Bone marrow-resident memory T cells survive pretransplant chemotherapy and contribute to early immune reconstitution of patients with acute myeloid leukemia given mafosfamide-purged autologous bone marrow transplantation

OBJECTIVE: Studies of memory T cells transferred with the graft are relevant to better understand the early immune reconstitution of patients given autologous bone marrow transplantation (A-BMT). A critical question is whether memory T cells resident in bone marrow (BM) of patients with hematological malignancies are resistant to either pretransplant chemotherapy or ex vivo pharmacological purging. PATIENTS AND METHODS: To address these issues, we evaluated the frequency of tetanus-toxoid (TT)-specific proliferating T-cell precursors (TT-PTCp) in BM and peripheral blood (PB) of eight patients with acute myeloid leukemia (AML) given A-BMT after in vitro purging of BM with mafosfamide. Patients were studied at the time of BM harvesting and five of them also after A-BMT. RESULTS: The range of TT-PTCp frequencies found after A-BMT were comparable with those observed in PB and in BM at the time of harvesting and did not differ significantly from those of eight age-matched healthy subjects who donated BM for a human leukocyte antigen-identical sibling. TT-PTCp frequencies in BM, studied before and after ex vivo purging, appeared not to be affected by incubation with mafosfamide. We also compared the T-cell receptor (TCR)-Vbeta-repertoire usage of TT-specific T-cell lines (TT-TCL) in BM of patients at the time of harvesting and in their PB 2 months after transplantation. The same TCR-clonotypes were detected in TT-TCL at time of harvesting and after A-BMT. CONCLUSION: These data indicate that BM-resident memory T cells of patients with AML are resistant to both pretransplant chemotherapy and ex vivo pharmacological purging and may contribute to immune reconstitution after A-BMT.     

Angiosarcoma of the small intestine: an immunoperoxidase study

A case of multifocal angiosarcoma of the small intestine is reported. These tumors often contain areas of solid sheets of cells and may be confused with poorly differentiated carcinoma or other sarcomas, as was the tumor in the reported case. Factor VIII-related antigen was demonstrated in biopsy samples by the peroxidase antiperoxidase method, showing the tumor to be an angiosarcoma. We conclude that the demonstration of factor VIII-related antigen in the neoplastic cells is an important aid in the diagnosis of angiosarcoma.     

TGF-β1 enhances cardiomyogenic differentiation of skeletal muscle-derived adult primitive cells

The optimal medium for cardiac differentiation of adult primitive cells remains to be established. We quantitatively compared the efficacy of IGF-1, dynorphin B, insulin, oxytocin, bFGF, and TGF-β1 in inducing cardiomyogenic differentiation. Adult mouse skeletal muscle-derived Sca1+/CD45-/c-kit-/Thy-1+ (SM+) and Sca1-/CD45-/c-kit-/Thy-1+ (SM-) cells were cultured in basic medium (BM; DMEM, FBS, IGF-1, dynorphin B) alone and BM supplemented with insulin, oxytocin, bFGF, or TGF-β1. Cardiac differentiation was evaluated by the expression of cardiac-specific markers at the mRNA (qRT-PCR) and protein (immunocytochemistry) levels. BM+TGF-β1 upregulated mRNA expression of Nkx2.5 and GATA-4 after 4 days and Myl2 after 9 days. After 30 days, BM+TGF-β1 induced the greatest extent of cardiac differentiation (by morphology and expression of cardiac markers) in SM- cells. We conclude that TGF-β1 enhances cardiomyogenic differentiation in skeletal muscle-derived adult primitive cells. This strategy may be utilized to induce cardiac differentiation as well as to examine the cardiomyogenic potential of adult tissue-derived stem/progenitor cells. Electronic supplementary material  The online version of this article (DOI:) contains supplementary material, which is available to authorized users. Returned for 1. Revision: 8 January 2008 1. Revision received: 8 April 2008 Ahmed Abdel-Latif and Ewa K. Zuba-Surma contributed equally to this work.     

Three-dimensional transesophageal echocardiographic delineation of ventricular septal aneurysm producing right ventricular outflow obstruction in an adult

We report three-dimensional echocardiographic delineation of a congenital aneurysm of the membranous interventricular septum causing right ventricular outflow tract obstruction in an adult patient. To our knowledge, these findings have not been described before.     

Factors associated with progression of the disease before transplantation in patients with autoimmune hepatitis

Abstract: Aims/Background: Studies on transplanted patients may provide clinically useful data on factors influencing progression of autoimmune hepatitis (AIH) since transplantation rather than death may now be considered as the most likely end-point of the disease. The aim of this work was to analyze risk factors related to progression of AIH before transplantation and provide guidelines for further prognostication with regards to the timing of transplantation. Methods: 80 liver transplants in 68 patients with AIH were performed in our unit. The diagnosis was established on conventional clinical criteria. Parameters such as sex, age at diagnosis and transplantation or duration of the disease were evaluated in relation to: patient HLA DR status, disease presentation (aggressive or non-aggressive), presence of anti-LKM antibodies and concurrent immune disease. Results: AIH with concurrent immune disease occurred more commonly in females (90 vs. 61%; p= 0.0075) and was linked with markedly slower progression of the disease (125 vs. 66 mo; p=0.002) as compared to subjects without such association. AIH without concurrent autoimmune disease occurred significantly more commonly in patients with DR3 phenotype (p= 0.01). Patients with positive anti-LKM autoantibodies were younger at transplantation (25.6 vs 43.5 yr; p= 0.006) and had more rapid progression of their disease (14.3 vs. 103 mo; p= 0.001). Unlike previously reported series of non-transplanted patients, all anti-LKM positive subjects had no concurrent autoimmune disease. Conclusions: Coincidence with another autoimmune disease is associated with a significantly longer disease history prior to transplantation and may possibly reflect greater responsiveness to immunosuppressive therapy before grafting. AIH without concurrent autoimmune disease, particularly if associated with DR4 negative phenotype, male sex and anti-LKM antibodies may characterize patients with rapid progression of the disease. None of these factors had a significant influence on 5 year survival after surgery.     

Combination Lipid-Lowering Therapies for the Prevention of Recurrent Cardiovascular Events

Purpose of Review

There has been confusion following the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Lipid guidelines on the role of non-statin medications for cardiovascular prevention.

Recent Findings

Several recent large trials have also now shown that lowering LDL with non-statins reduces cardiovascular events. In ASCVD patients on statins, adding ezetimibe or a PCSK9 inhibitor led to reductions in CV events in the IMPROVE IT, FOURIER, and most recently the ODYSSEY-OUTCOMES trials. Additional novel therapies reducing LDL and other atherogenic lipoproteins are in development during this exciting time in this field.

Summary

With recent evidence, the 2017 ACC Expert Consensus Decision pathway calls for initial therapy with statins, monitoring LDL levels, and then adding ezetimibe and/or PCSK9 inhibitors to further lower LDL-C to targets based on the patient’s risk.

     

In vitro histamine release from leukocytes in penicillin allergies.

The definite diagnosis of Type I allergy against penicillin is very important. The in vivo tests used for this purpose may have some disadvantages for the patient. Among the in vitro tests used for the evidence and differential diagnosis of Type I allergy against penicillin, the determination of histamine release from leukocytes and the detection of IgE by the RAST test are the most promising. We have used the test of histamine release from leukocyte in this study of 18 cases, nine of whom had Type I hypersensitivity reactions to penicillin and comprised the study group, the rest were control cases. The per cent of histamine release in the control group was "zero" while in the study group it ranged from 3.9 to 51.7 per cent. The results indicate that the method used in this study is a sensitive and reliable method for the diagnosis of Type I penicillin allergies.     

Low–Molecular-Weight-Heparins as Periprocedural Anticoagulation for Patients on Long-Term Warfarin Therapy: A Standardized Bridging Therapy Protocol

Background: Over 2 million patients in North America are on warfarin anticoagulation therapy for prevention of thromboembolism. Suspension of warfarin therapy is often required to prepare patients for invasive procedures or surgeries. To protect these patients against thromboembolism while they are off warfarin, shorter-acting parenteral agents such as low-molecular-weight heparins (LMWHs) are often used. We conducted a retrospective observational study of our anticoagulation clinic patients to assess the safety and efficacy of LMWHs using a standardized protocol for periprocedural anticoagulation therapy.Methods: We included 69 consecutive patients who required interruption of their long-term warfarin therapy between August 2001 and August 2002, and were deemed by the treating physician to be at high enough risk for perioperative thromboembolism to justify bridging anticoagulation. We used a standard bridging therapy protocol in our anticoagulation clinic. Sixty-six patients received enoxaparin and three patients received tinzaparin for a mean duration of 7.7 days postoperatively. Outcomes were assessed for 30 days post-procedure. Safety outcomes included major bleeding and minor bleeding. Efficacy outcomes included thromboembolic event or death.Results: There were two major bleeding events, one minor bleeding event, and no cases of thromboembolism. Twelve patients experienced some bruising around the injection site.Conclusions: LMWH administration using our standard outpatient bridging protocol for perioperative anticoagulation appears to be relatively safe and efficacious, offering an alternative to inpatient administration of intravenous unfractionated heparin (UFH). Our study provides additional evidence to the limited published observational data regarding the safety and efficacy of LMWH as bridging therapy in the perioperative and periprocedural setting. Large, multicenter, randomized controlled trials are necessary to fully assess the safety and efficacy of LMWH for perioperative anticoagulation.Abbreviated Abstract We conducted a retrospective observational study of 69 consecutive anticoagulation clinic patients on warfarin between August 2001 and August 2002, who were undergoing a procedure or surgery. The study was done to assess the safety and efficacy of an outpatient LMWH bridging protocol. Sixty-six patients received enoxaparin and three patients received tinzaparin for a mean duration of 3 days preoperatively and 7.7 days postoperatively. Outcomes were assessed for 30 days post-procedure. Safety outcomes included major bleeding and minor bleeding. Efficacy outcomes included thromboembolic event or death. There were two major bleeding events, one minor bleeding event, and no cases of thromboembolism. Twelve patients experienced some bruising around the injection site.