Citations

AbstractPrevious studies have demonstrated the in vitro and in vivo activity of CC-5013 (Revlimid), an immunomodulatory analog (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin (Rapamune), a specific mTOR inhibitor, combined with CC-5013. Based on the Chou-Talalay method, combination indices of less than 1 were obtained for all dose ranges of CC-5013 when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover, the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). Combining rapamycin and CC-5013 induced apoptosis of MM cells. Differential signaling cascades, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3′-kinase/Akt kinase (PI3K/Akt) pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies, therefore, provide the framework for clinical evaluation of mTOR inhibitors combined with IMiDs to improve patient outcome in MM.

ABSTRACT The human monoclonal antibody rHIgM22 enhances remyelination following spinal cord demyelination in a virus‐induced murine model of multiple sclerosis. Using three‐dimensional T2‐weighted in vivo spinal cord magnetic resonance imaging (MRI), we have therefore assessed the extent of spinal cord demyelination, before and after 5 weeks of treatment with rHIgM22, to determine whether antibody enhanced remyelination can be detected by MRI. A significant decrease was seen in T2 high signal lesion volume following antibody treatment. Histologic examination of the spinal cord tissue reveals that this decrease in lesion volume correlates with antibody promoted remyelination. To show that rHIgM22 enters the spinal cord and colocalizes with demyelinating lesions, we used ultrasmall superparamagnetic iron oxide particle (USPIO)‐labeled antibodies. This may be considered as additional evidence to the hypothesis that rHIgM22 promotes remyelination by local effects in the lesions, likely by binding to CNS cells. The reduction in high signal T2‐weighted lesion volume may be an important outcome measure in future clinical trials in humans.

Abstract OBJECTIVE To evaluate tumor control rates and complications after stereotactic radiosurgery for patients with nonfunctioning pituitary adenomas. METHODS Between 1992 and 2000, 33 patients underwent radiosurgery for treatment of nonfunctioning pituitary adenomas. Thirty-two patients (97%) had undergone one or more previous tumor resections. Twenty-two patients (67%) had enlarging tumors before radiosurgery. The median tumor margin dose was 16 Gy (range, 12–20 Gy). The median follow-up period after radiosurgery was 43 months (range, 16–106 mo). RESULTS Tumor size decreased for 16 patients, remained unchanged for 16 patients, and increased for 1 patient. The actuarial tumor growth control rates at 2 and 5 years after radiosurgery were 97%. No patient demonstrated any decline in visual function. Five of 18 patients (28%) with anterior pituitary function before radiosurgery developed new deficits, at a median of 24 months after radiosurgery. The actuarial risks of developing new anterior pituitary deficits were 18 and 41% at 2 and 5 years, respectively. No patient developed diabetes insipidus. CONCLUSION Stereotactic radiosurgery safely provides a high tumor control rate for patients with recurrent or residual nonfunctioning pituitary adenomas. However, despite encouraging early results, more long-term information is needed to determine whether radiosurgery is associated with lower risks of new endocrine deficits and radiation-induced neoplasms, compared with fractionated radiotherapy.

Abstract OBJECTIVE AND IMPORTANCE Melanocytic colonization of nonpigmented extracranial tumors has been reported in adenocarcinomas, squamous cell carcinomas, skin appendage tumors, and dermatofibrosarcoma protuberans. To our knowledge, melanocytic colonization of a meningioma has not previously been described. CLINICAL PRESENTATION We report an unusual case of a 70-year-old African-American woman who presented with a large frontoparietal meningioma that extended through the calvarium. INTERVENTION Craniotomy with gross total resection of the tumor was performed. Histochemistry, immunocytochemistry, ultrastructural analysis, and molecular genetic study via fluorescence in situ hybridization confirmed melanocytic colonization of a meningothelial meningioma. CONCLUSION With the inclusion of meningothelial meningioma, the spectrum of tumors affected by melanocytic colonization continues to expand.

Background— This study evaluated long-term results of aortic root replacement and valve-preserving aortic root reconstruction for patients with aneurysms involving the aortic root. Methods and Results— Two-hundred three patients aged 53±16 years (mean±SD; 153 male, 50 female) underwent elective or urgent aortic root surgery from 1971 to 2000 for an aortic root aneurysm: 149 patients underwent a composite valve conduit reconstruction, and 54 patients underwent valve-preserving aortic root reconstruction. Fifty patients had Marfan syndrome. In-hospital and 30-day mortality was 4.0% (8/203) overall: for a composite valve conduit procedure, the corresponding value was 4.0% (6/149) and for valve-preserving procedure, 3.7% (2/54) ( P =NS). Morbidity included 3 strokes (1%), 10 perioperative myocardial infarctions (5%), and 8 reoperations for bleeding (4%). Actuarial survival at 5, 10, 15, and 20 years was 93% (95% confidence interval [CI] = 88% to 97%), 79% (95% CI = 71% to 87%), 67% (95% CI = 57% to 79%), and 52% (95% CI = 36% to 69%), respectively. Freedom from reoperation was 72% (95% CI = 54% to 86%) at 20 years. Complications with anticoagulation occurred in 29 patients; with valve thrombosis, in 2; and with hemorrhage, in 27 (4 life threatening and 23 minor). Freedom from thromboembolism was 91% (95% CI = 77% to 98%) at 20 years. Freedom from endocarditis was 99% (95% CI = 92% to 100%) at 20 years. Multivariate analysis revealed preoperative mitral valve regurgitation (+3 to 4) and older age to be significant predictors of late death ( P ≤0.005), and Marfan syndrome, initial valve-preserving aortic root reconstruction, and need for a concomitant procedure at initial operation to be significant predictors of the need for reoperation ( P ≤0.01). Conclusions— Aortic root replacement for aortic root aneurysms can be done with low morbidity and mortality. Composite valve conduit reconstruction resulted in a durable result. There were few serious complications related to the need for long-term anticoagulation or a prosthetic valve. Reoperation was most commonly required because of failure of the aortic valve when a valve-preserving aortic root reconstruction was performed or for other cardiac or aortic disease elsewhere.

Background— Recently, we identified circulating smooth muscle progenitor cells (SPCs) in human peripheral blood. The integrin profile of such progenitors is currently unknown and may affect their in vivo homing characteristics. In this study, we determined the integrin profile of vascular progenitors and SPC adhesion to extracellular matrix (ECM) proteins in vitro and in vivo. Methods and Results— SPCs and endothelial progenitor cells (EPCs) were isolated from peripheral blood of healthy human subjects, and expression of surface integrins and adhesion to several vascular ECM proteins were determined. Homing of SPCs in vivo to specific ECM protein was determined by intracoronary infusion of fluorescent SPCs into porcine coronary arteries containing a fibronectin-coated mesh stent. SPCs had high expression of β 1 integrin, moderate expression of α 1 , low levels of α v β 3 , and did not express α v β 5 , β 2 , α 2 β 1 , or α 4 β 1 integrins. In contrast, EPCs had high expression of α 2 β 1 , α v β 3 , α v β 5 , β 1 , and α 1 and minimal expression of α 4 β 1 . Moreover, SPCs showed increased adherence to fibronectin and collagen type I compared with vitronectin, consistent with their integrin profile, and demonstrated a similar degree of in vivo attachment to fibronectin-coated mesh. Conclusions— These data for the first time show a spectrum of integrin expression on vascular progenitors and suggest the potential importance of integrins in mediating adherence of SPCs to specific ECM both in vitro and in vivo.

Background— Antiplatelet therapy and antithrombin therapy have been demonstrated to reduce the risk of cardiac events in patients presenting with acute coronary syndrome, yet all effective therapies also increase the risk of bleeding. Methods and Results— In the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial, 12 562 patients were randomized to clopidogrel or placebo in addition to aspirin, and the primary outcome was cardiovascular (CV) death, myocardial infarction (MI), or stroke. The benefits were consistent among those undergoing percutaneous coronary intervention (PCI) [9.6% for clopidogrel, 13.2% for placebo; relative risk (RR), 0.72; 95% CI, 0.57 to 0.90], coronary artery bypass grafting (CABG) surgery (14.5% for clopidogrel 16.2% for placebo; RR, 0.89; 95% CI, 0.71 to 1.11), and medical therapy only (8.1% for clopidogrel, 10.0% for placebo; RR, 0.80; 95% CI, 0.69 to 0.92; test for interaction among strata, 0.53). For CABG during the initial hospitalization (530 for placebo, 485 for clopidogrel), the frequency of CV death, MI or stroke before CABG was 4.7% for placebo and 2.9% for clopidogrel (RR, 0.56; 95% CI, 0.29 to 1.08). For the entire study, there was a 1% excess of major bleeding but no significant excess of life-threatening bleeding. Among patients undergoing CABG, the rates of life-threatening bleeding were 5.6% for clopidogrel and 4.2% for placebo (RR, 1.30; 95% CI, 0.91 to 1.95; both nonsignificant). Conclusions— The benefits versus risks of early and long-term clopidogrel therapy (freedom from CV death, MI, stroke, or life-threatening bleeding) are similar in those undergoing revascularization (CABG or PCI) and in the study population as a whole. Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks, even among those who proceed to CABG during the initial hospitalization.

We report an 8-year-old girl who presented with clinical features of an acute myocardial infarction. The angiographic appearance of the coronary arteries was normal. A thrombophilic state caused by a homozygote genotype for the prothrombin G20210A mutation was detected, and a patent foramen ovale (PFO) with right-to-left shunting after Valsalva maneuver was demonstrated by transesophageal contrast echocardiography. No other embolic source was identified. We suggest that paradoxical embolization through a PFO resulted in a myocardial infarction in this young patient with hereditary thrombophilia. We closed the patient’s PFO with a 25-mm PFO occluder. She was anticoagulated with warfarin for 6 months. After 6 months, a contrast echocardiogram showed no evidence of residual atrial shunt. There has been no evident recurrent paradoxical embolization.

Background. Although glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is prevalent in African Americans, their risk of associated neonatal hyperbilirubinemia has not been prospectively studied.Objective. To compare hemolysis and the risk of hyperbilirubinemia among African American, G-6-PD-deficient neonates (study group) and G-6-PD-normal control subjects.Methods. Consecutive, healthy, term and near-term, male neonates born to African American mothers comprised the patient cohort. G-6-PD testing was performed with umbilical cord blood samples. Routine management included measurement of the end tidal carbon monoxide level corrected for ambient carbon monoxide level (ETCOc) within 4 hours after delivery (assessment of hemolysis), ≥1 predischarge bilirubin determination, and additional bilirubin testing as clinically indicated. Indications for phototherapy were identical for study patients and control subjects. Neonates were monitored for the first 1 week of life. ETCOc results, the incidence of hyperbilirubinemia (defined as a transcutaneous or plasma total bilirubin concentration of ≥95th percentile for the hour of life), and the need for phototherapy were compared between the G-6-PD-deficient and G-6-PD-normal groups.Results. Five hundred male patients were enrolled, of whom 64 (12.8%) were G-6-PD-deficient. ETCOc values (median and interquartile range) were higher among G-6-PD-deficient neonates than among control neonates (2.4 ppm [2.0–2.9 ppm] vs 2.1 ppm [1.7–2.5 ppm]). More G-6-PD-deficient neonates developed hyperbilirubinemia than did control subjects (14 of 64, 21.9%, vs 29 of 436, 6.7%; relative risk: 3.27; 95% confidence interval: 1.83-5.86), whereas 13 (20.3%) met the criteria for phototherapy, compared with 25 control subjects (5.7%) (relative risk: 3.53; 95% confidence interval: 1.91-6.56). No cases of kernicterus were observed.Conclusions. Within the African American neonatal population, there is a subgroup of G-6-PD-deficient infants with elevated rates of hemolysis, a higher incidence of hyperbilirubinemia, and a greater requirement for phototherapy, compared with G-6-PD-normal control subjects. These newborns should be monitored vigilantly for the development of hyperbilirubinemia.