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The Neoproterozoic Jacobsville Sandstone outcrops along the south and east shores of Lake Superior, USA. It records intraplate deformation, some during its deposition and some afterwards, after the c. 1,100 Ma Midcontinent Rift (MCR) failed. Here we analyse 549 new detrital zircon ages from five sites, combined with prior data. Initially, local palaeo‐topography controlled the source material, including the MCR‐adjacent Penokean and Archaean rocks. With time the percentage of distal sources increased, including the c. 1,300–980 Ma Grenville orogeny and 1,480–1,360 Ma Granite‐Rhyolite Province. Sites near the Keweenaw fault contain a significant number of MCR‐age zircons, presumably uplifted to the surface, indicating fault motion during deposition. Only a relatively small percentage of 1,090–980 Ma Grenville‐age zircons from collisions to the east are present, suggesting that they were not efficiently transported to the Lake Superior area. This work is innovative in that it is the first to use detrital zircon geochronology to understand the internal stratigraphy of the Jacobsville Sandstone, whose provenance provides new information about the Neoproterozoic tectonic and sedimentary history of Laurentia. [ABSTRACT FROM AUTHOR]

Mild direct coal liquefaction (autogenous pressure, no catalyst, no H 2 gas) of Springfield coal in fluid catalytic cracking decant oil is shown to effectively produce coal extract precursors to spinnable mesophase pitch. This work demonstrates that the coal extract can be thermally treated to obtain mesophase pitch in a facile one-step process, bypassing the production of an intermediate isotropic pitch. Furthermore, the presence of 25 wt.% coal in the initial slurry can increase the yield to mesophase pitch nearly twofold and yield to carbon fiber by approximately 70%. The coal extract-derived mesophase pitch was melt-spun and heat treated to produce carbon fiber with graphitic texture, high modulus (>400 GPa) and tensile strength up to 943 MPa. Overall, this work demonstrates that coal can be effectively utilized to markedly amplify the mesophase pitch and carbon fiber yield from fluid catalytic cracking decant oil by relatively simple processing, while conserving utility as a precursor to high performance carbon fiber and potentially other high value graphitic products. [Display omitted] • Mild direct coal liquefaction in decant oil was used to obtain a coal extract. • The coal extract was thermally converted to a spinnable mesophase pitch. • Coal utilization improved yield to mesophase pitch nearly twofold. • Coal extract-derived carbon fiber displayed high modulus (>400 GPa). • Coal utilization resulted in a ∼70 % increase in yield to carbon fiber. [ABSTRACT FROM AUTHOR]

Abstract: Mafic dikes pervade the upper plate of the Heart Mountain Detachment (HMD), yet the dike concentration in the lower plate is sparse. Previous workers interpreted that these dikes were emplaced either coeval with or subsequent to the emplacement of the upper plate. The magnetic fabrics of 32 mafic dikes at Cathedral Cliffs were analyzed using low-field anisotropy of magnetic susceptibility (AMS) as a proxy for flow. These dikes intrude Ordovician–Mississippian carbonate and overlying Eocene volcanic rocks and are truncated along the nearly horizontal HMD. The dikes trend between N10°W and N20°E, are all steeply dipping, and range in width between 0.5 and 3m. Flow directions for the dikes were determined by the bearing and plunge of the K max (maximum principal susceptibility) axes relative to the dike orientation. About 66% of the dikes sampled show typical dike AMS patterns with K max and K int in the plane of the dike and K min normal to the dike plane. About 66% of the dikes sampled have K max inclinations >45° and thus were emplaced upward; 16% of the dikes have K max inclinations of <10° and thus were emplaced laterally. The remaining dikes have intermediate K max inclinations. With numerous dikes showing vertical to sub-vertical emplacement directions and with no magmatic source immediately below the detachment the dikes must predate emplacement of the upper plate. Therefore, upper plate dilation by dike intrusion could not be a driving force for protracted extension. Our date is consistent with a single catastrophic emplacement event, and inconsistent with an extensional allochthon model of incremental emplacement over long intervals of time. [Copyright &y& Elsevier]

Here, we present the detrital zircon age spectra for five (n = 36, 68, 66, 41, 29) red quartzite gastroliths collected from the top of the Upper Jurassic Morrison Formation in the eastern Bighorn Basin, Wyoming, USA. The detrital zircon age spectra reveal geon 17 maximum depositional ages, and age peaks that are Yavapai (geon 17), Penokean (geon 18) and Archean (>geon 25). The colour, texture, composition and zircon age spectra of these exoliths are indistinguishable from those of geon 16 (i.e. Baraboo interval) quartzites present in the Laurentian midcontinent more than 1,000 km to the east. We interpret that these gastroliths were ingested by dinosaurs, most likely sauropods, in the Laurentian midcontinent and then transported in their digestive tracts to the site of deposition. These data support the hypothesis of long‐distance dinosaur migration, perhaps following low energy, continental‐scale drainage systems that flowed from the Appalachian highlands to the Morrison Formation depositional basin. [ABSTRACT FROM AUTHOR]

Background Opportunistic infections are a significant cause of morbidity and mortality in children treated with chemotherapy. Historically, the neutropenic diet has been utilized to limit the incidence of infections by reducing exposure to potential pathogens. The neutropenic diet is utilized at our center for all allogeneic(allo) hematopoietic stem cell transplant (HSCT) patients at admission and restricts uncooked vegetables, fruits without thick peels, undercooked meats/seafood, and any restaurant food. Autologous (auto) HSCT patients follow a regular diet with food safety education according to Center for Disease Control (CDC) and Food and Drug Administration (FDA). The neutropenic diet is not endorsed by the CDC and FDA due to lack of evidence to support it. We hypothesize the neutropenic diet offers limited advantage over the FDA and CDC food safety guidelines in respect to rates of neutropenic fever or infection. Methods We performed a retrospective descriptive review of consecutive pediatric patients >1 year of age that underwent HSCT between June 2016 and February 2017 to assess fever and infectious complications occurring before engraftment. All patients were placed on prophylactic antibiotic therapy (cipro and pen VK) on admission until fever or engraftment. Results A total of 72 HSCT procedures were conducted on our inpatient unit (Auto, 24 and Allo 48). Median age at HSCT was 6 years (Range 1-24 years). Of 72 total transplants, 56 (78%) had at least one fever episode from the start of conditioning until engraftment. The median day of fever was day -2. 6 of 57 episodes of fever were due to blood steam infection (3 allogeneic; 3 autologous), Organisms included Bacillus species, Enterobacter cloacae, acid fast bacilli, Streptococcus oralis and Staph epidermidis. Twenty-eight patients had diarrhea, five had identified stool pathogens to include C.difficile (n=2), Adenovirus (n=3), Norovirus (n=1), E.coli (N=1), of note 2 patients had 2 concurrent infections present. Sixty seven(89%) patients received TPN for a median of 41 days (ranging from 9-233 days) for allogeneic and median of 20 days (ranging from 6-170 days) for autologous recipients. Thirty seven (49%) patients had clinically documented mucositis (see Table 1). Discussion Fevers were commonly chemotherapy related and infectious causes were rare for both auto HSCT on a regular diet and allo HSCT on a neutropenic diet. Antibiotic practices may contribute to outcomes. Further investigation evaluating the safety of the FDA diet during the neutropenic period of HSCT is warranted to improve overall nutrition and quality of life. [ABSTRACT FROM AUTHOR]

The mechanisms of lithospheric thinning and craton destruction have been hotly debated in the last decades. The Early Cretaceous Jiaodong and Liaodong extensional provinces (JEP and LEP, respectively) of the eastern North China craton are typical areas where the cratonic Archean lithosphere has been intensely extended and thinned. Various extensional structures, e.g., metamorphic core complexes (MCCs), low-angle detachment faults, and extensional basins, characterize the Early Cretaceous crustal deformation of the two provinces. However, profound differences exist in structural development and related magmatic activities between the two provinces. Distributed small-scale extensional basins were formed in association with exhumation of the Liaonan and Wanfu MCCs in the LEP, whereas the major Jiaolai Basin was developed coevally with exhumation of the Wulian, Queshan, and Linglong MCCs in the JEP. Sr-Nd isotope compositions of volcanic rocks from the basins of the two provinces are compatible with syntectonic magmatic activities of evolving magma sources in the LEP, but multiple and hybrid magma sources in the JEP. It is shown, from variations in structural styles, plutonic and volcanic activities, and thermal evolution of the two extensional provinces, that two stages (ca. 135-120 Ma and 120-100 Ma) of tectonic extension affected the JEP and LEP in the Early Cretaceous. We demonstrate that regional tectonic extension (parallel extension tectonics, or PET) is responsible for the formation of major extensional structures and the occurrence of the magmatic associations. Progressive wide rifting by coupled crust-mantle detachment faulting of a hot LEP lithosphere was accompanied by evolving magma sources from dominant ancient crust and enriched mantle to juvenile crust. Two stages of narrow rifting of a cold JEP lithosphere led to early crustal detachment faulting transitioning to late crust-mantle faulting, which resulted in intense magmatic activity from hybrid to multiple magma sources. These processes contributed to destruction of the craton, with thinning of its lithospheric keel and local transformation of the nature of the lithospheric mantle. It is expected that such a model is also applicable to interpretation of tectonic extension of contiguous areas of the North China craton and the remobilization of other cratons. [ABSTRACT FROM AUTHOR]

The inclusion of antithymocyte globulin (ATG) in cord blood transplantation is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute lymphoblastic leukemia (ALL) who received myeloablative total body irradiation–based conditioning and either single-unit (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. ATG recipients were more likely to be cytomegalovirus seronegative. The incidences of day 100 grades II to IV acute graft-versus-host disease (GVHD; 30% versus 54%, P = .0002) and chronic GVHD (22% versus 43%, P = .0008) were lower with ATG compared with non-ATG regimens. However, day 100 grades III to IV acute GVHD was comparable (11% versus 17%, P = .15). The 3-year incidences of transplant-related mortality (16% versus 17%, P = .98), relapse (17% versus 27%, P = .12), and leukemia-free survival (66% versus 55%, P = .23) in ATG and non-ATG recipients were similar. There were no differences in viral reactivation between treatment groups (60% versus 58%, P = .83). Therefore, the data suggest that incorporation of ATG with myeloablative conditioning regimens may be useful in reducing the risk of acute and chronic GVHD without any deleterious effect on transplant-related mortality, relapse, or leukemia-free survival in children and adolescents with ALL. [ABSTRACT FROM AUTHOR]

To determine whether in vivo T-cell depletion, which lowers GVHD, abrogates the antileukemic benefits of myeloablative total body irradiation-based conditioning and unrelated donor transplantation, in the present study, we analyzed 715 children with acute lymphoblastic leukemia. Patients were grouped for analysis according to whether conditioning included antithymocyte globulin (ATG; n = 191) or alemtuzumab (n = 132) and no in vivo T-cell depletion (n = 392). The median follow-up time was 3.5 years for the ATG group and 5 years for the alemtuzumab and T cell-replete groups. Using Cox regression analysis, we compared transplantation outcomes between groups. Compared with no T-cell depletion, grade 2-4 acute and chronic GVHD rates were significantly lower after in vivo T-cell depletion with ATG (relative risk [RR] = 0.66; P = .005 and RR = 0.55; P < .0001, respectively) or alemtuzumab (RR = 0.09; P < .003 and RR = 0.21; P < .0001, respectively). Despite lower GVHD rates after in vivo T-cell depletion, nonrelapse mortality, relapse, overall survival, and leukemia-free survival (LFS) did not differ significantly among the treatment groups. The 3-year probabilities of LFS after ATG-containing, alemtuzumab-containing, and T cell-replete transplantations were 43%, 49%, and 46%, respectively. These data suggest that in vivo T-cell depletion lowers GVHD without compromising LFS among children with acute lymphoblastic leukemia who are undergoing unrelated donor transplantation with myeloablative total body irradiation-based regimens. [ABSTRACT FROM AUTHOR]

How deep mantle processes affected plate interactions and the dynamics of deformation on both sides of the Paleo-Pacific has been a first order scientific challenge. The ubiquitous Early Cretaceous multiphase tectonic extensional structures in eastern Eurasia (EE) show marked contrasts to the episodic compressional structures in western North America (WNA), which provides convincing arguments linking deep and shallow tectonic processes. Recent studies on Early Cretaceous tectonics in EE have shown that the continent is characterized by multiple phase of tectonic extension and weak compression, forming extensional structures in several major provinces in a vast area of ca. 3000 km × 3000 km. The peak tectonic extension occurred at 135–120 Ma, in addition to extensional episodes at pre- (160–145 Ma) and post-peak (120 Ma-) stages. Kinematic analysis reveals an identical NW-SE-oriented tectonic extension field for their formation. In addition, synextensional magmatism sourced from ancient and juvenile crust or lithospheric mantle was episodically active and peaked at ca. 160, 125 and 100–80 Ma, respectively. Particularly, a magmatic flare-up of extensional origin occurred at 125 ± 5 Ma in eastern China. In contrast, the WNA Cordillera displays a prolonged and episodic tectonic compression beginning ~170 Ma (Jurassic). Tectonic deformation involved the Nevadan, Sevier and Laramide orogenies from ca. 175 Ma, 125 Ma and 80 Ma, respectively, to form the Cordillera orogenic system. During the Nevadan orogeny intensive plate convergence from 154 to 150 Ma contributed to continental arc magmatism. The Sevier orogen is characterized by thin-skinned thrust sheets while the Laramide is dominated by shallow slab dip oceanic subduction and basement-core uplifts of Archean crust in the foreland. Significant sinistral strike-slip shearing at ~140–125 Ma is documented in the Early Cretaceous. Widespread crustal shortening and emplacement of major batholiths (magmatic flare-up) were contemporaneous with accretion of the high pressure-low temperature (blueschist) Franciscan Complex at ca. 125–100 Ma during the Sevier orogeny. The EE extensional provinces constitute part of the retreating (Paleo-) Pacific-Eurasia subduction system, while crustal shortening along the WNA was resulted from the advancing Farallon-North America subduction system. Stratified mantle convection is needed, however, when taking the tectonic evolution of the continental margins and the mid-ocean range as an integral system of the evolving globe. Shallow-mantle convection contributed to subduction of oceanic plates, which resulted in Andean-type subduction zones on both sides of the Ocean at the early stage of subduction. Possibly from 160 Ma on, eastward deep mantle flow occurred, which induced migration of the shallow mantle convection systems. As a result, the west-dipping Paleo-Pacific slabs became steepened, stagnated and subsequently folded in the mantle transition zone, while the shallow part of the east-dipping Farallon slab became flattened, and its deep part subsequently penetrated the transition zone. The resultant eastward migration of shallow mantle convection systems continuously drove the retreating subduction of the Paleo-Pacific (or Izanagi) plate, advancing subduction of the Farallon plate and eastward migration of the Paleo-Pacific-Farallon mid-ocean ridge. As a consequence, multiple phases of tectonic extension dominated the deformation of the continental interior in EE and episodic compressional tectono-magmatic activities occurred along the continental margin of WNA. • Early Cretaceous structures in eastern Eurasia (EE) by multiphase tectonic extension • Early Cretaceous episodic compressional structures in western North America (WNA) • EE extension related to retreating (Paleo-) Pacific-Eurasia subduction system • WNA crustal shortening from advancing Farallon-North America subduction system • Migration of the shallow mantle convection systems attributed to deep mantle convection [ABSTRACT FROM AUTHOR]

In the major zones of crustal deformation within the Arabia-Sinai-Nubia plates, the interactions between the Sinai-Negev Shear Zone (SNSZ) and the Dead Sea Fault system (DSF) shed light on the interplay between neighboring, large-scale fault systems.The SNSZ is composed of several ~ E -W to ENE–WSW trending, mainly normal and dextral, strike-slip faults that are tens to hundreds of kilometers long. These faults form a ~ 120 km wide shear zone in the Sinai sub-plate. On reaching the plate-bounding Dead Sea Fault system (DSF), individual lineaments of the SNSZ are observed in the Arabian plate offset left-laterally by 105 km, which is the total estimated offset of the DSF. In this contribution, we review the geologic setting of the SNSZ and its complex relations with the DSF in light of newly obtained age-strain analyses. For this we use in-situ U- Pb geochronology in conjunction with twin analysis of syn -faulting calcite from both systems. The results indicate that the deformation along the SNSZ initiated in the Campanian-Maastrichtian or earlier, as the oldest dates are 73–71 Ma. The main phase of fault activity began in the late Oligocene – early Miocene (27–22 Ma) as documented by numerous dates that were obtained along several lineaments of the SNSZ. The activity continued until ~10 Ma, after which no direct ages have been obtained. The dominant phase of activity along the SNSZ at 27–22 Ma preceded the timing of initiation of lateral faulting along the DSF at ~20–18 Ma by a few Myr. For the overlapping period of activity between 20 and 10 Ma, episodes of fault activity along the SNSZ followed by episodes of fault activity along the DSF. Moreover, dominant episodes of activity along one fault system were associated with a decrease in activity along the other system. The temporal relations between the SNSZ and DSF highlight the possibility that these fault systems are mechanically interrelated, but the exact mechanism for this fault interaction needs further study. We consider the paleo-strain (or paleo-stress) that control the evolution and style of the SNSZ and assess them at the central Sinai-Negev region during the Cenozoic. We show that the formation of new plate boundaries at the region, i.e., the Red Sea - Suez rift and the DSF, affected the strain field within the SNSZ. The proximity of the two systems indicates that the DSF-related stress originated within the SNSZ and possibly caused structural and style changes in the latter system. Syn -faulting calcite-twins analyses within the SNSZ show pronounced spatial and temporal variations of the principal strain directions between and along individual faults. This observation demonstrates that the imposed stress within the central Sinai-Negev were not uniform over time. The high angle (>70o) between the traces of the SNSZ and the direction of the DSF-related maximum shortening likely suppressed the dextral motion along the SNSZ post-20 Ma. Field evidence, U-Pb dates, and recent seismicity shows that the current SNSZ is a long-lived structure that has been active during the Miocene alongside the dominantly DSF and may still be sporadically active today. • Tectonics of the ~120 km wide Sinai-Negev Shear Zone (SNSZ) is reviewed & analyzed. • U-Pb dates of syn -faulting calcites constrain the timing of the SNSZ activity. • Deformation initiated at 73–71 Ma with a main phase of activity between 27 and 22 Ma. • Temporal relations between the SNSZ and Dead Sea Fault (DSF) are presented. • Formation of the Suez rift and the DSF affected the stress field within the SNSZ. [ABSTRACT FROM AUTHOR]

High risk or relapsed pediatric acute myeloid leukemia (AML) is potentially curable with allogeneic hematopoietic stem cell transplantation (HSCT). Significant improvements have been made with supportive care practices, but there are limited HSCT outcome data for pediatric AML patients in the contemporary era. We report retrospective data in 87 pediatric patients with high risk or relapsed AML, who underwent HSCT at a single institution between 2008 and 2018. The median age at time of HSCT was 8 years (range: 0.6-20 years). Forty three patients (49%) were transplanted in CR1, 18 (21%) in CR2, and 26 (30%) with active disease (defined as any evidence of disease at the time of HSCT). Patients were transplanted using matched related (MRD, n=21), matched unrelated (MUD, n=25), mismatched unrelated (MMUD, n=15), haplo-identical (haplo, n=12) or umbilical cord blood (UCB, n=14) grafts. The majority of patients (78/87, 90%) received myeloablative conditioning. MRD and UCB graft recipients did not receive serotherapy. All other graft recipients (n=52) received serotherapy, the majority using an alemtuzumab-based conditioning regimen, 42/52 (81%). Haplo-identical transplants were performed using CD34+ selected grafts. Three-year overall survival (OS) and disease free survival (DFS) for the entire cohort were 52% (95% CI: 41-62%) and 49% (95% CI: 38-59%) respectively. OS differed significantly according to disease status at time of transplant (p=0.018), with 3 year OS: 60%, (95% CI: 43-74%) for those in CR1, 56%, (95% CI: 31-75%) for those in CR2 and 34% (95% CI: 17-52%) for those with active disease. OS differed by donor type (p=0.058). OS was comparable for patients with MRD (71%, 95% CI: 46-86%) and 10/10 MUD (59%, 95% CI: 37-75%) (p=0.67). Patients with alternate donor sources had worse outcomes (MMUD 33%, 95% CI: 10-59%; UCB 43%, 95% CI: 18-66%; Haplo 33%, 95% CI: 10-59%) as compared to MRD (MMUD vs MRD, p=0.042, UCB vs MRD, p=0.046, haplo vs MRD p=0.017). There was a low incidence of Grade III-IV acute GVHD (8%, n=7) and extensive chronic GVHD (9%, n=7) likely secondary to the use of alemtuzumab-based conditioning regimens. The 3-year non-relapse mortality was low at 11% (95% CI: 5-19%). The primary cause of death was relapse, with a 3-year cumulative incidence of relapse of 40%, (95% CI: 30-50%). Patients with active disease at HSCT had significantly higher cumulative incidence of relapse (sHR: 2.42, 95% CI: 1.18-4.95, p=0.016) compared to patients in remission. In the contemporary era, outcomes after allogeneic HSCT are comparable for MRD and 10/10 MUD for pediatric AML. Myeloablative and alemtuzumab based conditioning regimens were well tolerated with low rates of NRM and GVHD. Relapse remains the major cause of treatment failure. Future trials evaluating use of cellular therapies and targeted agents post-HSCT will be needed. [ABSTRACT FROM AUTHOR]

There is no consensus regarding the best donor for children undergoing stem cell transplantation in the absence of a matched related donor (MRD), especially for patients with nonmalignant diseases. The incidence of infections, GvHD, and graft failure remain major problems. Evaluate outcome for patients undergoing UCBT conditioned without serotherapy, which is as an attractive option for these patients because of immediate availability, lower incidence of GvHD, and high probability of adequate cell dose for young patients. From 2008-2019, we performed UCBT in 84 children, median age 10 mo. (range, 2–108 mo.) with: ALL (13), AML (15), MDS (5), SCID (36), IPEX (2), LAD (1), WAS (1), CGD (1), metabolic disorders (4), HLH (2), and hematologic disorders (4). Eleven patients (30%) with malignancies had minimal residual disease present before UCBT. Five patients with AML had chloromas present prior to UCBT. 26 patients with immune deficiencies had persistent infections at transplant. All patients were enrolled on prospective clinical trials. Pts with AML/ MDS/ or nonmalignant disorders received busulfan, cyclophosphamide, and fludarabine; pts with ALL received TBI (12Gy), cyclophosphamide, and fludarabine. No patient was treated with serotherapy. All cord blood units were matched 5 or 6/6 HLA antigens at A, B and allele at DR. Infused cord blood contained median TNC 15 × 107 kg (range, 5.1 – 26.4). All evaluable patients engrafted by day 42. The median time to neutrophil and platelet recovery were 18 days (range, 6-42d) and 35 days (range,22-85d), respectively. All evaluable patients achieved full donor chimerism (defined as > 95% donor cells in peripheral blood by day +42). The overall survival (OS) at 2 years was 75% with a median follow up of 5 years (range: 0.5 – 11yr). The OS for patients with SCID was 92% (33/36) at 2 years with engraftment of all lineages. The cumulative incidence of aGvHD grade II-IV by day 100 was 9% (n=8) with only 3 patients having grade IV. No pt developed cGvHD. Twenty-one patients died, 13/21, 62% died from disease relapse or disease progression. Treatment related mortality occurred for 7 patients; severe GvHD (n=2) and MOF (n=5). No infection related mortality was seen. We conclude that lacking a MRD, UCBT following myeloablative conditioning without serotherapy is an excellent curative option in young children. Our experience highlights minimal treatment related mortality, rapid engraftment, resolutions of antecedent infections, and a low incidence of GvHD. These results translate in a better quality of life for these young patients. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for transfusion-dependent b-thalassemia (TDT). Application of alternative donor HSCT for TDT is more accepted as rates of graft failure (GF) and GVHD decline. Alemtuzumab is a CD52 monoclonal antibody with potent lymphocytic activity that can reduce GVHD risk, though infectious associations have limited its use. We hypothesize that the addition of alemtuzumab to standard myeloablative conditioning in HSCT for TDT will reduce rates of GVHD without affecting engraftment or transplant-related mortality (TRM). We retrospectively reviewed engraftment, GVHD, and survival for TDT patients (pts) who underwent HSCT at Texas Children's Hospital between 2004-2018. All pts received myeloablative conditioning with IV targeted busulfan (AUC of 800-1200 μM per minute), cyclophosphamide 50 mg/kg daily for 4 days, and IV alemtuzumab (5-15kg= 3mg; 15-30kg=5mg; >30kg=10mg) from d -5 through d -2. Pts receiving MUD/MMUD HSCT additionally received fludarabine 30 mg/m2 for 4 days. GVHD prophylaxis included methotrexate (d +1,3,6,11) and a calcineurin inhibitor. Twenty-one consecutive pts underwent MRD (10), MUD (9), or MMUD (2) HSCT with a median age at HSCT of 6.5 yrs (range: 1.5-14.9). Stem cell source consisted of bone marrow (17), peripheral blood (3), MRD umbilical cord and marrow (1). Neutrophil engraftment (ANC>500/ml x 3 d) was achieved in all patients at a median of 19 d (range: 13-29). Median platelet engraftment (platelet > 20,000 × 7 d without transfusion) was 35.5 d (range: 15-123). Median RBC engraftment (Hb >8 g/dL x 7 d without transfusion) was 24 d (range: 10-115). No GF was observed. Poor graft function (PGF) was seen in 2 pts (9.5%) requiring stem cell boost or 2nd HSCT. Overall incidence of acute (grade II-IV) and chronic GVHD (all limited) of 9.5% and 14.2%, respectively. Five-year overall survival was 89.9% with a median follow-up of 3.6 yrs (range: 0-14.4). Two deaths occurred secondary to infections complications in the setting of PGF and GVHD, respectively. Myeloablative conditioning with alemtuzumab minimized the incidence of severe GVHD with good overall survival. GF, GVHD, and TRM rates were improved from previous reports in TDT. PGF in our UD cohort was comparable to previous reports of engraftment complications. The addition of Alemtuzumab is a reasonable strategy to reduce GVHD risk in MRD and UD HSCT for TDT, though durability of engraftment after UD HSCT requires further investigation. [ABSTRACT FROM AUTHOR]

Autoimmune cytopenias (AIC) are a known complication of hematopoietic stem cell transplant that can lead to increased morbidity and mortality. Higher rates of AIC have been reported in patients transplanted for nonmalignant conditions ranging from 19.5%-56% with the highest rate reported in very young infants (≤3 months) with non-malignant diseases who had undergone unrelated cord blood transplants following ablative conditioning with serotherapy. Evaluate incidence of AIC in non-malignant pediatric patients receiving an umbilical cord blood transplant conditioned with a fully ablative regimen without serotherapy. We performed a retrospective chart review of 42 pediatric patients receiving umbilical cord blood transplants (UCBT) for nonmalignant disease from 2009-2017. Indications included: SCID (30), IPEX (2), LAD (1), WAS (1), CGD (1), metabolic disorders (3), HLH (1), and other hematologic disorders (3). All patients received Busulfan, Cyclophosphamide, and Fludarabine without serotherapy. AIC included: Autoimmune hemolytic anemia, defined as clinically significant hemolysis (a drop in hemoglobin >2 g/dL, reticulocytosis) and positive direct antiglobulin test (DAT); Immune thrombocytopenia purpura, defined as presence of antiplatelet antibodies with new thrombocytopenia; and autoimmune neutropenia, defined as presence of anti-neutrophil antibodies and neutropenia <1000 not responsive to GCSF. All patients engrafted after receiving a cord blood unit with a median TNC of 15 × 107 kg (range, 5.1 – 26.4). The median time to neutrophil and platelet recovery were 18 days (range,6-30d) and 35 days (range,22-85d), respectively. All but one evaluable patient achieved full donor chimerism (defined as > 95% donor cells in peripheral blood by day +42). The overall incidence of AIC was 11.9% (n=5/42). For patients transplanted at age ≤3 months old, only 1 patient developed AIC (n=1/16). AIC included: AIHA (n=2), Evan's syndrome (n=2) and AIHA in combination with autoimmune neutropenia (n=1).There was no evidence of isolated ITP. Of note, one patient with leaky SCID who developed AIHA had a history of AIHA prior to transplant. Average time of onset of AICs post-transplant was 4.6 months (range 3.9-5.4 months). Four of the patients who had AICs had leaky SCID. The remaining patient had IPEX. All patients with AIC received UCB matched at 8 and 9 alleles. Mixed donor chimerism was noted in 3 patients at time of development of AIC. We have observed decreased rates of AIC after UCBT in pediatric patients with nonmalignant diseases, particularly in patients transplanted at ≤ 3 months age, which compared favorably to previous reports. We hypothesize that omission of serotherapy after UCBT allows for early T cell recovery perhaps allowing for expansion of regulatory T cells and decreased rates of autoimmunity. [ABSTRACT FROM AUTHOR]

Introduction There is no consensus about the best donor for children with non-malignant disorders in the absence of a matched related donor (MRD). Objectives Evaluate UCBT as an attractive option for these patients because of prompt availability, lower risk of GvHD, and increased cell dose at young ages. Methods From 2008-2017, we performed UCBT in 42 children, median age 5 mo. (range, 2–108 mo.) with: SCID (30), IPEX (2), LAD (1), WAS (1), CGD (1), metabolic disorders (3), HLH (1), and other hematologic disorders (3). 26 patients had persistent infections prior to transplant: PJP (5), fungal (1), RSV (4), Parainfluenza 3 (4), VZV (1), Norovirus (1), CMV (4), Rhinovirus (2), bacterial (4); with 9 patients having pneumonia (20%), and 7 (17%) patients requiring mechanical ventilation prior to transplantation. Thirty-four percent of patients were 6/6 HLA antigen matched, and 66% were one HLA antigen mismatched. All patients were enrolled on a prospective clinical trial using fully ablative busulfan, cyclophosphamide, and fludarabine without serotherapy. The median TNC was 15 × 107 kg (range, 5.1 – 26.4). Results The median time to neutrophil and platelet recovery were 18 days (range,6-30d) and 35 days (range,22-85d), respectively. All but one evaluable patient achieved full donor chimerism (defined as > 95% donor cells in peripheral blood by day +42). The overall survival (OS) at 2 years was 90% (95% CI:77-96%) with a median follow up of 4 years (range: 0.5 – 8.5yr). The OS for patients with SCID was 93.3% (28/30) at 2 years with engraftment of all lineages. Four patients died, from severe GvHD (n=2) and MOF (n=2). The cumulative incidence of aGvHD grade II-IV by day 100 was 16% (n=7) with only 2 (IV). No cGvHD has been seen. All but three patients developed engraftment syndrome at a median time of 19 days, (range: 6-46) successfully treated with steroids. All patients with viral infections at the time of transplant cleared infection at a median time of 54 days (range, 44-91). ELISpot analysis after resolution of infections showed T cell responses against the pertinent viruses. The median absolute CD3 (x10^6/L) counts by day 42 and 60 were 361 and 733; respectively. The median absolute CD3CD4 counts by day 42 and 60, were 296, and 506; respectively. The median absolute CD3CD8 absolute count by day 42 and 60, were 71 and 114; respectively. IVIg was discontinued at a median 138 days; (range: 52-769d). Median time to begin immunizations was 11 months, (range: 8-26). All evaluable patients have had correction of their immune or metabolic defect including adequate B cell function in SCID patients. Conclusion We conclude that in the absence of a MRD, UCBT following myeloablative conditioning without serotherapy is an excellent curative option in children with non-malignant disorders, producing rapid engraftment, prompt functional immune-reconstitution, and a low incidence of GvHD. [ABSTRACT FROM AUTHOR]

Primary Immune Regulatory Disorders (PIRD) are an expanding group of diseases caused by gene defects in several different immune pathways, such as regulatory T cell function. Patients with PIRD develop clinical manifestations associated with diminished and exaggerated immune responses. Management of these patients is complicated; oftentimes immunosuppressive therapies are insufficient, and patients may require hematopoietic cell transplant (HCT) for treatment. Analysis of HCT data in PIRD patients have previously focused on a single gene defect. This study surveyed transplanted patients with a phenotypic clinical picture consistent with PIRD treated in 33 Primary Immune Deficiency Treatment Consortium centers and European centers. Our data showed that PIRD patients often had immunodeficient and autoimmune features affecting multiple organ systems. Transplantation resulted in resolution of disease manifestations in more than half of the patients with an overall 5-years survival of 67%. This study, the first to encompass disorders across the PIRD spectrum, highlights the need for further research in PIRD management., (Copyright © 2020 Chan, Leiding, Liu, Logan, Burroughs, Allenspach, Skoda-Smith, Uzel, Notarangelo, Slatter, Gennery, Smith, Pai, Jordan, Marsh, Cowan, Dvorak, Craddock, Prockop, Chandrakasan, Kapoor, Buckley, Parikh, Chellapandian, Oshrine, Bednarski, Cooper, Shenoy, Davila Saldana, Forbes, Martinez, Haddad, Shyr, Chen, Sullivan, Heimall, Wright, Bhatia, Cuvelier, Goldman, Meyts, Miller, Seidel, Vander Lugt, Bacchetta, Weinacht, Andolina, Caywood, Chong, de la Morena, Aquino, Shereck, Walter, Dorsey, Seroogy, Griffith, Kohn, Puck, Pulsipher and Torgerson.)

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG , IL2RG , or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4 + and CD4 + CD45RA + cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4 + cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome., (© 2018 by The American Society of Hematology.)