides and killed GD2-expressing tumor cells. However, after repeated stimulation through their native TCR, the expansion of GD2-CAR.CD28ζ-VZVSTs was 3.3-fold greater ( < 0.001) than non-transduced VZVSTs, whereas GD2-CARζ- and GD2-CAR.41BBζ inhibited VZVST expansion ( < 0.01). Compared to control VZVSTs, GD2-CAR.ζ VZVSTs showed a greater frequency of apoptotic ( < 0.01) T cells, whereas prolonged downregulation of the native αβ TCR was observed in GD2-CAR.41BBζ VZVSTs ( < 0.001). We confirmed that CD28ζ can best maintain TCR function by expressing GD2.CARs in Epstein-Barr virus-specific T cells and CD19-CARs in VZVSTs. In response to CAR stimulation VSTs with CD28ζ endodomains also showed the greatest expansion (6 fold > GD2-CAR.41BBζ VZVSTs ( < 0.001), however anti-tumor efficacy was superior in GD2-CAR.41BBζ-VZVSTs. These findings demonstrate that CAR signaling domains can enhance or diminish the function of the native TCR and indicate that only CD28ζ may preserve the function of the native TCR in tonically signaling CAR-VSTs.
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http://dx.doi.org/10.3389/fmed.2018.00343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297364PMC
December 2018

A New Method for Reactivating and Expanding T Cells Specific for .

Mol Ther Methods Clin Dev 2018 Jun 14;9:305-312. Epub 2018 Mar 14.

Sheikh Zayed Institute and Center for Cancer and Immunology Research, Children's National Health System, Washington, DC 20010, USA.

Mucormycosis is responsible for an increasing proportion of deaths after allogeneic bone marrow transplantation. Because this disease is associated with severe immunodeficiency and has shown resistance to even the newest antifungal agents, we determined the feasibility of reactivating and expanding -specific T cells for use as adoptive immunotherapy in transplant recipients. extractpulsed monocytes were used to stimulate peripheral blood mononuclear cells from healthy donors, in the presence of different cytokine combinations. The generated -specific T cell products were phenotyped after the third stimulation and further characterized by the use of antibodies that block class I/II molecules, as well as pattern recognition receptors. Despite the very low frequency of -specific T cells of healthy donors, we found that stimulation with interleukin-2 (IL-2)/IL-7 cytokine combination could expand these rare cells. The expanded populations included 17%-83% CD4 T cells that were specific for antigens. Besides interferon-γ (IFN-γ), these cells secreted IL-5, IL-10, IL-13, and tumor necrosis factor alpha (TNF-α), and recognized fungal antigens presented by HLA-II molecules rather than through nonspecific signaling. The method described herein is robust and reproducible, and could be used to generate adequate quantities of activated -specific T cells for clinical testing of safety and antifungal efficacy in patients with mucormycosis.
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http://dx.doi.org/10.1016/j.omtm.2018.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054701PMC
June 2018

Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells.

Cancer Discov 2017 11 22;7(11):1238-1247. Epub 2017 Aug 22.

Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, and Baylor College of Medicine, Houston, Texas.

Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer. The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-0538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669830PMC
November 2017

Graft versus leukemia response without graft-versus-host disease elicited by adoptively transferred multivirus-specific T-cells.

Mol Ther 2015 Jan 30;23(1):179-83. Epub 2014 Sep 30.

1] Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA [2] Program for Cell Enhancement and Technologies for Immunotherapy, Sheikh Zayed Institute for Pediatric Surgical Innovation, and Center for Cancer and Immunology Research, Children's National Health System, Washington, District of Columbia, USA.

A 12-year-old boy with refractory acute lymphoblastic leukemia received a haploidentical transplant from his mother. As prophylaxis for Epstein-Barr virus (EBV), cytomegalovirus (CMV) and adenovirus, he received ex vivo expanded virus-specific donor T cells 3.5 months after transplant. Four weeks later leukemic blasts bearing the E2A deletion, identified by fluorescent in situ hybridization (FISH), appeared transiently in the blood followed by a FISH-negative hematological remission, which was sustained until a testicular relapse 3.5 months later. Clearance of the circulating leukemic cells coincided with a marked increase in circulating virus-specific T cells. The virus-specific cytotoxic T-cell (CTL) line showed strong polyfunctional reactivity with the patient's leukemic cells but not phytohemagglutinin (PHA) blasts, suggesting that virus-specific CTL lines may have clinically significant antileukemia activity.
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http://dx.doi.org/10.1038/mt.2014.192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4426803PMC
January 2015

Combining brain diagnosis and therapy in a single strategy: the safety, reliability, and cost implications using same-day versus separate-day stereotactic procedures.

Stereotact Funct Neurosurg 2011 5;89(6):346-56. Epub 2011 Nov 5.

Department of Neurological Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Background: A therapeutic radiosurgery procedure usually follows a separate diagnostic stereotactic procedure after days or weeks.

Objectives: To define the clinical reliability, safety, and cost implications of same-day diagnostic stereotactic biopsy and therapeutic radiosurgery.

Methods: During an 8-year interval, 26 patients underwent stereotactic brain biopsy followed by immediate therapeutic stereotactic radiosurgery in a single-day combined procedure. The intraoperative diagnosis was determined using standard histopathological techniques. Diagnostic accuracy, hospital costs, and contribution margins associated with this treatment strategy were compared to those of 26 case-matched patients (controls) who underwent a stereotactic diagnostic procedure followed by a separate-day outpatient SRS procedure within 6 weeks during the same time interval.

Results: The intraoperative diagnosis correlated with the final histopathological diagnosis in 96% of the patients. Biopsy-related morbidity did not occur in this series. The mean total costs of same-day patients was significantly lower than the costs of patients who had two-stage procedures (USD 9,077 ± 2,366 vs. 11,284 ± 3,025; p = 0.008). The net contribution to the hospital margin of USD 13,736 was not significantly different between the two management strategies.

Conclusions: The advantages of the same-day approach included a single stereotactic head frame application, reduced total admission time, consecutive histopathological diagnosis and therapy in a single hospital admission, and reduced total hospital costs. For patients who are highly suspected to have a brain tumor for which SRS is likely to be an effective therapeutic strategy, same-day diagnostic stereotactic biopsy followed by therapeutic SRS proved to be a safe, reliable, and cost-effective management strategy.
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http://dx.doi.org/10.1159/000332057DOI Listing
April 2012

Comparative study of semi-implicit schemes for nonlinear diffusion in hyperspectral imagery.

IEEE Trans Image Process 2007 May;16(5):1303-14

Laboratory of ApIlied Remote Sensing and Image Processing (LARSIP), University of Puerto Rico, Mayagüez, PR 00681-9048, USA.

Nonlinear diffusion has been successfully employed over the past two decades to enhance images by reducing undesirable intensity variability within the objects in the image, while enhancing the contrast of the boundaries (edges) in scalar and, more recently, in vector-valued images, such as color, multispectral, and hyperspectral imagery. In this paper, we show that nonlinear diffusion can improve the classification accuracy of hyperspectral imagery by reducing the spatial and spectral variability of the image, while preserving the boundaries of the objects. We also show that semi-implicit schemes can speedup significantly the evolution of the nonlinear diffusion equation with respect to traditional explicit schemes.
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http://dx.doi.org/10.1109/tip.2007.894266DOI Listing
May 2007