Autologous Hematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: A Real-world Case Series

Objective To examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting. Methods This was a retrospective cohort study of PwMS treated with AHSCT at 2 centers in London, UK, consecutively between 2012 and 2019 who had ≥6 months of follow-up or died at any time. Primary outcomes were survival free of multiple sclerosis (MS) relapses, MRI new lesions, and worsening of Expanded Disability Status Scale (EDSS) score. Adverse events rates were also examined. Results The cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS. At baseline, the median EDSS score was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6–85 months). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of participants at 2 years and in 85% at 4 years. EDSS score progression–free survival (PFS) was 75% at 2 years and 65% at 4 years. Epstein-Barr virus reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplantation-related deaths within 100 days (2.5%), all after fluid overload and cardiac or respiratory failure. Conclusions Efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher. Classification of Evidence This study is rated Class IV because of the uncontrolled, open-label design

Key components of anaphylaxis management plans: consensus findings from a national electronic Delphi study

OBJECTIVES: There is no international consensus on the components of anaphylaxis management plans and responsibility for their design and delivery is contested. We set out to establish consensus among relevant specialist and generalist clinicians on this issue to inform future randomized controlled trials. DESIGN: A two-round electronic Delphi study completed by a 25-person, multidisciplinary expert panel. Participants scored the importance of a range of statements on anaphylaxis management, identified from a systematic review of the literature, on a five-point scale ranging from 'very important' to 'irrelevant'. Consensus was defined a priori as being achieved if 80% or more of panel members rated a statement as 'important' or 'very important' after Round 2. SETTING: Primary and secondary care and academic settings in the UK and Ireland. PARTICIPANTS: Twenty-five medical, nursing and allied health professionals. MAIN OUTCOME MEASURES: Consensus on the key components of anaphylaxis management plans. RESULTS: The response rate was 84% (n = 21) for Round 1 and 96% (n = 24) for Round 2. The key components of emergency care on which consensus was achieved included: awareness of trigger factors (100%); recognition and emergency management of reactions of different severity (100%); and clear information on adrenaline (epinephrine) use (100%). Consensus on longer-term management issues included: clear written guidelines on anaphylaxis management (96%); annual review of plans (87%); and plans that were tailored to individual needs (82%). CONCLUSIONS: This national consensus-building exercise generated widespread agreement that emergency plans need to be simple, clear and generic, making them easy to implement in a crisis. In contrast, long-term plans need to be negotiated between patient/carers and professionals, and tailored to individual needs. The effectiveness of this expert-agreed long-term plan now needs to be evaluated rigorously

Measurement of the muon decay spectrum with the ICARUS liquid Argon TPC

Examples are given which prove the ICARUS detector quality through relevant physics measurements. We study the muon decay energy spectrum from a sample of stopping muon events acquired during the test run of the ICARUS T600 detector. This detector allows the spatial reconstruction of the events with fine granularity, hence, the precise measurement of the range and dE/dx of the muon with high sampling rate. This information is used to compute the calibration factors needed for the full calorimetric reconstruction of the events. The Michel rho parameter is then measured by comparison of the experimental and Monte Carlo simulated muon decay spectra, obtaining rho = 0.72 +/- 0.06(stat.) +/- 0.08(syst.). The energy resolution for electrons below ~50 MeV is finally extracted from the simulated sample, obtaining (Emeas-Emc)/Emc = 11%/sqrt(E[MeV]) + 2%.Comment: 16 pages, 8 figures, LaTex, A4. Some text and 1 figure added. Final version as accepted for publication in The European Physical Journal

Acute Response of Peripheral Blood Cell to Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetic Patient

Autologous nonmyeloablative hematopoietic stem cell transplantation (AHST) was the first therapeutic approach that can improve β cell function in type 1 diabetic (T1D) patients. This study was designed to investigate the potential mechanisms involved.We applied AHST to nine T1D patients diagnosed within six months and analyzed the acute responses in peripheral blood for lymphocyte subpopulation as well as for genomic expression profiling at the six-month follow-up.We found six patients obtained insulin free (IF group) and three remained insulin dependent (ID group); C-peptide production was significantly higher in IF group compared to ID group. The acute responses in lymphocytes at six-month follow-up include declined CD3(+)CD4(+), CD3(+)CD8(+) T cell population and recovered B cell, NK cell population in both groups but with no significant differences between the two groups; most immune-related genes and pathways were up-regulated in peripheral blood mononuclear cell (PBMC) of both groups while none of transcription factors for immune regulatory component were significantly changed; the IF group demonstrated more AHST-modified genetic events than the ID group and distinct pattern of top pathways, co-expression network as well as 'hub' genes (eg, TCF7 and GZMA) were associated with each group.AHST could improve the islet function in newly diagnosed T1D patients and elimination of the islet specific autoreactive T cells might be one of the mechanisms involved; T1D patients responded differently to AHST possibly due to the distinct transcriptional events occurring in PBMC.ClinicalTrials.gov NCT00807651

An in vitro model of early anteroposterior organization during human development.

The body plan of the mammalian embryo is shaped through the process of gastrulation, an early developmental event that transforms an isotropic group of cells into an ensemble of tissues that is ordered with reference to three orthogonal axes1. Although model organisms have provided much insight into this process, we know very little about gastrulation in humans, owing to the difficulty of obtaining embryos at such early stages of development and the ethical and technical restrictions that limit the feasibility of observing gastrulation ex vivo2. Here we show that human embryonic stem cells can be used to generate gastruloids-three-dimensional multicellular aggregates that differentiate to form derivatives of the three germ layers organized spatiotemporally, without additional extra-embryonic tissues. Human gastruloids undergo elongation along an anteroposterior axis, and we use spatial transcriptomics to show that they exhibit patterned gene expression. This includes a signature of somitogenesis that suggests that 72-h human gastruloids show some features of Carnegie-stage-9 embryos3. Our study represents an experimentally tractable model system to reveal and examine human-specific regulatory processes that occur during axial organization in early development

TIA-1 Cytotoxic Granule-Associated RNA Binding Protein Improves the Prognostic Performance of CD8 in Mismatch Repair-Proficient Colorectal Cancer

Evidence suggests a confounding effect of mismatch repair (MMR) status on immune response in colorectal cancer. The identification of innate and adaptive immune cells, that can complement the established prognostic effect of CD8 in MMR-proficient colorectal cancers patients, representing 85% of all cases, has not been performed

Autologous haematopoietic stem cell transplantation and other cellular therapy in multiple sclerosis and immune-mediated neurological diseases : updated guidelines and recommendations from the EBMT autoimmune diseases working party (ADWP) and the joint accreditation committee of EBMT and ISCT (JACIE)

These updated EBMT guidelines review the clinical evidence, registry activity and mechanisms of action of haematopoietic stem cell transplantation (HSCT) in multiple sclerosis (MS) and other immune-mediated neurological diseases and provide recommendations for patient selection, transplant technique, follow-up and future development. The major focus is on autologous HSCT (aHSCT), used in MS for over two decades and currently the fastest growing indication for this treatment in Europe, with increasing evidence to support its use in highly active relapsing remitting MS failing to respond to disease modifying therapies. aHSCT may have a potential role in the treatment of the progressive forms of MS with a significant inflammatory component and other immune-mediated neurological diseases, including chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica, myasthenia gravis and stiff person syndrome. Allogeneic HSCT should only be considered where potential risks are justified. Compared with other immunomodulatory treatments, HSCT is associated with greater short-term risks and requires close interspeciality collaboration between transplant physicians and neurologists with a special interest in these neurological conditions before, during and after treatment in accredited HSCT centres. Other experimental cell therapies are developmental for these diseases and patients should only be treated on clinical trials