ABSTRACT
Takotsubo cardiomyopathy is a rare disorder associated with catecholamine discharge in response to episodes of stress. We present the case of a 39-year-old patient with no other significant medical history who suffered acute ECG changes, left ventricular dysfunction with regional wall motion abnormalities and raised cardiac enzymes following a period of severe and sustained hypertension and tachycardia associated with resection of tumour from the floor of the fourth ventricle. We believe this to be only the second case of a takotsubo cardiomyopathy related to intracranial surgery. It demonstrates the need for consideration, recognition and diagnosis of takotsubo cardiomyopathy following periods of severe peri-operative stress.
ABSTRACT
Increased levels of naturally occurring regulatory T cells (T(Reg) cells) have been found in a variety of solid tumours and haematological malignancies. In multiple myeloma (MM), evidence suggests that T(Reg) cells are increased though controversy exists with regards to their function and no relationship to disease stage and treatment has been demonstrated. Here, we demonstrate significantly elevated levels of functional CD4(+)CD25(+)FoxP3(+) T(Reg) cells in a large cohort of patients with MM as well as monoclonal gammopathy of uncertain significance (MGUS) in comparison to age-matched, healthy controls. The frequency of Double Negative T(Reg) cells was also evaluated, demonstrating that these cells were reduced in patients with MM. Furthermore, a characteristic profile of immunomodulatory cytokines in the peripheral blood and bone marrow of patients with MM and MGUS was demonstrated, compared with healthy controls. This data adds further evidence to the understanding of the role of T(Reg) cell subsets in tumour immunology and the fundamentals of the host/tumour immune conflict.
Subject(s)
Multiple Myeloma/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Aged , Aged, 80 and over , CD3 Complex/immunology , CD4 Antigens/immunology , CD4-Positive T-Lymphocytes/immunology , CD8 Antigens/immunology , Case-Control Studies , Cytokines/immunology , Female , Flow Cytometry , Forkhead Transcription Factors/immunology , Humans , Immunophenotyping , Interleukin-2 Receptor alpha Subunit/immunology , Lymphocyte Count , Male , Middle Aged , Paraproteinemias/immunology , Receptors, Antigen, T-Cell, alpha-beta/analysis , Statistics, NonparametricABSTRACT
BACKGROUND AND OBJECTIVE: Methylating agents are effective chemotherapy agents for Hodgkin lymphoma, but are associated with the development of second primary cancers. Cytotoxicity of methylating agents is mediated primarily by the DNA mismatch repair (MMR) system. Loss of MLH1, a major component of DNA MMR, results in tolerance to the cytotoxic effects of methylating agents and persistence of mutagenised cells at high risk of malignant transformation. We hypothesised that a common substitution in the basal promoter of MLH1 (position -93, rs1800734) modifies the risk of cancer after methylating chemotherapy. METHODS: 133 patients who developed cancer following chemotherapy and/or radiotherapy (n = 133), 420 patients diagnosed with de novo myeloid leukaemia, 242 patients diagnosed with primary Hodgkin lymphoma, and 1177 healthy controls were genotyped for the MLH1 -93 polymorphism by allelic discrimination polymerase chain reaction (PCR) and restriction fragment length polymorphism assay. Odds ratios and 95% confidence intervals for cancer risk by MLH1 -93 polymorphism status, and stratified by previous exposure to methylating chemotherapy, were calculated using unconditional logistic regression. RESULTS: Carrier frequency of the MLH1 -93 variant was higher in patients who developed therapy related acute myeloid leukaemia (t-AML) (75.0%, n = 12) or breast cancer (53.3%. n = 15) after methylating chemotherapy for Hodgkin lymphoma compared to patients without previous methylating exposure (t-AML, 30.4%, n = 69; breast cancer patients, 27.2%, n = 22). The MLH1 -93 variant allele was also over-represented in t-AML cases when compared to de novo AML cases (36.9%, n = 420) and healthy controls (36.3%, n = 952), and was associated with a significantly increased risk of developing t-AML (odds ratio 5.31, 95% confidence interval 1.40 to 20.15), but only in patients previously treated with a methylating agent. CONCLUSIONS: These data support the hypothesis that the common polymorphism at position -93 in the core promoter of MLH1 defines a risk allele for the development of cancer after methylating chemotherapy for Hodgkin lymphoma. However, replication of this finding in larger studies is suggested.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Antineoplastic Agents, Alkylating/adverse effects , Hodgkin Disease/drug therapy , Hodgkin Disease/genetics , Neoplasms, Second Primary/etiology , Nuclear Proteins/genetics , Polymorphism, Genetic , Adolescent , Adult , Aged , Alleles , Base Sequence , Case-Control Studies , DNA Methylation , DNA Primers/genetics , DNA Repair/genetics , Female , Humans , Leukemia, Myeloid, Acute/chemically induced , Leukemia, Myeloid, Acute/etiology , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , MutL Protein Homolog 1 , Neoplasms, Second Primary/chemically induced , Neoplasms, Second Primary/genetics , Promoter Regions, Genetic , Risk FactorsSubject(s)
Carrier Proteins/metabolism , Colitis/drug therapy , Glycoproteins/therapeutic use , Membrane Glycoproteins/metabolism , Receptors, Cytoplasmic and Nuclear/therapeutic use , Receptors, Tumor Necrosis Factor/therapeutic use , Animals , Colitis/metabolism , Glycoproteins/genetics , Glycoproteins/metabolism , Humans , Mice , Mice, Knockout , Osteoprotegerin , RANK Ligand , Receptor Activator of Nuclear Factor-kappa B , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Tumor Necrosis Factor/genetics , Receptors, Tumor Necrosis Factor/metabolism , Recombinant Proteins/therapeutic useABSTRACT
Autoimmune associated bone disease and intestinal inflammation are closely linked with deregulation and hyperactivation of autoreactive CD4 T cells. How these T cells are activated and mediate disease is not clear. Here we show that in the Interleukin 2-deficient mouse model of autoimmunity spontaneous osteopenia and colitis are caused by increased production of the ligand for receptor activator of NFkappaB (RANKL). RANKL acting via its receptor, receptor activator of NFkappaB (RANK), increases bone turnover and promotes intestinal dendritic cell (DC) survival in vivo. Modulation of RANKL-RANK interactions with exogenous recombinant osteoprotegerin (Fc-OPG) reverses skeletal abnormalities and reduces colitis by decreasing colonic DC numbers. This study identifies a common causal link between bone disease and intestinal inflammation and establishes the importance of DC in mediating colonic inflammation in vivo.
Subject(s)
Adjuvants, Immunologic/pharmacology , Bone and Bones/drug effects , Dendritic Cells/drug effects , Glycoproteins/pharmacology , Inflammation/drug therapy , Animals , Bone Diseases, Metabolic/drug therapy , Bone Diseases, Metabolic/genetics , Bone Diseases, Metabolic/immunology , Bone and Bones/immunology , Carrier Proteins/metabolism , Colon/drug effects , Colon/immunology , Dendritic Cells/immunology , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Inflammation/immunology , Interleukin-2/genetics , Interleukin-2/immunology , Membrane Glycoproteins/metabolism , Mice , Mice, Transgenic , Osteoprotegerin , RANK Ligand , Receptor Activator of Nuclear Factor-kappa B , Receptors, Cytoplasmic and Nuclear , Receptors, Tumor Necrosis Factor , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
A 43 year old male presented with a marked eosinophilia and associated systemic symptoms. A diagnosis of myelodysplasia was made on the basis of bone marrow morphology and karyotype. Over a 12 month period the disease transformed into acute lymphoblastic leukaemia, confirmed by flow cytometry, cytochemistry, and immunohistochemistry. Karyotyping was abnormal with 5q- and -7 which persisted from diagnosis through to blastic transformation. He died following initial induction chemotherapy. Eosinophilic myelodysplasia is an uncommon condition in haematological practice and no previous report of lymphoblastic transformation has been found.
