Outcome in haematological patients who develop critical illness has significantly improved over the last two decades, but less so in allogeneic BMT recipients. We prospectively investigated the ...outcome of 44 haematological patients with allogeneic BM or haematopoietic SCT (ABMT/AHSCT) requiring admission to the intensive care unit (ICU) of Ghent University Hospital between January 2000 and December 2007. We related outcome to the cause of critical illness, which was categorized as documented or clinically suspected bacterial infection, non-bacterial infection and non-infectious disease. Mechanical ventilation was required in 32 patients, and 12 patients received renal replacement therapy. Overall ICU-mortality, in-hospital mortality and 6-month mortality rates were 61, 75 and 80%, respectively. Hospital mortality rates in patients with bacterial infection (n=14), non-bacterial infection (n=13) and non-infectious disease (n=17) were 43, 85 and 94% (P=0.003). After adjustment for severity of illness sequential organ failure assessment (SOFA) score, bacterial infection (odds ratio 0.06, 0.01-0.36, P=0.002) was associated with significantly lower odds for hospital mortality. On the basis of our experience, ICU referral of ABMT/AHSCT patients is justifiable, as an acceptable fraction of these patients have longer-term survival. Documented or clinically suspected bacterial infection as the cause of critical illness is associated with better prognosis in comparison with other causes.
Peripheral blood T cells transduced with a tumor-specific T-cell receptor (TCR) face problems of auto-reactivity and lack of efficacy caused by cross-pairing of exogenous and endogenous TCR chains, ...as well as short term in vivo survival due to activation and growth factor-induced differentiation. We here studied an alternative strategy for the efficient generation of naive CD8(+) T cells with a single TCR. TCR-transduced human postnatal thymus-derived and adult mobilized blood-derived hematopoietic progenitor cells (HPCs) were differentiated to CD4(+)CD8(+) double-positive T cells using OP9-Delta-like 1 (OP9-DL1) cultures. Addition of the agonist peptide induced double positive cells to cross-present the peptide, leading, in the absence of co-stimulation, to cell cycle arrest and differentiation into mature CD8(+) T cells. Comprehensive phenotypic, molecular and functional analysis revealed the generation of naive and resting CD8(+) T cells through a process similar to thymic positive selection. These mature T cells show a near complete inhibition of endogenous TCRA and TCRB rearrangements and express high levels of the introduced multimer-reactive TCR. Upon activation, specific cytokine production and efficient killing of tumor cells were induced. Using this strategy, large numbers of high-avidity tumor-specific naive T cells can be generated from readily available HPCs without TCR chain cross-pairing.
Human T lymphocytes can be generated from CD34 progenitor cells from different sources. This can be obtained in an in vivo model wherein human thymic tissue and fetal liver is transplanted in an ...immunodeficient mouse. However, human T cells are also generated in immunodeficient mice without co-transplantation of human thymus or in in vitro hybrid human–mouse fetal thymus organ culture. This shows that xenogeneic mouse thymus tissue supports human T cell differentiation. Finally, human T cells are generated on co-culture with murine stromal cells that express the Delta-like1 ligand for the Notch receptor. How these different environments influence the human T cell repertoire is reviewed and discussed.
Sinonasal malignant neoplasms are uncommon, with an annual incidence of less than 1/100,000. About 80% of these are squamous cell carcinoma. Adenocarcinoma and adenoid cystic carcinoma are next in ...frequency. Lymphoma of the nasal cavity, paranasal sinuses and nasopharynx are rare, constituting less than 5% of all extranodal lymphomas.
A 47-year-old man was referred to our hospital because of severe headache and progressive facial pain. He also complained of right-sided visual acuity. He had a manifest exopthalmia with disturbed eye movements. Nasoscopy showed a large mass with atypical appearance. CT and MRI showed a bilateral ethmoid mass invading the frontal sinuses, the right orbit, the lamina cribrosa and the right frontal cerebral region, and growing posteriorly through the choana. The first biopsies were inconclusive, showing only necrotic cells and purulent inflammation with epithelial elements. A larger biopsy demonstrated a high-grade malignant tumour with necrosis. The differential diagnosis of undifferentiated sinonasal carcinoma, undifferentiated neuro-endocrine tumour or T-cell lymphoma was suggested. In the meantime our patient developed high fever and sudden-onset pancytopenia. Bone marrow punction showed 65% blasts, leading to the diagnosis of AML type M2. He was immediately referred for chemotherapy, but died in intensive care before his first session. The biopsy of the sinonasal mass was diagnosed surprisingly as a natural killer cell lymphoma stage IVB.
Natural killer cell lymphoma is rare in Europe. The simultaneous appearance of a NK-cell lymphoma and acute myelogenous leukemia has, as far as we know, never been described in the English literature before.
Abstract
Background
Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly ...investigated area.
Methods
This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT.
Results
We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases.
Conclusions
These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.
hMPV infection after allo-HCT frequently involves the lower respiratory tract (40%). Proven pulmonary involvement was associated with substantial all-cause mortality rate (21%) at day 30 after hMPV detection, particularly in those with lymphopenia.
To assess the influence of high‐dose chemotherapy and age on the intrinsic capacity of stem cells to generate T cells, CD34+ cells derived from bone marrow used in clinical transplantation were ...evaluated in an in vitro T‐cell assay using a mouse thymic microenvironment. CD34+ cells were sorted from healthy donor and autologous back‐up bone marrow after density gradient centrifugation and depletion for CD1, 3, 4, 7, 8, 19 and glycophorin A using magnetic beads. CD34+ cells were then introduced in day 14–15 fetal SCID mouse thymus lobes by incubation in hanging drops for 48 h. After transfer to gelfoam rafts they were cultured for variable time periods. The lobes were then homogenized in a tissue grinder for flow cytometric analysis gating on human cells. These were evaluated for CD4, CD8, CD3 and HLA‐DR surface expression. 51 samples were analysed and three patterns of T‐cell precursor development could be observed. In pattern A no human cells could be recovered, in pattern B maturation stopped at the CD4+CD8−CD3− pre‐T‐cell stage, and in pattern C maturation to double‐positive CD4+CD8+ thymocytes was reached. In 25 healthy donors under age 40 three showed pattern A, 12 pattern B and 10 pattern C, whereas in 16 healthy donors over the age 40 there were respectively four with A, seven with B and only five with C (P=0.01). In 10 patients who had previously received chemotherapy, none developed pattern C, five pattern B and five pattern A, in contrast to 15/41 pattern C, 19/41 pattern B and 7/41 pattern A in healthy donors. These data suggest an intrinsic loss of T‐cell generation capacity from adult bone marrow stem cells in comparison to reports on stem cells of fetal origin. This loss correlated weakly with age, irrespective of thymic involution, and may be further reduced by prior chemotherapy.
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