Abstract Abstract 4945 Introduction Clinical trials describing LPD therapy and outcomes overwhelmingly exclude individuals ≥80 years of age. Thus, ability to deliver LPD therapy to this age group is not defined, and tolerance to therapy and response rates and survival data are not available. Methods We retrospectively identified all individuals diagnosed with any LPD at ≥80 years of age at our institution between 1997 and 2010. Data included age at diagnosis, diagnosis, therapy for LPD, comorbidities (disease count), survival from date of diagnosis of LPD, chemotherapy dose intensity (percent of 100% dose based on standard regimen dosing), hospitalization for any reason during chemotherapy, and response. Survival was analyzed by Kaplan-Meier analysis and data sets were compared using Student's t-test or Chi-square as appropriate. Results Of a total of 518 individuals diagnosed with any LPD, we identified 33(6.4%) who were diagnosed ≥80 years of age. All were male consistent with our veteran population. Data is illustrated in tables 1 and 2. Fifteen (15) had Large B-cell lymphoma, 4 CLL/SLL, 2 follicular, 2 mantle zone, 1 marginal zone, 2 lymphoplasmacytic, 3 T-cell. Two (2) could not be classified despite AFIP review. Twenty-two (22) individuals were treated with 73 cycles of chemotherapy (25 CHOP, 30 R-CHOP, 3 CVP, 11 R-CVP, 4 PO cyclophosphamide). One (1) individual with LBCL had no evidence of disease following excisional biopsy and declined further therapy, and 1 received radiotherapy. A total of 27 (82%) patients died during observation. Deaths were predominantly due to LPD. Of those not treated, 5 of 9 had low-grade LPD and were among longer-term survivors. Median survival, illustrated in the figure, was 18.8 months and was not different between treated and untreated group. This compares with 72.7 months predicted survival for an average 84-year old (WWW.SSA.GOV). Discussion LPD is common in individuals ≥80 years of age with large B-cell lymphoma being most common in our population. Despite multiple co-morbidities, the data show that reasonable dose intensity combination chemotherapy may be delivered to treat octogenarians, however hospitalization was required for 1/3 patients during chemotherapy. While survival was not different between treated and untreated groups, the individuals who were treated likely had more severe or advanced stage LPD. Prospective studies with sufficient number of individuals within each diagnostic category should be done to clarify benefits of chemotherapy in ≥80 year old patients with LPD. Disclosures: No relevant conflicts of interest to declare.

Abstract Anti-platelet therapy with aspirin (ASA) is standard therapy for patients with peripheral arterial disease (PAD). While ASA is not felt to impact the natural history of PAD, it decreases mortality from stroke, myocardial infarction, and other co-morbidities in the patients with PAD. Anticoagulation with warfarin (WAR) is indicated in arterial and venous thrombo-embolic conditions such as deep vein thrombosis and atrial fibrillation, but is generally considered not beneficial in patients with PAD. We retrospectively identified patients via ICD9 code who were diagnosed with PAD between January and December 2000, and assessed their course through July 2005. Of 530 individuals, 45 had a history of taking ASA and WAR concomitantly, 116 of taking WAR alone, 219 of taking ASA alone, and 150 received neither drug. Age, mortality, prevalence of hemorrhage and of co-morbid conditions (smoking, diabetes mellitus, atrial fibrillation, stroke, myocardial infarction, hypertension, coronary artery disease, hyperlipidemia, congestive heart failure, renal failure, and chronic obstructive pulmonary disease) that could affect mortality or hemorrhage were determined. Results are illustrated in the table. Group WAR+ASA WAR ASA Neither n=45 n=116 n=219 n=150 ICH= Intracranial ST= Soft Tissue * Mean ± SD Mortality n (%) 12 (26.7) 51 (44.0) 91 (41.6) 71 (47.3) Hemorrhage N (%) 6 (13.3) 10 (8.6) 6 (2.7) 17 (11.3) Type of Hemorrhage 3-GI 8-GI 6-GI 13-GI 2-ICH 1-Nose 3-ICH 1-ST 1-ST 1-Hematuria Age* 73 ± 9 73 ± 9 73 ± 9 72 ± 11 Co-Morbid Conditions/Patient* 5.4 ± 1.7 4.1 ± 1.6 3.5 ± 1.6 2.9 ± 1.7 INR* 2.2 ± 0.7 2.2 ± 0.5 The higher number (not statistically significant) of co-morbid conditions in patients receiving WAR was because most of these individuals had atrial fibrillation. We observed a significant decrease in mortality in patients receiving WAR+ASA compared to patients on WAR alone (Chi-square, p=0.044) and neither drugs (p=0.014), and a trend for decreased mortality compared with patients on ASA alone (p=0.062). However, we observed an increased prevalence of hemorrhage in patients receiving WAR with or without ASA compared with individuals receiving ASA alone (WAR vs ASA p=0.016; WAR+ASA vs ASA p=0.002). We suspect that the frequent hemorrhagic events observed in individuals on neither drug may in part explain why these individuals were not on ASA and/or WAR. This retrospective data suggests combination therapy with WAR+ASA may be better than either agent alone or no therapy for reducing mortality in patients with PAD. Further, this data suggests that the pathogenesis of PAD may involve both platelet and non-platelet mediated hypercoagulable states.

Resveratrol is a phytoalexin naturally present in fruits, medicinal plants and wines. It has a diversity of biological activities. While its role in the protection against coronary heart disease (CHD) in people with moderate wine consumption, remains unclear, resveratrol preferentially inhibits the growth of leukemia cells in culture. Potential mechanisms for its anti-leukemia effect include induction of leukemia cell differentiation, apoptosis, and cell cycle arrest at S-phase; and inhibition of DNA synthesis by inhibiting ribonucleotide reductase or DNA polymerase. Preliminary results suggest that resveratrol also inhibits the viability of freshly isolated leukemia cells, especially promyelocytic leukemia cells. Because of its low in vivo toxicity, resveratrol deserves further investigation as an anti-leukemia agent.

Endotoxin selectively induces monocyte Mn superoxide dismutase (SOD) without affecting levels of Cu,Zn SOD, catalase, or glutathione peroxidase. However, little is known about the structure-activity relationship and the mechanism by which endotoxin induces Mn SOD. In this study we demonstrated that a mutant Escherichia coli endotoxin lacking myristoyl fatty acid at the 3' R-3-hydroxymyristate position of the lipid A moiety retained its full capacity to coagulate Limulus amoebocyte lysate compared with the wild-type E. coli endotoxin and markedly stimulated the activation of human monocyte nuclear factor-kappaB and the induction of Mn SOD mRNA and enzyme activity. However, in contrast to the wild-type endotoxin, it failed to induce significant production of tumor necrosis factor-alpha and macrophage inflammatory protein-1alpha by monocytes and did not induce the phosphorylation and nuclear translocation of mitogen-activated protein kinase. These results suggest that 1) lipid A myristoyl fatty acid, although it is important for the induction of inflammatory cytokine production by human monocytes, is not necessary for the induction of Mn SOD, 2) endotoxin-mediated induction of Mn SOD and inflammatory cytokines are regulated, at least in part, through different signal transduction pathways, and 3) failure of the mutant endotoxin to induce tumor necrosis factor-alpha production is, at least in part, due to its inability to activate mitogen-activated protein kinase.

Relapsing thrombotic thrombocytopenic purpura (TTP) is a rare disorder with most individuals experiencing 1 to 5 relapses. We report a patient with 18 episodes of thrombotic thrombocytopenic purpura (TTP), the highest number of relapses thus far described. The last 11 episodes were treated with regimens containing cyclosporine. The patient's medical record was reviewed for pertinent clinical, laboratory, and treatment data. We summarized various parameters for each episode and compared characteristics of relapses treated with vs. without cyclosporine. The initial episode of TTP was unusual in that it failed to respond to plasmapheresis, glucocorticoids, and fresh frozen plasma (FFP). It remitted only following splenectomy. Episodes 2–7 responded to FFP plus prednisone. Episode 8 failed to respond to prednisone plus FFP but remitted promptly with cyclosporine plus prednisone. Subsequently, 2 relapses responded to cyclosporine alone, 2 to cyclosporine plus FFP, 4 to cyclosporine plus prednisone ± FFP, and 2 to cyclosporine, FFP, prednisone, and plasma exchange. There was no difference in remission duration, or in severity or duration of relapses treated with vs. without cyclosporine. Use of cyclosporine, however, significantly decreased the requirement for prednisone and the length of maintenance therapy; thus it is effective mainly as an adjunctive therapy for TTP. Am. J. Hematol. 57:57–61, 1998. Published 1998 Wiley-Liss, Inc.1 This article is a U.S. Government work and, as such, is in the public domain in the United States of America.

Normal human peripheral blood mononuclear cells (MNCs), particularly T lymphocytes (T cells), are a rich source of granulocyte-macrophage colony-stimulating factor (GM-CSF). Glucocorticoids are known to inhibit GM-CSF production in in vitro cultures of a human fibroblast cell line and in normal human blood monocytes and alveolar macrophages. To determine whether glucocorticoids also inhibit GM-CSF production from normal human MNCs and T cells, we set up cultures of normal human MNCs and T cells in a liquid system in the presence and absence of 5, 50, and 250 microg/dL of hydrocortisone, and an hour later, a constant dose of 50-ng/mL Escherichia coli lipopolysaccharide (LPS) or 10-microg/mL phytohemagglutinin (PHA) was added. After three days, cell counts and GM-CSF levels were determined. Administering 50- and 250-microg/dL hydrocortisone decreased lymphocyte recovery from MNC cultures with LPS (p < or = 0.01), and 250 microg/dL of hydrocortisone decreased lymphocyte recovery from MNC and T-cell cultures with PHA (p < or = 0.03). The amount of GM-CSF produced from PHA-stimulated MNCs was about 100-fold higher than that produced from LPS-stimulated MNCs. The magnitude of GM-CSFs produced in MNC and T-cell cultures stimulated by PHA was comparable (p=0.88). Administering hydrocortisone at 5, 50, and 250 pg/dL decreased GM-CSF production (p < 0.003) in LPS- or PHA-stimulated MNC cultures and in PHA-stimulated T-cell cultures. PHA (not tested with LPS)-stimulated GM-CSF messenger RNA (mRNA) expression was blocked by hydrocortisone. These results indicate that lower concentrations of hydrocortisone inhibit GM-CSF production from normal human blood MNCs and T cells entirely by inhibiting the expression of GM-CSF mRNA, and higher concentrations of hydrocortisone inhibit by a combined effect of inhibiting the expression of GM-CSF mRNA and decreasing the lymphocyte count.

Noninvasive evaluation for iron deficiency is compromised in many individuals due to the presence of chronic inflammatory processes and/or malignancy, thus necessitating bone marrow examination for definitive diagnosis. However, bone marrow aspiration is not obtainable or is inadequate for interpretation (dry tap) in some individuals, and decalcified bone marrow biopsies require 24-48 hr to prepare, and may falsely indicate absence of iron. We evaluated the accuracy of bone marrow biopsy imprints (touch preparations) compared with aspirate particle smears for semiquantitation of bone marrow iron stores. Results indicate that Prussian blue-stained bone marrow biopsy imprints accurately reflect the quantity of iron, compared with bone marrow aspirate particle smears, allowing for rapid determination of iron stores in individuals in whom a bone marrow aspirate cannot be obtained.

We studied the role of lipoxygenase products on the proliferation and recovery of granulocyte-macrophage progenitors (CFU-GM) in liquid cultures of normal human blood mononuclear cells containing physiologic or slightly higher than physiologic concentrations of hydrocortisone (HC). Lipoxygenase blockade by addition of nordihydroguaiaretic acid (NDGA) resulted in enhanced recovery of CFU-GM (mean increase of 230%). The number of CFU-GM recovered from 14-day liquid cultures containing 1.0 microM HC plus 10 microM NDGA was a mean of six times higher than the number present in the inoculum. Effects of addition of selected 5-lipoxygenase products into the culture containing a lipoxygenase blocker on the CFU-GM recovery and proliferative activity were dose- and metabolite-specific. Leukotriene (LT) B4 and 5-hydroxy-eicosatetraenoic acid (5-HETE) decreased recovery of CFU-GM while LTC4 and LTD4 had biphasic effects--lower doses decreased while higher doses had no effect on CFU-GM recovery. Lipoxygenase blockade decreased the percent of CFU-GM in DNA synthesis phase. Readdition of LTB4 did not reverse this effect while LTD4 had a biphasic effect--low concentrations increased the percent of CFU-GM in DNA synthesis phase to levels equivalent to CFU-GM in cultures without NDGA while higher concentrations had no effect. In semisolid CFU-GM assays, lipoxygenase blockade with NDGA completely prevented CFU-GM colony formation, suggesting that NDGA inhibits proliferation and/or differentiation of CFU-GM in semisolid culture assays. The results of our studies suggest that 5-lipoxygenase metabolites are physiologically important in regulating the proliferation of CFU-GM and, thus, granulopoiesis.