Predicting outcome after lung resection for invasive pulmonary aspergillosis in patients with neutropenia

STUDY OBJECTIVES: To investigate the factors that predict survival after lung resection for invasive pulmonary aspergillosis (IPA) in patients with neutropenia, in order to assist the selection of patients who are most likely to have a successful outcome. DESIGN: Retrospective single-center study. SETTING: University hospital hemato-oncologic isolation unit and division of thoracic surgery. PATIENTS: Forty-one patients with hematologic disease and suspected IPA who underwent lung resection. INTERVENTIONS: Lobectomy (n = 23), wedge resection (n = 16), and enucleation (n = 2). RESULTS: Mortality within 30 days was 10% (4 of 41 patients). Major perioperative complications occurred in 10%. One death was possibly related to surgery (pleural aspergillosis). Of the patients with proven aspergillosis, 87.1% were cleared of infection, but fungal relapse occurred in 10%. Overall survival was 65% at 6 months, 58% at 12 months, and 40% at 5 years after surgery. Baseline characteristics and intraoperative data did not differ significantly between survivors and nonsurvivors at 6 months or 12 months after surgery. Perioperative complications did not significantly influence the outcome. Multivariate analysis of 12-month survival revealed that the variables, progression, or recurrence of the underlying hematologic disease (relative risk [RR], 4.64; 95% confidence interval [CI], 3.51 to 5.77; p < 0.0001), fungal relapse (RR, 5.06; 95% CI, 3.83 to 6.28; p < 0.0001), and to a minor extent the type of the underlying hematologic disease (p < 0.018) were the most important predictors of patient survival. CONCLUSIONS: Lung resection for IPA is feasible with an acceptable operative risk. While at 10%, the perioperative mortality is considerable; the nonsurgical mortality is reported to be between 30% and 90%. Fungal infection is cleared in > 80% of patients. Mid- to long-term survival can be achieved if the underlying hematologic disease is under control. It is not yet possible to define a group of patients with IPA who are most likely to benefit from lung resection.     

ANGIOTENSIN II ANTAGONISTS: A NEW CLASS OF ANTIHYPERTENSIVE AGENT

SUMMARY Losartan is an orally active angiotensin II antangonist that selectively blocks effects mediated by the stimulation of the AT₁ subtype of the angiotensin II receptor. This agent, at doses of 50-150mg/day, is as effective at lowering blood pressure as chronic angiotensin converting enzyme (ACE) inhibitors. Losartan is generally well tolerated and has an incidence of adverse effects very similar, in double-blind controlled trials, to that of placebo. It does not cause coughing, the most common side-effect of the ACE inhibitors, most probably because angiotensin II antagonism has no impact on ACE, an enzyme known to process bradykinin and other cough-inducing peptides. Losartan is a promising antihypertensive agent with the potential to become a first-line option for the treatment of patients with high blood pressure.     

Single-center outcome analysis of 1,161 patients with St. Jude medical and ATS open pivot mechanical heart valves

BACKGROUND AND AIM OF THE STUDY: The clinical performance of mechanical heart valves and valve-related complications are important safety endpoints in patients after heart valve replacement. In this retrospective analysis, the mid- to long-term clinical outcomes of two similar bileaflet heart valves, routinely implanted at the authors' institution over an 11-year period, were compared. METHODS: Between January 1993 and December 2003, a total of 1,161 patients (758 males, 403 females) received either a St. Jude Medical (SJM) or ATS mechanical heart valve. Follow up was obtained via an in-house Quality Management Database, ascertained by telephone questionnaire of the patients and/or family physicians. Follow up was 98.9% complete; the median follow up was 4.6 years; total follow up was 5,624 patient-years (pt-yr). RESULTS: A total of 604 SJM and 601 ATS prostheses was implanted as isolated (n = 669) or combined (n = 492) procedures. The overall 30-day mortality for SJM and ATS was 4.1% and 3.4%, respectively (p = 0.45). Cumulative survival and freedom from valve-related mortality at 10 years for SJM and ATS valves were 66 +/- 3% versus 68 +/- 5% (p = 0.84) and 96 +/- 1% versus 97 +/- 1% (p = 0.36), respectively. No structural valve failure was encountered for both valve types. Freedom from overall valve-related complications at 10 years was 79 +/- 4% for SJM and 66 +/- 6% for ATS (p = 0.08). The linearized rates for valve-related adverse events for SJM and ATS valves, respectively, were: thromboembolism 0.9 and 1.1%/pt-yr; major bleeding requiring transfusion 0.3 and 0.5%/pt-yr; prosthetic endocarditis 0.03 and 0.1%/pt-yr; paravalvular leak 0.1 and 0.6%/pt-yr. CONCLUSION: On the basis of an 11-year experience, both bileaflet valves showed very good clinical results, with low incidences of adverse events during the mid-term outcome. Gender and/or concomitant coronary artery disease were not predictors for reduced life expectancy.     

Oral iloprost in Raynaud's phenomenon secondary to systemic sclerosis: a multicentre, placebo-controlled, dose-comparison study

OBJECTIVE: To identify the optimal dose of oral iloprost on the basis of efficacy and tolerability in patients with Raynaud's phenomenon secondary to systemic sclerosis. DESIGN: Multicentre, randomized, parallel-group comparison of two different doses of oral iloprost and placebo. SETTING: European university hospitals. PATIENTS: A total of 103 patients with Raynaud's phenomenon secondary to systemic sclerosis. INTERVENTION: Patients received one of three treatments for 6 weeks: placebo, oral iloprost 50 microg or oral iloprost 100 microg. Each treatment was taken twice daily, giving total daily doses of iloprost of 100 and 200 microg. MEASUREMENTS: The frequency, total daily duration and severity of Raynaud's attacks were recorded in a specially designed patient diary; physician's global assessment and adverse events were recorded at visits to the clinic. Analysis was performed on an intention-to-treat population. RESULTS: A total of 103 patients were recruited, 89 completed the assessments throughout the treatment period and 82 completed an additional 6 weeks of follow-up after treatment. Thirty-five patients received placebo, 33 received iloprost 50 microg and 35 received iloprost 100 microg. The mean percentage reductions in the frequency, total daily duration and severity of Raynaud's attacks were numerically greater in the iloprost groups at the end of treatment and at the end of follow-up. At the end of treatment (6 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.03), but not in the severity (P = 0.07) or the frequency of attacks (P = 0.37). At the end of follow-up (12 weeks), there were significant treatment differences in the total daily duration of attacks (P = 0.001) and in the severity of attacks (P = 0.007), but not in the frequency of attacks (P = 0.07). Percentages of patients improved at the end of treatment as assessed by the physician were 44% placebo, 57% iloprost 50 microg and 64% iloprost 100 microg (not significant). Side-effects were reported by 80% of patients on placebo, 85% on oral iloprost 50 microg and 97% on oral iloprost 100 microg. Premature discontinuations of treatment in each group were 9, 30 and 51%, respectively, with 6, 27 and 51% being due to adverse events. CONCLUSION: The results on the daily duration of Raynaud's attacks suggest that both 50 and 100 microg oral iloprost twice daily may be effective in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. The 50 microg iloprost dose was better tolerated in this patient group.      

Acute myeloid leukemia M4 with bone marrow eosinophilia (M4Eo) and inv(16)(p13q22) exhibits a specific immunophenotype with CD2 expression

Extensive immunologic marker analysis was performed to characterize the various leukemic cell populations in eight patients with inv(16)(p13q22) in association with acute myeloid leukemia with abnormal bone marrow eosinophilia (AML-M4Eo). The eight AML cases consisted of heterogeneous cell populations; mainly due to the presence of multiple subpopulations, which varied in size between the patients. However, the immunophenotype of these subpopulations was comparable, independent of their relative sizes. Virtually all AML-M4Eo cells were positive for the pan-myeloid marker CD13. In addition, the AML were partly positive for CD2, CD11b, CD11c, CD14, CD33, CD34, CD36, CDw65, terminal deoxynucleotidyl transferase (TdT), and HLA-DR. Double immunofluorescence stainings demonstrated coexpression of the CD2 antigen and myeloid markers and allowed the recognition of multiple AML subpopulations. The CD2 antigen was expressed by immature AML cells (CD34+, CD14-) and more mature monocytic AML cells (CD34-, CD14+), whereas TdT expression was exclusively found in the CD34+, CD14- cell population. The eight AML-M4Eo cases not only expressed the CD2 antigen, but also its ligand CD58 (leukocyte function antigen-3). Culturing of AML-M4Eo cell samples showed a high spontaneous proliferation in all three patients tested. Addition of a mixture of CD2 antibodies against the T11.1, T11.2, and T11.3 epitopes diminished cell proliferation in two patients with high CD2 expression, but no inhibitory effects were found in the third patient with low frequency and low density of CD2 expression. These results suggest that high expression of the CD2 molecule in AML-M4Eo stimulates proliferation of the leukemic cells, which might explain the high white blood cell count often found in this type of AML.     

Platelet adhesion to cyanogen-bromide fragments of collagen alpha 1(I) under flow conditions

The aim of this investigation was to identify domains of collagen type I that can support platelet adhesion under flow conditions. Four cyanogen bromide (CB) fragments composing 87% of the collagen alpha 1(I)-chain were studied under static and flow conditions. Under static conditions, bovine and human collagen fragment alpha 1(I)CB3 induced aggregate formation, whereas alpha 1(I)CB7 and alpha 1(I)CB8 supported adhesion of dendritic and contact platelets. Bovine alpha 1(I)CB6 weakly supported platelet adhesion. At shear rate 300/s, collagen fragment alpha 1(I)CB3 strongly supported platelet adhesion, whereas lower platelet adhesion was observed to alpha 1(I)CB7 and alpha 1(I)CB8. The fragment alpha 1(I)CB6 did not support platelet adhesion under flow conditions. Adhesion to alpha 1(I)CB3 was completely inhibited by a low concentration (0.6 IgG microgram/mL) of anti-GPIa monoclonal antibody (MoAb), whereas this concentration of antibody partially inhibited adhesion to alpha 1(I)CB7 and alpha 1(I)CB8. At higher concentrations (3 micrograms/mL) the anti-glycoprotein Ia (GPIa) antibody completely inhibited adhesion to alpha 1(I)CB8 and further reduced adhesion to alpha 1(I)CB7. Platelet adhesion to alpha 1(I)CB3, alpha 1(I)CB7, and alpha 1(I)CB8 was strongly inhibited by an anti-GPIb MoAb. A MoAb against the GPIb-binding site of von Willebrand factor (vWF) strongly inhibited platelet adhesion to alpha 1(I)CB7 and alpha 1(I)CB8, whereas platelet adhesion to alpha 1(I)CB3 was not inhibited. We conclude that under flow conditions alpha 1(I)CB3, alpha 1(I)CB7, and alpha 1(I)CB8 support GPIa/IIa-dependent platelet adhesion. The GPIb-vWF interaction is important under flow conditions for adhesion to alpha 1(I)CB7 and alpha 1(I)CB8 and probably also to alpha 1(I)CB3.     

Generation of natural killer cells from both Fc gamma RII/III+ and Fc gamma RII/III- murine fetal liver progenitors

In vitro culture of day-15.5 murine fetal liver (FL) cells in the presence of recombinant interleukin-2 (IL-2) results in the expansion of Fc gamma RII/III+ CD3-Ti-NK1.1+ cells displaying both natural killer (NK) and antibody-dependent cell cytotoxicity (ADCC) cytolytic activities. These FL-derived NK cells express Fc gamma RIII (CD16) in association with an Fc epsilon RI gamma homodimer on their surface. In contrast, in vitro expansion of FL cells in the absence of IL-2 generates noncytotoxic cells belonging to the myelomonocytic lineage (Mac1+Gr1+NK1.1-). Hence, IL-2 appears to be critical for the proliferation and differentiation of NK cells from FL progenitors. Experiments in which FL cells were fractionated by density gradient centrifugation before in vitro expansion showed that NK progenitors are contained within a cell population with a density of 1.04 < d < 1.08 g/mL. Cells with d > 1.08 g/mL (representing > or = 40% of FL cells) have no such NK progenitor activity. In addition, after intrathymic injection into Ly5 congenic host animals, day-15.5 CD4-CD8- FL cells mature into CD4+CD8+ thymocytes within 12 days. Interestingly, this T- cell progenitor activity is restricted to subpopulations of FL cells that also contain NK progenitors, but is absent in high-density (d > 1.08 g/mL) FL cells. Finally, fractionation of FL cells according to surface expression of Fc gamma RII/III complexes shows that NK (and T- lymphocyte) progenitors are found in both Fc gamma RII/III+ and Fc gamma RII/III-FL subpopulations.