Sequential vs myeloablative vs reduced intensity conditioning for patients with myelodysplastic syndromes with an excess of blasts at time of allogeneic haematopoietic cell transplantation: a retrospective study by the chronic malignancies working party of the EBMT.

The optimal conditioning for patients with higher risk MDS receiving potentially curative allogeneic haematopoietic stem cell transplant(allo-HCT) remains to be defined. This is particularly the case for patients with excess of blasts at time of allo-HCT. Sequential (Seq) conditioning, whereby chemotherapy is followed rapidly by transplant conditioning, offers an opportunity to decrease disease burden, potentially improving outcomes allo-HCT outcomes. Herein we present the only analysis comparing Seq to myeloablative (MAC) and reduced intensity conditioning (RIC) specifically focussed on MDS patients with excess of blasts at allo-HCT. 303 patients were identified in the EBMT registry, receiving RIC (n = 158), Seq (n = 105), and MAC (n = 40). Median follow-up was 67.2 months and median age at allo-HCT was 59.5 years (IQR 53.5-65.6). For the entire cohort, 3 y overall survival (OS) was 50% (95% CI 45-56%) and relapse free survival (RFS) 45% (95% CI 40-51%). No significant differences in OS (log-rank p = 0.13) and RFS (log-rank p = 0.18) were observed between conditioning protocols. On multivariable analysis, lower performance status, worse IPSS-R cytogenetics, sibling donor (compared to 8/8 MUD) and ≥20% blasts at allo-HCT were associated with worse outcomes. In conclusion, the Seq protocol did little to influence the outcome in this high-risk group of patients, with outcomes mostly determined by baseline disease risk and patient characteristics such as performance status.

Revealing Charge Carrier Mobility and Defect Densities in Metal Halide Perovskites via Space-Charge-Limited Current Measurements.

Space-charge-limited current (SCLC) measurements have been widely used to study the charge carrier mobility and trap density in semiconductors. However, their applicability to metal halide perovskites is not straightforward, due to the mixed ionic and electronic nature of these materials. Here, we discuss the pitfalls of SCLC for perovskite semiconductors, and especially the effect of mobile ions. We show, using drift-diffusion (DD) simulations, that the ions strongly affect the measurement and that the usual analysis and interpretation of SCLC need to be refined. We highlight that the trap density and mobility cannot be directly quantified using classical methods. We discuss the advantages of pulsed SCLC for obtaining reliable data with minimal influence of the ionic motion. We then show that fitting the pulsed SCLC with DD modeling is a reliable method for extracting mobility, trap, and ion densities simultaneously. As a proof of concept, we obtain a trap density of 1.3 × 1013 cm-3, an ion density of 1.1 × 1013 cm-3, and a mobility of 13 cm2 V-1 s-1 for a MAPbBr3 single crystal.

Trends in allogeneic haematopoietic cell transplantation for myelofibrosis in Europe between 1995 and 2018: a CMWP of EBMT retrospective analysis.

We performed a retrospective assessment of patient- and transplant-specific characteristics and outcomes for 4142 patients undergoing allogeneic haematopoietic cell transplant for myelofibrosis between 1995 and 2018 across 278 centres. Activity increased steadily across the four analysed eras (<2006, 2006-2010, 2011-2014 and 2015-2018). Median recipient age increased over time between the earliest and most recent cohort (49.4 years (range, 20.1-68) versus 59.3 years (range, 18.1-78.1). Increasing number of patients with a Karnofsky performance status <90 underwent transplant over time. Increased utilisation of matched unrelated donors was apparent (<2006, 22.5% versus 2015-18, 45.2%; p < 0.001). Decreased use of myeloablative conditioning, increased use of busulphan-based platforms and anti-thymocyte globulin was evident. Of note, rates of acute (a)GVHD grade II-IV by day +100 decreased over time (p = 0.027) as did rates of chronic (c) GVHD, predominantly extensive cGVHD (<2006, 36% (31-41%) versus 2015-18, 23% (21-25%); p = 0.001). Overall, significant factors associated with worse overall survival and non-relapse mortality (NRM) remained older age, use of donors other than matched sibling, recipient CMV seropositivity and a lower Karnofsky performance status (<90). Multivariable analysis demonstrated improvements in overall survival and reductions in relapse risk over time with stable NRM rates despite increasing numbers of older, less fit patients and use of unrelated donors.

An international survey on the management of patients receiving CAR T-cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT.

PURPOSE OF THE STUDY: Two chimeric antigen receptor (CAR) T-cell therapies - Tisagenlecleucel (Kymriah™) and Axicabtagene ciloleucel (Yescarta™) - have been approved for commercial use. In order to inform forthcoming EBMT guidelines on the management of adults and children undergoing autologous CAR T-cell therapy, we undertook a survey of experienced clinicians. METHODS: An online survey with a dual focus on (1) 'real world' patient eligibility criteria and (2) models of care for patient follow-up was sent to experienced physicians. RESULTS: There were 41 respondents (10 countries) and 93% worked in FACT-JACIE-accredited transplant centres. Most felt that a history of malignancy (57%), prior allo-HCT for B-NHL (78%-81%) and prior treatment with anti-CD19/CD3 BiTE antibodies (76%-86%) do not constitute contra-indications to CAR T therapy. Clinicians were divided as to whether CNS involvement represented an exclusion criterion. There was agreement that patients with viral infections (HIV, Hepatitis B or Hepatitis C) are not eligible. There is no common model of care for long-term follow-up. Most respondents believed that patients should attend the hospital two (43%) to three (33%) times weekly during the first month following discharge. A majority (69%) of respondents work in centres where there is an MDT meeting with a specific focus on follow-up following CAR T Therapy. Follow-up care is currently delivered either in HCT or haematology-oncology outpatient clinics. CONCLUSION: The responses reveal wide variation in perceived patient eligibility criteria and highlight the need for consensus guidelines. The findings also illustrate the embryonic nature of current follow-up arrangements.

Active and latent ovine herpesvirus-2 (OvHV-2) infection in a herd of captive white-tailed deer (Odocoileus virginianus).

Malignant catarrhal fever (MCF) is the clinical manifestation of infection of certain ruminant species with one of a group of pathogenic gammaherpesviruses known as MCF viruses. Cattle and numerous exotic ruminant species are susceptible to clinical disease that may be sporadic or occasionally epidemic in nature. The most common MCF virus worldwide is ovine herpesvirus (OvHV)-2. Reservoir hosts such as sheep, carry and excrete OvHV-2, but do not develop clinical signs, while clinically susceptible species develop severe and often fatal disease. The existence of latent infection in clinically susceptible hosts is poorly understood, but is documented in some ruminant species. Twenty-six animals from a captive herd of white-tailed deer (Odocoileus virginianus) died and were examined from October 2006 to December 2010. Fifteen of these animals (58%) showed clinical signs and gross and microscopical lesions consistent with MCF, while 11 (42%) did not. Polymerase chain reaction (PCR) amplification yielded product consistent with OvHV-2 DNA in samples of spleen from all 26 deer. To examine the possibility of latent infection in this herd, peripheral blood mononuclear cells were examined by PCR for OvHV-2 DNA, and the test was positive in 23/32 (72%) clinically normal deer. Archived serum samples were used to examine the history of MCF exposure in the herd using a competitive enzyme-linked immunosorbent assay, which demonstrated that 10/40 (25%) deer tested had MCF viral antibodies, with nine deer being seropositive over multiple years. Combined with previous observations in deer and other species, these results suggest the existence of latent infection of white-tailed deer with OvHV-2.

Review of idiopathic eosinophilic meningitis in dogs and cats, with a detailed description of two recent cases in dogs.

Eosinophilic meningoencephalitis (EME) has been described in various species of animals and in humans. In dogs it has been associated with protozoal infections, cuterebral myiasis and various other aetiologies. Ten cases of idiopathic eosinophilic meningoencephalitis have been reported in dogs and one in a cat where the origin was uncertain or unknown. The dogs were all males, of various breeds but with a predominance of Golden Retrievers and Rottweilers; they generally had a young age of onset. Two cases with no apparent underlying aetiology were diagnosed on post mortem examination. The 18-month-old, male Boerboel presented with sudden onset of cerebellar ataxia, as well as various asymmetrical cranial nerve deficits of 2 weeks' duration and without progression. Haematology revealed a peripheral eosinophilia. Necropsy showed extreme generalised congestion especially of the meninges and blood smear and histological sections of various tissues showed intravascular erythrocyte fragmentation with the formation of microcytes. Histopathology revealed severe diffuse cerebrocortical subarachnoidal meningitis and submeningeal encephalitis, the exudate containing variable numbers of eosinophils together with neutrophils and mononuclear cells. There was also deeper white matter and hippocampal multifocal perivascular mononuclear encephalitis and multifocal periventricular malacia, gliosis and phagocytosis of white matter. The cerebellum, brain stem and spinal c showed only mild multifocal oedema or scattered occasional axon and myelin degeneration respectively, with no inflammation. Immunohistochemical staining of central nervous tissue for Toxoplasma gondii failed to show any antigen in the central nervous tissue. Ultrastructure of a single submeningeal suspected parasitic cyst showed it to be chromatin clumping within a neuron nucleus indicating karyorrhexis. Gram stain provided no evidence of an aetiological agent. The 3-year-old Beagle bitch had a Caesarian section after developing a non-responsive inertia 8 days prior to presentation. This animal's clinical signs included status epilepticus seizures unrelated to hypocalcaemia and warranted induction of a barbiturate coma. She died 4 hours later. Post mortem and histopathological findings in the brain were almost identical to those of the Boerboel and she also showed histological evidence of recent active intravascular haemolysis with microcyte formation. Rabies, distemper and Neospora caninum immunohistochemical stains were negative in the brains of both dogs. Immunohistochemical staining of the cerebral and meningeal exudates of the Beagle for T- and B-lymphocyte (CD3 and CD79a) markers showed a predominance of T-lymphocytes with fewer scattered B lymphocytes. A possible allergic response to amoxicillin/clavulanate is considered, as this appeared to be the only feature common to the recent history of both animals. An overview of EME in humans, dogs and cats is given and the previously published cases of idiopathic EME in dogs and the single published cat case are briefly reviewed.

Biological effectiveness of neutrons and pi-mesons in gut, bone, and transplantable tumours.

At the Munich RENT-facility a screening project was performed to define the biological characteristics of a fission neutron beam envisaged for radiotherapy. The quantitative endpoints used were jejunal crypt survival, late rectal stenosis in rats, osseous healing in traumatized rat femur and regrowth delay of murine transplantable tumours. The results obtained in normal tissues (with the possible exception of bone) demonstrate a high RBE, in accordance with the well documented dependence of RBE on neutron energy. The RBE-values measured in tumours after single dose treatment endorsed the high effectiveness, although--as has been the case with other beams--they gave no conclusive evidence of a therapeutic advantage. Nevertheless, the specific beam characteristics, i.e. a high RBE at the surface and a fast decline of the biologically effective depth dose suggest possible advantages of the RENT beam when applied in the treatment of selected superficial tumours.

Iron plaque on roots of Aster tripolium L.: interaction with zinc uptake.

The iron plaque on roots of Aster tripolium L. growing in waterlogged salt marsh soil adsorbed appreciable amounts of Zn and Cu, with maximum Zn/Fe and Cu/Fe ratios of 0.1 When concentrations of Zn or Cu adsorbed in the iron plaque are expressed as mg metal kg-1 FeOOH (assuming that iron plaque consists mainly of FeOOH), the Zn and Cu concentrations of the iron plaque was up to 680 and up to 2000 times higher than in the surrounding sediment, respectively. The Zn concentration in red roots (with iron plaque) was higher than in white roots (without iron plaque). Zn concentrations in field sampled roots were correlated with the amount of Zn on the roots and the Zn concentration in the soil, whereas Cu concentrations in the roots were only significantly correlated to the Cu concentration in the soil. In vitro experiments showed that red roots take up more Zn than white roots. Measurement of Zn uptake by excised roots showed that the uptake of Zn into the xylem fluid was significantly higher in roots with 500-2000 nmol Fe cm-2 on the root surface compared to roots with less than 500 or more than 2000 nmol Fe cm-2 on the root surface. The results indicate that iron plaque enhances uptake of Zn by the roots but may act as a barrier when large amounts of Fe are deposited on the root surface. The role of the iron plaque on roots of salt marsh plants growing in soil contaminated with heavy metals is discussed.