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Thromboangiitis obliterans (TAO) and antiphospholipid syndrome (APS) share the clinical characteristics of arterial thrombosis and recurrent thrombophlebitis. Although the association of anticardiolipin antibodies (aCLa) and TAO has been previously recognized, the prevalence and the clinical impact of this association remains unclear. aCLa were measured by double ELISA in patients with TAO (n=47), premature atherosclerosis (pASO) (n=48) and otherwise healthy individuals (n=48). Antibody status was then compared to clinical presentation and outcomes in patients meeting the diagnostic criteria for TAO. The prevalence of aCLa was significantly higher in patients with TAO (36%) compared to either pASO (8%; p=0.01) or healthy individuals (2%; p,0.001). Patients with TAO and a high antibody titer tended to be younger and suffer a significantly higher rate of major amputations compared to those without the antibody (100% versus 17%; p=0.003). Clinical features of TAO not significantly altered by the presence of aCLa included upper limb involvement, digital necrosis, superficial thrombophlebitis (or deep venous thrombosis). Protein C, protein S, and anti-thrombin III were normal in all individuals. TAO is associated with an increased prevalence of aCLa. The presence of a high antibody titer in these patients is associated with increased morbidity, including major limb amputation. In patients meeting the diagnostic criteria for TAO, screening for aCLa should be considered. Although attractive, the efficacy of chronic anticoagulation in this setting remains to be proven.

Purpose: Radioimmunotherapy (RIT) with yttrium-90 (90Y)-labeled anti-CD20 antibody (90Y ibritumomab tiuxetan; Zevalin, IDEC Pharmaceuticals Corporation, San Diego, CA) has a high rate of tumor response in patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL). This study presents the safety data from 349 patients in five studies of outpatient treatment with 90Y ibritumomab tiuxetan. Patients and Methods: Patients received rituximab 250 mg/m2 on days 1 and 8, and either 0.4 mCi/kg (15 MBq/kg) or 0.3 mCi/kg (11 MBq/kg) of 90Y ibritumomab tiuxetan on day 8 (maximum dose, 32 mCi). Patients were observed for up to 4 years after therapy or until progressive disease. Results: Infusion-related toxicities were typically grade 1 or 2 and were associated with rituximab. No significant organ toxicity was noted. Toxicity was primarily hematologic, with nadir counts occurring at 7 to 9 weeks and lasting approximately 1 to 4 weeks depending on the method of calculation. After the 0.4-mCi/kg dose, grade 4 neutropenia, thrombocytopenia, and anemia occurred in 30%, 10%, and 3% of patients, respectively, and after the 0.3-mCi/kg dose, these grade 4 toxicities occurred in 35%, 14%, and 8% of patients, respectively. The risk of hematologic toxicity increased with degree of baseline bone marrow involvement with NHL. Seven percent of patients were hospitalized with infection (3% with neutropenia) and 2% had grade 3 or 4 bleeding events. Myelodysplasia or acute myelogenous leukemia was reported in five patients (1%) 8 to 34 months after treatment. Conclusion: Single-dose 90Y ibritumomab tiuxetan RIT has an acceptable safety profile in relapsed NHL patients with less than 25% lymphoma marrow involvement, adequate marrow reserve, platelets greater than 100,000 cells/μL, and neutrophils greater than 1,500 cells/μL.

Abstract Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are syndromes of acute respiratory failure that result from acute pulmonary edema and inflammation. The development of ALI/ARDS is associated with several clinical disorders including direct pulmonary injury from pneumonia and aspiration as well as indirect pulmonary injury from trauma, sepsis, and other disorders such as acute pancreatitis and drug overdose. Although mortality from ALI/ARDS has decreased in the last decade, it remains high. Despite two major advances in treatment, low VT ventilation for ALI/ARDS and activated protein C for severe sepsis (the leading cause of ALI/ARDS), additional research is needed to develop specific treatments and improve understanding of the pathogenesis of these syndromes. The NHLBI convened a working group to develop specific recommendations for future ALI/ARDS research. Improved understanding of disease heterogeneity through use of evolving biologic, genomic, and genetic approaches should provide major new insights into pathogenesis of ALI. Cellular and molecular methods combined with animal and clinical studies should lead to further progress in the detection and treatment of this complex disease.

The POEMS syndrome (coined to refer to polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) remains poorly understood. Ambiguity exists over the features necessary to establish the diagnosis, treatment efficacy, and prognosis. We identified 99 patients with POEMS syndrome. Minimal criteria were a sensorimotor peripheral neuropathy and evidence of a monoclonal plasmaproliferative disorder. To distinguish POEMS from neuropathy associated with monoclonal gammopathy of undetermined significance, additional criteria were included: a bone lesion, Castleman disease, organomegaly (or lymphadenopathy), endocrinopathy, edema (peripheral edema, ascites, or effusions), and skin changes. The median age at presentation was 51 years; 63% were men. Median survival was 165 months. With the exception of fingernail clubbing (P = .03) and extravascular volume overload (P = .04), no presenting feature, including the number of presenting features, was predictive of survival. Response to therapy (P < .001) was predictive of survival. Pulmonary hypertension, renal failure, thrombotic events, and congestive heart failure were observed and appear to be part of the syndrome. In 18 patients (18%), new disease manifestations developed over time. More than 50% of patients had a response to radiation, and 22% to 50% had responses to prednisone and a combination of melphalan and prednisone, respectively. We conclude that the median survival of patients with POEMS syndrome is 165 months, independent of the number of syndrome features, bone lesions, or plasma cells at diagnosis. Additional features of the syndrome often develop, but the complications of classic multiple myeloma rarely develop.

Purpose: We conducted this study because the duration of excess lung cancer risk among former smokers has been inconsistently reported, doubt has been raised regarding the population impact of smoking cessation, and differential risk reduction by histologic cell type after smoking cessation needs to be confirmed. Methods: The Iowa Women’s Health Study is a prospective cohort study of 41,836 Iowa women aged 55 to 69 years. In 1986, mailed questionnaires were used to collect detailed smoking history. Age-adjusted lung cancer incidence through 1999 was analyzed according to years of smoking abstinence. Relative risks were estimated using Cox regression analysis. Results: There were 37,078 women in the analytic cohort. Compared with the never smokers, former smokers had an elevated lung cancer risk (relative risk, 6.6; 95% confidence interval, 5.0 to 8.7) up to 30 years after smoking cessation for all former smokers. However, a beneficial effect of smoking cessation was observed among recent and distant former smokers. The risk of adenocarcinoma remained elevated up to 30 years for both former heavier and former lighter smokers. Conclusion: The risk for lung cancer is increased for both current and former smokers compared with never smokers and declines for former smokers with increasing duration of abstinence. The decline in excess lung cancer risk among former smokers is prolonged compared with other studies, especially for adenocarcinoma and for heavy smokers, suggesting that more emphasis should be placed on smoking prevention and lung cancer chemoprevention.

Angiogenesis plays an important role in the biology of multiple myeloma (MM) and has prognostic importance in this disease. Solitary plasmacytoma is a localized plasma cell malignancy that progresses to MM in a significant number of patients. We examined if angiogenesis is increased in solitary plasmacytoma and if it can help identify patients likely to progress to myeloma. We studied angiogenesis in plasmacytoma biopsy samples and bone marrow biopsies from 25 patients. High-grade angiogenesis was present in 64% of plasmacytomas. In contrast, bone marrow angiogenesis was low in all patients. Patients with high-grade angiogenesis in the plasmacytoma sample were more likely to progress to myeloma and had a shorter progression-free survival compared with patients with low-grade angiogenesis (P = .02). Angiogenesis is increased in solitary plasmacytoma and is a significant predictor of progression to myeloma and provides further evidence of its importance in the pathogenesis of myeloma.

A paradoxical increase in mortality attributable to diabetes has occurred, particularly during the last decade, despite the overall decrease in mortality attributable to coronary artery disease in patients without diabetes. Insulin resistance with or without frank type 2 diabetes has emerged as a major determinant of accelerated coronary artery disease and its sequelae. The advent of insulin sensitizers enables clinicians to target treatment of insulin resistance, as well as hyperglycemia and dyslipidemia. The prevalence of diabetes in the United States is enormous and is increasing rapidly. Patients with diabetes respond less favorably to percutaneous coronary interventions and surgery compared with nondiabetic patients. These considerations led to the initiation of the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. It is designed to determine whether treatment targeted to attenuate insulin resistance can arrest or retard progression of coronary artery disease compared with treatment targeted to the same level of glycemic control with an insulin-providing approach. It is designed also to determine whether early revascularization reduces mortality and morbidity in patients with type 2 diabetes whose cardiac symptoms are mild and stable. Despite challenges in study design and enrollment, intensive follow-up, and the long duration of follow-up planned, the questions being addressed are compelling and seem to merit the effort.

Abstract This study examined the prognostic value of circulating peripheral blood plasma cells (PBPCs) in patients with primary systemic amyloidosis (AL). A sensitive slide-based immunofluorescence technique was used to assess 147 patients for circulating PBPCs. Circulating monoclonal plasma cells were quantified as a percentage of circulating cytoplasmic immunoglobulin-positive cells (PBPC%). The absolute circulating plasma cell count was also determined. When analyzed retrospectively, 24 (16%) of 147 patients were found to have detectable circulating PBPCs. Overall survival for patients with high PBPC%'s (> 1%) was poorer (median survival, 10 vs 29 months;P = .002). Similarly, overall survival for patients with high PBPC counts (> 0.5 × 106/L) was significantly poorer (median, 13 vs 31 months;P = .003). Increased percentages of bone marrow plasma cells (BMPC%; P = .0004), increased levels of serum β2-microglobulin (P = .04), and dominant cardiac amyloid involvement (P = .03) also predicted poorer survival. The combined consideration of circulating PBPCs and BMPC% identified low-, intermediate-, and high-risk groups with median survivals of 37.5, 15.5, and 10 months, respectively (P = .0003). Multivariate analysis revealed circulating PBPCs and BMPC% to be independent prognostic factors for survival. Patients with PBPC%'s of 2% or higher were significantly more likely to have a coexisting clinical diagnosis of multiple myeloma (50% vs 12%, P = .008). The prognostic value of circulating PBPCs may help select treatment for patients with AL.

Purpose: The purpose of this article is to determine the response rate and toxicity of PCV administered before radiation therapy in patients with newly diagnosed LGO/LGOA and to explore correlations between response with 1p/19q deletions and aberrant p53 expression. Background: Despite prolonged survival of patients with low-grade oligodendroglioma (LGO) and oligoastrocytoma (LGOA), the majority will succumb to progressive disease. Because procarbazine, lomustine (CCNU), and vincristine (PCV) is active in patients with recurrent LGO/LGOA, we hypothesized that it would be beneficial as primary therapy. Methods: Adult patients with residual tumor on magnetic resonance imaging scan following biopsy or subtotal resection of LGO/LGOA received up to six cycles of PCV. Radiation therapy (59.4 or 54.0 Gy) began within 10 weeks of completing chemotherapy or immediately if there was evidence of tumor progression on PCV. Tumor tissue was analyzed by fluorescent in situ hybridization for 1p and 19q deletion and by immunohistochemistry for p53 expression. Results: Eight of 28 (29%) and 13 of 25 (52%) eligible patients demonstrated tumor regression as assessed by the treating physician and a blinded central neuroradiology reviewer, respectively. Myelosuppression was the predominant toxicity. Loss of 1p and 19q were associated with LGO but not LGOA (P = .009), were inversely associated with p53 detection, and were not associated with response to PCV (possibly because of the small sample size). Conclusion: PCV produces tumor regressions in a meaningful proportion of patients with LGO/LGOA. Toxicity, especially myelosuppression, is significant. Loss of 1p and 19q seems limited to patients with pure LGO and is inversely related to p53 alterations.

ABSTRACT We investigated the effect of multiple freeze-thaw cycles on mumps, measles, and rubella virus serum antibody levels with whole-virus immunoglobulin G enzyme-linked immunoassays. Fresh serum samples from nine healthy adult volunteers were divided into six sets of five aliquots each. Samples were taken through a total of 10 freeze-thaw cycles and stored at 4°C until assayed. Each assay measurement was done in replicates of five, and the mean value was reported. After completing 10 freeze-thaw cycles, we found no clinically or statistically significant effect on measured antibody levels and found no discernible detrimental effect on the ability to measure these antibodies by enzyme-linked immunoassays.