Refined HLA-DPB1 mismatch with molecular algorithms predicts outcomes in hematopoietic stem cell transplantation

HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (GVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and the Predicted Indirectly Recognizable HLA Epitopes Score (PS) in a cohort of 1,514 patients receiving hematopoietic stem cell transplants from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and - DQB1 loci. HLA-DPB1 alloimmunity in the graft-versus-host direction, determined by high graft-versus-host ME/PS, was associated with a reduced risk of relapse (hazard ratio [HR]=0.83, P=0.05 for ME) and increased risk of grade 2-4 acute GVHD (HR=1.44, P<0.001 for ME), whereas high host-versus-graft ME/PS was only associated with an increased risk of grade 2-4 acute GVHD (HR=1.26, P=0.004 for ME). Notably, in the permissive mismatch subgroup classified by TCE grouping, high host-versus-graft ME/PS was associated with an increased risk of relapse (HR=1.36, P=0.026 for ME) and grade 2-4 acute GVHD (HR=1.43, P=0.003 for PS-II). Decision curve analysis showed that graftversus- host ME outperformed other models and provided the best clinical net benefit for the modification of acute GVHD prophylaxis regimens in patients with a high risk of developing clinically significant acute GVHD. In conclusion, molecular assessment of HLA-DPB1 mismatch enables separate prediction of host-versus-graft or graft-versus-host alloresponse quantitatively and allows further refinement of HLA-DPB1 permissiveness as defined by conventional TCE grouping

Paleohydrology of extraordinary floods along the Swakop River at the margin of the Namib Desert and their paleoclimate implications

The Swakop River is a major ephemeral river (drainage basin area about 30,000 km2) crossing the western Namib Desert. Its hydrology and limited water resources depend on storms and floods. Therefore, the hydrology and flow regime in the Swakop River basin determines the availability of water for human use. In this study we present a millennia-long record of extreme floods, using paleoflood hydrological methods and optically stimulated luminescence (OSL) ages. The record includes 44 large floods ranging in date from the late Pleistocene to the present. The oldest six to eight floods are dated from the late Pleistocene to the mid-Holocene (between 14,900 ± 1700 and 5100 ± 620 years ago), with calculated peak discharges of 550–1280 m3 s−1. Eighteen floods, eleven of which were between 1000 and 1600 m3 s−1, occurred between 740 ± 90 and 190 ± 10 years ago. Additional 17 later floods occurred between about AD 1850 and 1963, with peak discharges between 100 and 1000 m3 s−1. The historical record which partly parallels the latter period recorded 17 large floods during the period 1893–1963. Flood frequency analysis (FFA) of the combined systematically gaged record (1963–2003) and the paleoflood record since AD 1270 (740 ± 90 years, the most complete record), was applied using the maximum likelihood method. A two-component extreme value distribution (TCEV) estimates the 1% annual exceedance probability magnitude, using only the systematic gaged record at 520 m3 s−1. The combined paleoflood, historical, and gage records resulted in a much larger magnitudes for the 1% annual exceedance probability flood magnitude of 1320–1350 m3 s−1. The 0.1% annual exceedance probability magnitude is estimated at 770 m3 s−1 and 2100–2150 m3 s−1, respectively. The hydroclimatic interpretation of this paleoflood record is complex, due to the discontinuity of the record. During the late Holocene, our flood data show three intervals differing in their flood regime: (1) 1280 ± 80 to 740 ± 90 years BP, with one extraordinary flood (>200 m3 s−1) about every 180 years; (2) 740 ± 90 to 200 ± 45 14C years BP, with one large flood per 80 years; and (3) 200 ± 45 14C years BP to AD1963, with one large flood per 7 years. Interval 2 represents large floods, probably related to the transition from a drier climate to the colder and probably wetter climate of the Little Ice Age (LIA). The third period relates to the end of the LIA and to a wetter period of the 19th and early 20th centuries in which more rainfall in the Kalahari and Namib Deserts and many historical floods were documented. The presence of three distinct calcretes rich in calcified rhizoliths at one of the sites, two of which were dated by OSL to 13.2 ± 1.9 ka and 8.8 ± 1.0 ka, indicates, at least locally, higher moisture availability than in the current semiarid climate; the presence of denser vegetation can be associated with increased groundwater seepage and wetter climatic conditions.The research was funded by the 6th Framework of the European Commission through the WADE project “Floodwater Recharge of Alluvial Aquifers in Dryland Environments” (contract GOCE-CT-2003-506680).Peer reviewe

Characteristics and Outcomes of Stem Cell Transplant Patients during the COVID-19 Era: A Systematic Review and Meta-Analysis

This systematic review and meta-analysis aims to identify the outcomes of stem cell transplant (SCT) patients during the COVID-19 era. Pooled event rates (PER) were calculated, and meta-regression was performed. A random effects model was utilized. In total, 36 eligible studies were included out of 290. The PER of COVID-19-related deaths and COVID-19-related hospital admissions were 21.1% and 55.2%, respectively. The PER of the use of hydroxychloroquine was 53.27%, of the receipt of immunosuppression it was 39.4%, and of the use of antivirals, antibiotics, and steroids it was 71.61%, 37.94%, and 18.46%, respectively. The PER of the time elapsed until COVID-19 infection after SCT of more than 6 months was 85.3%. The PER of fever, respiratory symptoms, and gastrointestinal symptoms were 70.9, 76.1, and 19.3%, respectively. The PER of acute and chronic GvHD were 40.2% and 60.9%, respectively. SCT patients are at a higher risk of severe COVID-19 infection and mortality. The use of dexamethasone improves the survival of hospitalized SCT patients with moderate to severe COVID-19 requiring supplemental oxygen or ventilation. The SCT patient group is a heterogeneous group with varying characteristics. The quality of reporting on these patients when infected with COVID-19 is not uniform and further prospective or registry studies are needed to better guide clinical care in this unique setting

Frequency of boulders transport during large floods in hyperarid areas using paleoflood analysis: an example from the Negev desert, Israel

Tuesday, 12 October 2021Direct measurements of boulder entrainment in desert wadis are not available. The 2004 flood (peak discharge - 470 m3 s-1; recurrence interval - 120 years) in the hyperarid, ungauged Nahal Hatzera, ephemeral stream (45 km2 ), in the Negev Desert, transported and deposited 0.85-1.5 m concrete boulders and slabs detached from infrastructure upstream and natural boulders. EDM and drone air-photographic surveys documented the geometry of the study reach and the location of boulders. Analyses of flood slackwater deposits established a paleoflood record of 23 floods with peak discharges of 200-760 m3 s-1, during the last 600 years. 1-D HEC-RAS hydraulic analysis provided water surface profiles, discharges and hydraulics, long the study reach and velocity, shear stress and stream power for each boulder. MAX program and Pearson 3 distribution were used for flood frequency analysis. Most of the concrete boulders were deposited in the sub-critical backwater of channel constrictions where velocities were 1.5-2.1 m s1. The largest boulders were deposited in super-critical flow where velocity was 8-9.2 m s-1. The alluvial channel enables to transport these concrete boulders, reflecting the unstable, active sandy layer of the channel bed over which the boulders moved. The maximum flood shear stress and stream power characterize medium-large floods with return period of 20-120 years and not for the largest floods, as expected. Boulders <2.1 m and weighing <15 tonnes can be transported at least once in 120 years. The shear stress and stream power indicate that the moderate-large floods are the most geomorphically effective floods rather than the largest floods in Nahal Hatzera basin. Nevertheless, the 'geomorphic effectiveness' of the 2004 flood ¿ a typical desert flash flood, was small based on the minor changes along the channel and banks indicating that their resistance thresholds were not exceeded and energy expenditure was mainly on boulders entrainment and transport

Frequency of boulders transport during large floods in hyperarid areas using paleoflood analysis – An example from the Negev Desert, Israel

Direct measurements of boulder entrainment in desert wadis are not available. The 2004 flood (peak discharge – 470 m s; recurrence interval – 120 years) in the hyperarid, ungauged Nahal Hatzera ephemeral stream (45 km), transported and deposited 0.85–2.1 m concrete boulders and slabs detached from infrastructure upstream and natural boulders. EDM and drone air-photographic surveys documented the geometry of the study reach and the location of boulders. Analyses of flood slackwater deposits established a paleoflood record of 23 floods with peak discharges of 200–760 m s, during the last 600 years. 1-D HEC-RAS hydraulic analysis provided water surface profiles, discharges and hydraulics, along the study reach and velocity, shear stress and stream power for each boulder. MAX program and Pearson 3 distribution were used for flood frequency analysis. Most of the concrete boulders were deposited in the sub-critical backwater of channel constrictions where velocities were 1.5–2.1 m s. The largest boulders were deposited in super-critical flow where velocity was 8–9.2 m s. The alluvial channel enabled to transport these concrete boulders, reflecting the unstable, active sandy layer of the channel bed over which the boulders moved. The maximum flood shear stress and stream power characterize medium-large floods with return period of 20–120 years and not for the largest floods, as expected. Boulders about 2.1 m and weighing about 15 t can be transported at least once in 120 years. The shear stress and stream power indicate that the moderate-large floods are the most geomorphically effective floods rather than the largest floods in Nahal Hatzera basin. Nevertheless, the ‘geomorphic effectiveness’ of the 2004 flood – a typical desert flash flood with high peak and short duration, was small based on the minor changes along the channel and banks indicating that their resistance thresholds were not exceeded and energy expenditure was mainly on boulders entrainment and transport.The authors wish to thank the Royal Geographical Society Thesiger-Oman International Fellowship UK, for fund no. THES03/16, to P.A

Frequency of boulders transport during large floods in hyperarid areas using paleoflood analysis – An example from the Negev Desert, Israel

Direct measurements of boulder entrainment in desert wadis are not available. Also, estimating the hydraulic conditions and frequency of natural boulders transport is difficult because their presence cannot be related to their arrival date, discharge or any other hydraulic parameter. The 2004 flood (peak discharge of 470 m3 s-1; recurrence interval &gt;100 years) in the ungauged Nahal Hatzera ephemeral stream (45 km2), transported and deposited concrete boulders and slabs detached from infrastructure upstream as well as natural boulders, 0.85-1.5 m in size, at the outlet of the Makhtesh Hatzera Erosion Cirque (MHEC). Geometrical survey and a drone air-photographic survey documented the geometry of the study reach and the location of boulders. Accumulations and analyses of flood slackwater deposits along the study reach established a paleoflood record of 23 floods with peak discharges of 200-760 m3 s-1 during the last 600 years (radiocarbon ages). Step back-water hydraulic analysis using the 1-D HEC-RAS program, provided water surface profiles to show the hydraulics along the study reach and assigned a peak discharge to the 2004 flood using the clear high water marks of the flood, as well as to the paleoflood-related sedimentary units. The hydraulic program also provided velocity, shear stress and stream power for each boulder at its specific location along the study reach and within the cross section. The Max program was used for flood frequency analysis (FFA) of the paleoflood record. The results indicate that most of the concrete boulders were deposited in the sub-critical backwater of channel constrictions where velocities were 1.5-2.1 m s-1. The largest boulders, were deposited in super-critical flow where velocity was 8-9.2 m s-1. For the sandy alluvial bed of the Nahal Hatzera channel, maximum shear stresses of 250-900 N m-2 are available to transport a range of concrete boulders sizes (0.85-1.5 m), reflecting the unstable, active sandy layer of the channel bed over which the boulders moved. The mobile boulders probably were deposited on the falling limb of the flood and actually represent conditions of dis-entrainment. The FFA analysis and resulting peak discharges provide maximum depositional hydraulic values for return periods of 10-1000 years: velocities 7.1-9.8 m s-1, shear stress - 310-507 N m-2 and stream power - 2500-4972 N m-1 s-1. The frequency of the 2004 flood, based on the FFA, indicates that boulders up to 2.1 m and weighing up to 15 tonnes can be transported at least once in 120 years. The geomorphic effectivity of this typical desert flash flood was small based on it's qualitative properties - high peak, short duration and the small visible changes along the course of the channel and banks indicating that surface and channel resistance thresholds were not exceeded

Donor selection for KIR alloreactivity is associated with superior survival in haploidentical transplant with PTCy

With the continuous increase in the use of haploidentical donors for transplantation, the selection of donors becomes increasingly important. Haploidentical donors have been selected primarily based on clinical characteristics, while the effects of killer cell immunoglobulin-like receptors (KIRs) on outcomes of haploidentical-hematopoietic stem cell transplantation (haplo-HSCT) with post-transplant cyclophosphamide (PTCy) remain inconclusive. The present study aimed to thoroughly evaluate the effect of KIRs and binding ligands assessed by various models, in addition to other patient/donor variables, on clinical outcomes in haplo-HSCT. In a cohort of 354 patients undergoing their first haplo-HSCT, we found that a higher Count Functional inhibitory KIR score (CF-iKIR) was associated with improved progression-free survival (adjusted hazard ratio [HR], 0.71; P = .029) and overall survival (OS) (HR, 0.66; P = .016), while none of the other models predicted for survival in these patients. Moreover, using exploratory classification and regression tree analysis, we found that donor age &lt;58 years combined with cytomegalovirus-nonreactive recipient was associated with the best OS, whereas donor age &gt;58 years was associated with the worst OS. In the rest of our cohort (80%), cytomegalovirus-reactive recipients with a donor &lt;58 years old, a higher CF-iKIR was associated with superior OS. The 3-year OS rates were 73.9%, 54.1% (HR, 1.84; P = .044), 44.5% (HR, 2.01; P = .003), and 18.5% (HR, 5.44; P &lt;.001) in the best, better, poor, and worse donor groups, respectively. Our results suggest that KIR alloreactivity assessed by CF-iKIR score can help optimize donor selection in haplo-HSCT

SIRPα Mismatch Is Associated With Relapse Protection and Chronic Graft-Versus-Host Disease After Related Hematopoietic Stem Cell Transplantation for Lymphoid Malignancies

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematologic malignancies. Alloreactivity after HSCT is known to be mediated by adaptive immune cells expressing rearranging receptors. Recent studies demonstrated that the innate immune system could likewise sense the non-self signals and subsequently enhance the alloimmune response. We recently demonstrated that the donor/recipient mismatch of signal regulatory protein α (SIRPα), an immunoglobulin receptor exclusively expressed on innate cells, is associated with a higher risk of cGVHD and relapse protection in a cohort of acute myeloid leukemia patients who underwent allo-HSCT. Whether these effects also occur in other hematologic malignancies remains unclear. In the present study, we compared outcomes by SIRPα match status in a cohort of 310 patients who received allo-HSCT from an HLA matched-related donor for the treatment of lymphoid malignancies. Multivariable analysis showed that SIRPα mismatch was associated with a significantly higher rate of cGVHD (hazard ratio [HR] 1.8, P= .002), cGVHD requiring systemic immunosuppressive therapy (HR 1.9, P= .005), a lower rate of disease progression (HR 0.5, P= .003) and improved progression-free survival (HR 0.5, P= .001). Notably, the effects of SIRPα mismatch were observed only in the patients who achieved &gt;95% of donor T-cell chimerism. The mismatch in SIRPα is associated with favorable relapse protection and concurrently increased risk of cGVHD in patients who undergo allo-HSCT for lymphoid malignancies, and the optimal donor could be selected based on the finding of the study to mitigate the risk of GVHD and relapse

Mismatch in SIRPα, a regulatory protein in innate immunity, is associated with chronic GVHD in hematopoietic stem cell transplantation

Recent compelling evidence showed that innate immune effector cells could recognize allogeneic grafts and prime an adaptive immune response. Signal regulatory protein α (SIRPα) is an immunoglobulin superfamily receptor that is expressed on myeloid cells; the interaction between SIRPα and its ubiquitously expressed ligand CD47 elicits an inhibitory signal that suppresses macrophage phagocytic function. Additional studies showed that donor-recipient mismatch in SIRPα variants might activate monocytic allorecognition, possibly as the result of non-self SIRPα-CD47 interaction. However, the frequency of SIRPα variation and its role in hematopoietic stem cell transplantation (HSCT) remains unexplored. We studied 350 patients with acute myeloid leukemia/myelodysplastic syndrome who underwent HLA-matched related HSCT and found that SIRPα allelic mismatches were present in 39% of transplantation pairs. SIRPα variant mismatch was associated with a significantly higher rate of chronic graft-versus-host disease (GVHD; hazard ratio [HR], 1.5; P = .03), especially de novo chronic GVHD (HR, 2.0; P = .01), after adjusting for other predictors. Those with mismatched SIRPα had a lower relapse rate (HR, 0.6; P = .05) and significantly longer relapse-free survival (RFS; HR, 0.6; P = .04). Notably, the effect of SIRPα variant mismatch on relapse protection was most pronounced early after HSCT and in patients who were not in remission at HSCT (cumulative incidence, 73% vs 54%; HR, 0.5; P = .01). These findings show that SIRPα variant mismatch is associated with HSCT outcomes, possibly owing to innate allorecognition. SIRPα variant matching could provide valuable information for donor selection and risk stratification in HSCT

Frontline treatment with the combination obinutuzumab ± chlorambucil for chronic lymphocytic leukemia outside clinical trials: Results of a multinational, multicenter study by ERIC and the Israeli CLL study group

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a “real-world” setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a “real-world” setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.Fil: Herishanu, Yair. Universitat Tel Aviv; IsraelFil: Shaulov, Adir. Hadassah Hebrew University Medical Center; IsraelFil: Fineman, Riva. Rambam Health Care Campus; IsraelFil: Basik Kinda, Sandra. University Hospital Centre Zagreb; CroaciaFil: Aviv, Ariel. Technion - Israel Institute of Technology; IsraelFil: Wasik Szczepanek, Ewa. Medical University of Lublin; PoloniaFil: Jaksic, Ozren. Dubrava University Hospital, Zagreb; CroaciaFil: Zdrenghea, Mihnea. Luliu Hatieganu University Of Medicine And Pharmacy; RumaniaFil: Greenbaum, Uri. oroka University Medical Center; Israel. Ben Gurion University; IsraelFil: Mandac, Inga. Clinical Hospital Merkur; CroaciaFil: Simkovic, Martin. University Hospital And Medical School Hradec Kralove; República ChecaFil: Morawska, Marta. St. John's Cancer Center; PoloniaFil: Benjamini, Ohad. Chaim Sheba Medical Center, Ramat Gan; IsraelFil: Spacek, Martin. Charles University And General Hospital In Prague; República ChecaFil: Nemets, Anatoly. Barzilai University Medical Center; IsraelFil: Bairey, Osnat. Universitat Tel Aviv; IsraelFil: Trentin, Livio. Università di Padova; ItaliaFil: Ruchlemer, Rosa. Shaare Zedek Medical Center; IsraelFil: Laurenti, Luca. Fondazione Policlinico Universitario Agostino Gemelli; ItaliaFil: Ciocan, Oana Stanca. Coltea Clinical Hospital; RumaniaFil: Doubek, Michael. University Hospital Brno; República Checa. Masaryk University; República ChecaFil: Shvidel, Lev. The Hebrew University of Jerusalem; IsraelFil: Dali, Nagib. Ziv Medical Center; IsraelFil: Mirás, Fátima. Hospital 12 de Octubre; EspañaFil: De Meûter, Anne. Institut Jules Bordet; BélgicaFil: Dimou, María. Laikon Hospital; GreciaFil: Mauro, Francesca R.. Università degli Studi di Roma "La Sapienza"; ItaliaFil: Coscia, Marta. Università di Torino; ItaliaFil: Bumbea, Horia. Emergency University Clinical Hospital; RumaniaFil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin