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Medicine Jan 2019Metastatic thymic carcinoma in the spine is a rare disease with no standard curative managements yet. The objective of this study is to report a very rare case of spinal... (Review)
Review
RATIONALE
Metastatic thymic carcinoma in the spine is a rare disease with no standard curative managements yet. The objective of this study is to report a very rare case of spinal metastases of thymic carcinoma successfully operated by combination of instrumentation and cement augmentation together with adjuvant treatment. The management of these unique cases has yet to be well-documented.
PATIENT CONCERNS
A 57-year-old man presented with a 6-month history of continuous and progressive back pain. The patient, who had been diagnosed of thymic carcinoma (stage IV B) for 3 years, received surgical treatment of median sternotomy thymectomy, followed by 3 cycles of chemotherapy and 12 cycles of radiotherapy.
DIAGNOSIS
Magnetic resonance imaging (MRI) of spine showed spinal cord compression secondary to the epidural component of the T4 mass, with increased metastatic marrow infiltration of the left T4 vetebral body, which presented as a solid tumor. Post-operative pathology confirmed the diagnosis of spinal metastases of thymic carcinoma.
INTERVENTIONS
The patient underwent exploratory surgery, circumferential spinal cord decompression, cement augmentation and a stabilization procedure via a posterior approach.
OUTCOMES
The patient's neurological deficits improved significantly after the surgery, and the postoperative period was uneventful at the 3-month follow-up visit. There were no other complications associated with the operation during the follow-up period.
LESSONS
Taken together, the lesion's clinical features, imaging results, and pathological characteristics are unique. Combined efforts of specialists from orthopedics, neurosurgery, thoracic surgery, and medical oncology led to the successful diagnosis and management of this patient. Metastatic thymic carcinoma of the spine, although rare, should be part of the differential diagnosis when the patient has a history of thymic carcinoma and presents with back pain and radiculopathy. We recommend the posterior approach for spinal decompression of the metastatic thymic carcinoma when the tumor has caused neurological deficits. Osteoplasty by cement augmentation is also a good choice for surgical treatment.
Topics: Bone Cements; Decompression, Surgical; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neurosurgical Procedures; Spinal Cord Compression; Spinal Neoplasms; Spine; Thymoma; Treatment Outcome
PubMed: 30653174
DOI: 10.1097/MD.0000000000014198 -
British Journal of Haematology Oct 2009We developed the strategy of umbilical cord blood transplants (UCBT) with co-infusion of a limited number of highly purified mobilized haematopoietic stem cells (MHSC)... (Review)
Review
We developed the strategy of umbilical cord blood transplants (UCBT) with co-infusion of a limited number of highly purified mobilized haematopoietic stem cells (MHSC) from a human leucocyte antigen (HLA) unrestricted third party donor (TPD). Short post-transplant periods of neutropenia were usually observed in adults with haematological neoplasms receiving UCBT with a relatively low cell content and 0-3 HLA mismatches after myeloablative conditioning. This resulted from an early and initially predominant engraftment of the TPD-MHSC. After a variable period of double complete TPD + UCB chimerism, final full UCB chimerism was achieved (cumulative incidence >90%) within 100 d. Early recovery of the circulating neutrophils resulting from the 'bridge transplant' of the TPD-MHSC reduced the incidence of serious neutropenia-related infections, also facilitating the use of drugs with myelosuppressive side effects to combat other infections. The observed incidence of graft-versus-host disease and relapses was low, with overall and disease-free survival curves comparable to those of HLA identical sibling transplants. Post-transplant recovery of natural killer cells occurred soon after the transplant and B cells recovered around 6 months, but T-cell recovery took more than 1 year. Available data show that T cell recovery derives from UCB-HSC through thymic differentiation and that cytomegalovirus (CMV)-specific lymphocytes develop following CMV reactivations.
Topics: Cord Blood Stem Cell Transplantation; Graft Rejection; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Survival Analysis; T-Lymphocyte Subsets; Tissue Donors; Treatment Outcome
PubMed: 19796265
DOI: 10.1111/j.1365-2141.2009.07766.x -
Stem Cells (Dayton, Ohio) Nov 2020Understanding physiologic T-cell development from hematopoietic stem (HSCs) and progenitor cells (HPCs) is essential for development of improved hematopoietic cell...
Understanding physiologic T-cell development from hematopoietic stem (HSCs) and progenitor cells (HPCs) is essential for development of improved hematopoietic cell transplantation (HCT) and emerging T-cell therapies. Factors in the thymic niche, including Notch 1 receptor ligand, guide HSCs and HPCs through T-cell development in vitro. We report that physiologically relevant oxygen concentration (5% O , physioxia), an important environmental thymic factor, promotes differentiation of cord blood CD34+ cells into progenitor T (proT) cells in serum-free and feeder-free culture system. This effect is enhanced by a potent reducing and antioxidant agent, ascorbic acid. Human CD34+ cell-derived proT cells in suspension cultures maturate into CD3+ T cells in an artificial thymic organoid (ATO) culture system more efficiently when maintained under physioxia, compared to ambient air. Low oxygen tension acts as a positive regulator of HSC commitment and HPC differentiation toward proT cells in the feeder-free culture system and for further maturation into T cells in the ATO. Culturing HSCs/HPCs in physioxia is an enhanced method of effective progenitor T and mature T-cell production ex vivo and may be of future use for HCT and T-cell immunotherapies.
Topics: Cell Differentiation; Cell- and Tissue-Based Therapy; Hematopoietic Stem Cell Transplantation; Humans; Stem Cells; T-Lymphocytes; Transplantation Conditioning
PubMed: 32761664
DOI: 10.1002/stem.3259 -
Neuroimmunomodulation 2023Considering significance of mechanisms of central tolerance for development of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), and...
INTRODUCTION
Considering significance of mechanisms of central tolerance for development of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), and suppressive influence of circulating proinflammatory cytokines and alterations in brain-thymus communication, characteristic for the central nervous system (CNS) autoimmune diseases, on thymopoiesis, the study interogated putative strain-based thymus-related specificities relevant for the opposite effects of ageing on susceptibility of Dark Agouti (DA) and Albino Oxford (AO) rats to EAE.
METHODS
Quantitative and qualitative changes in thymopoiesis including underlying mechanisms were examined using flow cytometry and RT-qPCR quantification of mRNAs for molecules relevant for integrity of stroma and T-cell development, respectively.
RESULTS
With ageing, differently from DA rats, in AO rats the surface density of CD90, a negative regulator of selection threshold, on thymocytes undergoing lineage commitment was upregulated (consistent with TGF-β expression downregulation), whereas the generation of natural CD4+CD25+Foxp3+ regulatory T cells (nTregs) was impaired reflecting differences in thymic expression of cytokines supporting their development. Additionally, specifically in old AO rats, in whom EAE development depends on IL-17-producing CD8+ T cells, their thymic differentiation was augmented, reflecting augmented thymic IL-4 expression. In turn, differently from old DA rats developing self-limiting EAE, in age-matched AO rats developing EAE of prolonged duration, EAE development led to impaired generation of nTregs and accumulation of proinflammatory, cytotoxic CD28-CD4+ T cells in the periphery.
DISCUSSION
The study indicates that strain differences in age-related changes in the efficacy of central tolerance, in addition to enhanced thymic generation of CD8+ T cells prone to differentiate into IL-17-producing cells, could partly explain the opposite effect of ageing on DA and AO rat susceptibility to EAE induction. Additionally, it suggested that EAE development leading to a less efficient thymic output of CD4+ cells and nTregs in old AO rats than their DA counterparts could contribute to prolonged EAE duration in AO compared with DA rats.
CONCLUSION
The study warns to caution when designing therapeutic interventions to enhance thymic activity in genetically diverse populations, e.g., humans, and interpreting their outcomes. Furthermore, it indicates that CNS autoimmune pathology may additionally worsen thymic involution and age-related immune changes.
Topics: Humans; Rats; Animals; Encephalomyelitis, Autoimmune, Experimental; Interleukin-17; Spinal Cord; Aging; Cytokines
PubMed: 37952531
DOI: 10.1159/000535150 -
Cytotherapy 2007Over the past years unrelated cord blood transplant (UCBT) has emerged as an effective alternative to unrelated donor blood and marrow transplantation. However, despite... (Review)
Review
Over the past years unrelated cord blood transplant (UCBT) has emerged as an effective alternative to unrelated donor blood and marrow transplantation. However, despite several advantages, its success is limited by the high incidence of opportunistic infections (OI), most of which are viral. Infection-related mortality is the primary cause of death after UCBT with most deaths occurring in the first 3-6 months post transplant. For several months, until recovery of the thymus is restored to support de novo T cell generation, protective antiviral immunity depends on the activity of post-thymic T cells infused within the cord blood (CB) grafts. However, almost all CB T cells are antigen inexperienced (naïve) lymphocytes that have been functionally altered by placental factors to protect pregnancy. CB T cells need to undergo in vivo priming, Th1/Tc1 maturation, and peripheral expansion before they can afford immunologic protection. This article provides an overview of what is currently known regarding the reconstitution of adaptive immunity following UCBT including our own data from prospective analyses of pediatric cohorts. Remarkable immunophenotypic changes are notable already in the first 2-3 weeks post-UCBT. These changes result from apparent 'homeostatic' peripheral T cell expansion in the lymphopenic environment. While we can identify patient- and graft-specific predictive factors, the concordant emergence of T cell subsets displaying the phenotype of Th1/Tc1 cytotoxic effector cells can be statistically linked to those UCBT recipients who will subsequently develop viral and other opportunistic infections. Antigen presenting dendritic cell reconstitution may also reflect alterations in immunocompetence due to OI and/or GVHD.
Topics: Cord Blood Stem Cell Transplantation; Fetal Blood; Flow Cytometry; Humans; Lymphocyte Activation; T-Lymphocytes; Time Factors
PubMed: 17453963
DOI: 10.1080/14653240701231014 -
BMC Veterinary Research May 2021Mechanisms of fetal death following maternal PRRSV2 infection remain uncharacterized, although hypoxia from umbilical cord lesions and/or placental detachment due to...
BACKGROUND
Mechanisms of fetal death following maternal PRRSV2 infection remain uncharacterized, although hypoxia from umbilical cord lesions and/or placental detachment due to apoptosis are hypothesized. We performed two experiments examining hypoxia and apoptosis in PRRSV-infected and non-infected, third-trimester fetuses to elucidate possible associations with fetal death. Fetuses were selected based on four phenotypic infection groups: fetuses from non-challenged control gilts (CTRL); low viral load fetuses (LVL; Exp 1) or uninfected fetuses (UNINF; Exp 2) from inoculated gilts; viable high viral load fetuses (HVL-VIA); and HVL meconium-stained fetuses (HVL-MEC).
RESULTS
In experiment 1, paraffin embedded fetal tissues collected 21 days post maternal infection (DPI) were examined for DNA fragmentation associated with apoptosis. Positively stained foci were larger and more numerous (P < 0.05) in heart, liver, and thymus of HVL-VIA and HVL-MEC compared to CTRL and LVL fetuses. In experiment 2, group differences in gene expression within the hypoxia (HIF1a, IDO1, VEGFa, LDHA, NOS2, NOX1) and apoptosis (CASP3, CASP7, CASP8, CASP9, RIPK1, RIPK3) pathways were assessed by RT-qPCR in fetal tissues collected at 12 DPI. High viral load fetuses showed differential expression relative to the CTRL and UNINF (P < 0.05 for all). Brain tissue from HVL-VIA and HVL-MEC fetuses presented increased expression of CASP7, CASP8, RIPK3, HIF1a and IDO1. Fetal heart showed increased expression of CASP8, HIF1a, IDO and NOX1 and a decrease in NOS2 expression in infected groups. CASP7, CASP9, RIPK1 and RIPK3 were only increased in the heart of HVL-VIA while VEGFa was only increased for HVL-MEC fetuses. Thymus from HVL-MEC had decreased expression of CASP9 and there was increased IDO1 in all infected fetuses.
CONCLUSIONS
There is strong evidence of apoptosis occurring in the heart, liver and thymus of highly viral load fetuses at 21 DPI. Furthermore, there was clear upregulation of apoptotic genes in the heart of high viral load infected fetuses and less prominent upregulation in the brain of PRRSV-infected fetuses, whereas thymus appears to be spared at 12 DPI. There was no strong evidence of hypoxia at 12 DPI in brain and thymus but some indication of hypoxia occurring in fetal heart.
Topics: Animals; Apoptosis; Brain; Female; Fetal Hypoxia; Fetus; Gene Expression; Myocardium; Porcine Reproductive and Respiratory Syndrome; Porcine respiratory and reproductive syndrome virus; Pregnancy; Pregnancy Complications, Infectious; Sus scrofa; Swine; Thymus Gland; Viral Load
PubMed: 33933084
DOI: 10.1186/s12917-021-02883-0 -
Environmental Research Jul 2015The fetal time period is a critical window of immune system development and resulting heightened susceptibility to the adverse effects of environmental exposures....
The fetal time period is a critical window of immune system development and resulting heightened susceptibility to the adverse effects of environmental exposures. Epidemiologists and toxicologists have hypothesized that phthalates, bisphenol A (BPA) and perfluoroalkyl substance have immunotoxic properties. Immunotoxic effects of chemicals may manifest in an altered immune system profile at birth. Immunoglobulin E, thymic stromal lymphopoietin (TSLP), and interleukin-33 (IL-33) are integral in the etiology of childhood allergy and detectable at birth. The objective of this study was to determine the association between maternal levels of phthalates, bisphenol A (BPA), and perfluoroalkyl substances and elevated umbilical cord blood levels of IgE, TSLP, and IL-33. This study utilized data collected in the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a trans-Canada cohort study of 2001 pregnant women. Of these women, 1258 had a singleton, term birth and cord blood sample. A Bayesian hierarchical model was employed to determine associations between log-transformed continuous variables and immune system biomarkers while adjusting for potential confounding from correlated environmental contaminants. Inverse, nonlinear associations were observed between maternal urinary MCPP levels and elevated levels of both IL-33/TSLP and IgE and between maternal urinary BPA levels and elevated levels of IL-33/TSLP. In this primarily urban Canadian population of pregnant women and their newborns, maternal urinary and plasma concentrations of phthalate metabolites, BPA, and perfluoroalkyl substances were not associated with immunotoxic effects that manifest as increased odds of elevated levels of IgE, TSLP or IL-33.
Topics: Adult; Benzhydryl Compounds; Cytokines; Female; Fetal Blood; Fluorocarbons; Humans; Immunoglobulin E; Infant, Newborn; Interleukin-33; Interleukins; Maternal Exposure; Phenols; Phthalic Acids; Pregnancy; Thymic Stromal Lymphopoietin
PubMed: 25913155
DOI: 10.1016/j.envres.2015.04.010 -
Frontiers in Immunology 2022Due to their suppressive capacity, the adoptive transfer of regulatory T cells (Treg) has acquired a growing interest in controlling exacerbated inflammatory responses....
Due to their suppressive capacity, the adoptive transfer of regulatory T cells (Treg) has acquired a growing interest in controlling exacerbated inflammatory responses. Limited Treg recovery and reduced quality remain the main obstacles in most current protocols where differentiated Treg are obtained from adult peripheral blood. An alternate Treg source is umbilical cord blood, a promising source of Treg cells due to the higher frequency of naïve Treg and lower frequency of memory T cells present in the fetus' blood. However, the Treg number isolated from cord blood remains limiting. Human thymuses routinely discarded during pediatric cardiac surgeries to access the retrosternal operative field has been recently proposed as a novel source of Treg for cellular therapy. This strategy overcomes the main limitations of current Treg sources, allowing the obtention of very high numbers of undifferentiated Treg. We have developed a novel good manufacturing practice (GMP) protocol to obtain large Treg amounts, with very high purity and suppressive capacity, from the pediatric thymus (named hereafter thyTreg). The total amount of thyTreg obtained at the end of the procedure, after a short-term culture of 7 days, reach an average of 1,757 x10 (range 50 x 10 - 13,649 x 10) cells from a single thymus. The thyTreg product obtained with our protocol shows very high viability (mean 93.25%; range 83.35% - 97.97%), very high purity (mean 92.89%; range 70.10% - 98.41% of CD25FOXP3 cells), stability under proinflammatory conditions and a very high suppressive capacity (inhibiting in more than 75% the proliferation of activated CD4 and CD8 T cells at a thyTreg:responder cells ratio of 1:1). Our thyTreg product has been approved by the Spanish Drug Agency (AEMPS) to be administered as cell therapy. We are recruiting patients in the first-in-human phase I/II clinical trial worldwide that evaluates the safety, feasibility, and efficacy of autologous thyTreg administration in children undergoing heart transplantation (NCT04924491). The high quality and amount of thyTreg and the differential features of the final product obtained with our protocol allow preparing hundreds of doses from a single thymus with improved therapeutic properties, which can be cryopreserved and could open the possibility of an "off-the-shelf" allogeneic use in another individual.
Topics: Adoptive Transfer; Adult; CD8-Positive T-Lymphocytes; Cell- and Tissue-Based Therapy; Child; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Forkhead Transcription Factors; Humans; T-Lymphocytes, Regulatory
PubMed: 35651624
DOI: 10.3389/fimmu.2022.893576 -
Cardiovascular Drugs and Therapy Jan 2005Urotensin II (U-II) is the most potent vasoconstrictor known, even more potent than endothelin-1. It was first isolated from the fish spinal cord and has been recognized... (Review)
Review
Urotensin II (U-II) is the most potent vasoconstrictor known, even more potent than endothelin-1. It was first isolated from the fish spinal cord and has been recognized as a hormone in the neurosecretory system of teleost fish for over 30 years. After the identification of U-II in humans and the orphan human G-protein-coupled receptor 14 as the urotensin II receptor, UT, many studies have shown that U-II may play an important role in cardiovascular regulation. Human urotensin II (hU-II) is an 11 amino acid cyclic peptide, generated by proteolytic cleavage from a precursor prohormone. It is expressed in the central nervous system as well as other tissues, such as kidney, spleen, small intestine, thymus, prostate, pituitary, and adrenal gland and circulates in human plasma. The plasma U-II level is elevated in renal failure, congestive heart failure, diabetes mellitus, systemic hypertension and portal hypertension caused by liver cirrhosis. The effect of U-II on the vascular system is variable, depending on species, vascular bed and calibre of the vessel. The net effect on vascular tone is a balance between endothelium-independent vasoconstriction and endothelium-dependent vasodilatation. U-II is also a neuropeptide and may play a role in tumour development. The development of UT receptor antagonists may provide a useful research tool as well as a novel treatment for cardiorenal diseases.
Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Humans; Kidney Diseases; Organ Specificity; Receptors, G-Protein-Coupled; Urotensins; Vasoconstrictor Agents
PubMed: 15883758
DOI: 10.1007/s10557-005-6899-x -
Stem Cells (Dayton, Ohio) Sep 2014A system that allows manipulation of the human thymic microenvironment is needed both to elucidate the extrinsic mechanisms that control human thymopoiesis and to...
A system that allows manipulation of the human thymic microenvironment is needed both to elucidate the extrinsic mechanisms that control human thymopoiesis and to develop potential cell therapies for thymic insufficiency. In this report, we developed an implantable thymic microenvironment composed of two human thymic stroma populations critical for thymopoiesis; thymic epithelial cells (TECs) and thymic mesenchyme (TM). TECs and TM from postnatal human thymi were cultured in specific conditions, allowing cell expansion and manipulation of gene expression, before reaggregation into a functional thymic unit. Human CD34+ hematopoietic stem and progenitor cells (HSPC) differentiated into T cells in the aggregates in vitro and in vivo following inguinal implantation of aggregates in immune deficient mice. Cord blood HSPC previously engrafted into murine bone marrow (BM), migrated to implants, and differentiated into human T cells with a broad T cell receptor repertoire. Furthermore, lentiviral-mediated expression of vascular endothelial growth factor in TM enhanced implant size and function and significantly increased thymocyte production. These results demonstrate an in vivo system for the generation of T cells from human HSPC and represent the first model to allow manipulation of gene expression and cell composition in the microenvironment of the human thymus.
Topics: Animals; Cell Proliferation; Cellular Microenvironment; Gene Expression; Humans; Lymphopoiesis; Mice; Mice, Inbred NOD; Mice, SCID; Thymus Gland; Tissue Engineering; Vascular Endothelial Growth Factor A
PubMed: 24801626
DOI: 10.1002/stem.1731