Translational Studies in Elderly Patients with Acute Myeloid Leukemia

The production of blood cells (hematopoiesis) takes place in the bone marrow. Acute myeloid leukemia (AML) is a clonal disease, which is characterized by an increase in the number of myeloid cells in the bone marrow and an arrest in their maturation. This frequently results in a severe suppression of normal hematopoiesis (granulocytopenia, anemia and/or thrombocytopenia).1,2 AML is a heterogeneous disease, characterized by a diversity of morphologic, cytogenetic and immunophenotypic features. Until recently, the morphologic classification was according to the French-American-British group,3-5 which distinguishes AML into nine distinct subtypes (FAB M0-M7, M4eo) that differ with respect to the particular myeloid lineage involved and the degree of leukemic-cell differentiation. This distinction is based on the morphologic appearance of the blasts and their reactivity with histochemical stains. In addition, immunologic methods have been incorporated into the diagnostic criteria for some FABgroups, e.g. M0 and M7.6,7 Cytogenetic abnormalities of the chromosomes in the leukemic blasts have also been shown to be associated with specific FAB subtypes, e.g. t(15;17) with acute promyelocytic leukemia (APL; AML M3).8 Recently, the World Health Organization (WHO) has proposed a new classification for myeloid neoplasms.9 In this classification, genetic features (cytogenetic and molecular genetic) and clinical features have been integrated with morphology and immunophenotype to define distinct disease entities. Within the category of AML, four main groups have been recognized: 1. AML with recurrent cytogenetic translocations; 2. AML with myelodysplasia-related features; 3. therapy-related AML and MDS; and 4. AML not otherwise specified

The pedicled omentoplasty and split skin graft (POSSG) for reconstruction of large chest wall defects. A validity study of 34 patients

The aim of this study was to evaluate retrospectively the results of pedicled omentoplasty and split skin graft (POSSG) in reconstructing (full thickness) chest wall defects, and to define its role as a palliative procedure for local symptom control. Thirty-four patients with recurrent breast cancer (n = 25), radiation-induced necrosis (n = 5) or sarcoma (n = 4) of the chest wall were selected for the study. All patients underwent curative or palliative chest wall resection with reconstruction by pedicled omentoplasty and split skin graft (POSSG), between 1986 and 1994. Reconstructive outcome, complications, local tumour and symptom control following surgery was measured. The most common complication was shown to be partial necrosis of the omental flap (35%), followed by respiratory problems (26%), facial hernia (26%) and thoracic wound problems (15%), which were mostly treated in a conservative way (68%). The 3-year local tumour-free interval after POSSG in patients curatively treated for breast cancer is 16%. Seventy per cent of the patients who underwent palliative resection had longstanding relief of local pain, bleeding or foetor due to local tumour growth. It can be concluded that large (full thickness) chest wall defects after resection of local recurrence, primary malignancy or osteoradionecrosis of the chest wall can successfully be reconstructed by POSSG. Chest wall resection in patients treated with palliative intention is effective in local symptom control

A jet-induced outflow of warm gas in 3C 293

Using long slit emission-line spectra we detect a fast outflow of ionized gas, with velocities up to 1000 km/s, in the nearby powerful radio galaxy 3C 293 (z = 0.045). The fast outflow is located about 1 kpc east of the nucleus, in a region of enhanced radio emission due to the presence of a distorted radio jet. We present results that indicate that this fast outflow is caused by a jet-ISM interaction. The kinematics of the outflowing ionized gas are very similar to those of a fast outflow of neutral hydrogen gas in this galaxy, suggesting that both outflows are the result of the same driving mechanism. While the mass of the outflowing ionized gas is about 1 x 10e5 M_sun, the total HI mass involved in the neutral outflow is about 100 times higher (10e7 M_sun). This shows that, despite the high energies that must be involved in driving the outflow, most of the gas remains, or becomes again, neutral. Other outflows of ionized gas, although not as pronounced as in the region of the enhanced radio emission, are also seen in various other regions along the axis of the inner radio jets. The regular kinematics of the emission-line gas along the major axis of the host galaxy reveal a rotating ionized gas disk 30 kpc in extent.Comment: 15 pages, 10 figures. Accepted for publication in MNRAS. A full resolution version can be found at http://www.astro.rug.nl/~emonts/MF268rv.pd

Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients

Paraneoplastic cerebellar degeneration (PCD) is a heterogeneous group of disorders characterized by subacute cerebellar ataxia, specific tumour types and (often) associated antineuronal antibodies. Nine specific antineuronal antibodies are associated with PCD. We examined the relative frequency of the antineuronal antibodies associated with PCD and compared the neurological symptoms and signs, associated tumours, disability and survival between groups of PCD with different antibodies. Also, we attempted to identify patient-, tumour- and treatment-related characteristics associated with functional outcome and survival. In a 12-year period, we examined >5000 samples for the presence of antineuronal antibodies. A total of 137 patients were identified with a paraneoplastic neurological syndrome and high titre (> or =400) antineuronal antibodies. Fifty (36%) of these patients had antibody-associated PCD, including 19 anti-Yo, 16 anti-Hu, seven anti-Tr, six anti-Ri and two anti-mGluR1. Because of the low number, the anti-mGluR1 patients were excluded from the statistical analysis. While 100% of patients with anti-Yo, anti-Tr and anti-mGluR1 antibodies suffered PCD, 86% of anti-Ri and only 18% of anti-Hu patients had PCD. All patients presented with subacute cerebellar ataxia progressive over weeks to months and stabilized within 6 months. The majority of patients in all antibody groups had both truncal and appendicular ataxia. The frequency of nystagmus and dysarthria was lower in anti-Ri patients (33 and 0%). Later in the course of the disease, involvement of non-cerebellar structures occurred most frequently in anti-Hu patients (94%). In 42 patients (84%), a tumour was detected. The most commonly associated tumours were gynaecological and breast cancer (anti-Yo and anti-Ri), lung cancer (anti-Hu) and Hodgkin's lymphoma (anti-Tr and anti-mGluR1). In one anti-Hu patient, a suspect lung lesion on CT scan disappeared while the PCD evolved. Seven patients improved by at least 1 point on the Rankin scale, while 16 remained stable and 27 deteriorated. All seven patients that improved received antitumour treatment for their underlying cancer, resulting in complete remission. The functional outcome was best in the anti-Ri patients, with three out of six improving neurologically and five were able to walk at the time of last follow-up or death. Only four out of 19 anti-Yo and four out of 16 anti-Hu patients remained ambulatory. Also, survival from time of diagnosis was significantly worse in the anti-Yo (median 13 months) and anti-Hu (median 7 months) patients compared with anti-Tr (median >113 months) and anti-Ri (median >69 months). Patients receiving antitumour treatment (with or without immunosuppressive therapy) lived significantly longer [hazard ratio (HR) 0.3; 95% confidence interval (CI) 0.1-0.6; P = 0.004]. Patients > or =60 years old lived somewhat shorter from time of diagnosis, although statistically not significant (HR 2.9; CI 1.0-8.5; P = 0.06)

CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age

Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) proteins P-glycoprotein, encoded by the MDR1/ABCB1 gene, multidrug resistant-related protein (MRP/ABCC1), the lung resistance-related protein (LRP), or major vault protein (MVP), and the breast cancer resistance protein (BCRP/ABCG2). The clinical value of MDR1, MRP1, LRP/MVP, and BCRP messenger RNA (mRNA) expression was prospectively studied in 154 newly diagnosed AML patients ≥60 years who were treated in a multicenter, randomized phase 3 trial. Expression of MDR1 and BCRP showed a negative whereas MRP1 and LRP showed a positive correlation with high white blood cell count (respectively, p < 0.05, p < 0.001, p < 0.001 and p < 0.001). Higher BCRP mRNA was associated with secondary AML (p < 0.05). MDR1 and BCRP mRNA were highly significantly associated (p < 0.001), as were MRP1 and LRP mRNA (p < 0.001) expression. Univariate regression analyses revealed that CD34 expression, increasing MDR1 mRNA as well as MDR1/BCRP coexpression, were associated with a lower complete response (CR) rate and with worse event-free survival and overall survival. When adjusted for other prognostic actors, only CD34-related MDR1/BCRP coexpression remained significantly associated with a lower CR rate (p = 0.03), thereby identifying a clinically resistant subgroup of elderly AML patients

Timescales of merger, starburst and AGN activity in radio galaxy B2 0648+27

In this paper we use neutral hydrogen HI and optical spectroscopic observations to compare the timescales of a merger event, starburst episode and radio-AGN activity in the radio galaxy B2 0648+27. We detect a large ring-like structure of HI in emission around the early-type host galaxy of B2 0648+27 (M_HI = 8.5 x 10^9 Msun, diameter = 190 kpc). We interpret this as the result of a major merger that occurred > 1.5 Gyr ago. From modelling optical long-slit spectra we find that a young stellar population of 0.3 Gyr, indicative of a past starburst event, dominates the stellar light throughout the galaxy. The off-set in time between the merger event and the starburst activity in B2 0648+27 suggests that the starburst was triggered in an advanced stage of the merger, which can be explained if the gas-rich progenitor galaxies contained a bulge. Although the exact age of the radio source remains uncertain, there appears to be a significant time-delay between the merger/starburst event and the current episode of radio-AGN activity. We also observe an outflow of emission-line gas in this system, which is likely related to superwinds driven by the stars that formed during the starburst event. We argue that the radio galaxy B2 0648+27 is a link in the evolutionary sequence between Ultra-Luminous Infrared Galaxies (ULIRGs) and genuine early-type galaxies

Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation

Recipients of a partially T-cell-depleted (TCD) allogeneic stem cell transplantation (allo-SCT) developing reactivation of Epstein-Barr virus (EBV) with quantified viral DNA levels exceeding 1000 genome equivalents/milliliter (geq/mL) are at high risk for EBV-lymphoproliferative disease (EBV-LPD). We studied whether preemptive therapy with rituximab prevents EBV-LPD, LPD-mo

MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia

The expression of P-glycoprotein (P-gp), encoded by the MDR1 gene, is an independent adverse prognostic factor for response and survival in de novo acute myeloid leukemia (AML). Little is known about MDR1 expression during the development of disease. The present study investigated whether MDR1 gene- related clonal selection occurs in the development from diagnosis to relapsed AML, using a genetic polymorphism of the MDR1 gene at position 2677. Expression and function of P-gp were studied using monoclonal antibodies MRK16 and UIC2 and the Rhodamine 123 retention assay with or without PSC 833. No difference was found in the levels of P-gp function and expression between diagnosis and relapse in purified paired blast samples from 30 patients with AML. Thirteen patients were homozygous for the genetic polymorphism of MDR1 (n = 7 for guanine, n = 6 for thymidine), whereas 17 patients were heterozygous (GT). In the heterozygous patients, no selective loss of one allele was observed at relapse. Homozygosity for the MDR1 gene (GG or TT) was associated with shorter relapse-free intervals (P =.002) and poor survival rates (P =.02), compared with heterozygous patients. No difference was found in P-gp expression or function in patients with AML with either of the allelic variants of the MDR1 gene. It was concluded that P-gp function or expression is not upregulated at relapse/refractory disease and expression of one of the allelic variants is not associated with altered P-gp expression or function in AML, consistent with the fact that MDR1 gene-related clonal selection does not occur when AML evolves to recurrent disease. (Blood. 2001;97:3605-3611

Improved ventricular function during inhalation of PGI(2) aerosol partly relies on enhanced myocardial contractility

Inhaled prostacyclin (PGI(2)) aerosol induces selective pulmonary vasodilation. Further, it improves right ventricular ( RV) function, which may largely rely on pulmonary vasodilation, but also on enhanced myocardial contractility. We investigated the effects of the inhaled PGI(2) analogs epoprostenol (EPO) and iloprost (ILO) on RV function and myocardial contractility in 9 anesthetized pigs receiving aerosolized EPO (25 and 50 ng center dot kg(-1) center dot min(-1)) and, consecutively, ILO (60 ng center dot kg(-1) center dot min(-1)) for 20 min each. We measured pulmonary artery pressure ( PAP), RV ejection fraction (RVEF) and RV end-diastolic-volume (RV-EDV), and left ventricular end-systolic pressure-volume-relation (end-systolic elastance, E-es). EPO and ILO reduced PAP, increased RVEF and reduced RVEDV. E-es was enhanced during all doses tested, which reached statistical significance during EPO25ng and ILO, but not during EPO50ng. PGI(2) aerosol enhances myocardial contractility in healthy pigs, contributing to improve RV function. Copyright (C) 2005 S. Karger AG, Basel