Citations

Abstract Rationale Transforming growth factor (TGF)-β has a central role in driving many of the pathological processes that characterize pulmonary fibrosis. Inhibition of the integrin αvβ6, a key activator of TGF-β in lung, is an attractive therapeutic strategy, as it may be possible to inhibit TGF-β at sites of αvβ6 up-regulation without affecting other homeostatic roles of TGF-β. Objectives To analyze the expression of αvβ6 in human pulmonary fibrosis, and to functionally test the efficacy of therapeutic inhibition of αvβ6-mediated TGF-β activation in murine bleomycin–induced pulmonary fibrosis. Methods Lung biopsies from patients with a diagnosis of systemic sclerosis or idiopathic pulmonary fibrosis were stained for αvβ6 expression. A range of concentrations of a monoclonal antibody that blocks αvβ6-mediated TGF-β activation was evaluated in murine bleomycin–induced lung fibrosis. Measurements and Main Results αvβ6 is overexpressed in human lung fibrosis within pneumocytes lining the alveolar ducts and alveoli. In the bleomycin model, αvβ6 antibody was effective in blocking pulmonary fibrosis. At high doses, there was increased expression of markers of inflammation and macrophage activation, consistent with the effects of TGF-β inhibition in the lung. Low doses of antibody attenuated collagen expression without increasing alveolar inflammatory cell populations or macrophage activation markers. Conclusions Partial inhibition of TGF-β using αvβ6 integrin antibodies is effective in blocking murine pulmonary fibrosis without exacerbating inflammation. In addition, the elevated expression of αvβ6, an activator of the fibrogenic cytokine, TGF-β, in human pulmonary fibrosis suggests that αvβ6 monoclonal antibodies could represent a promising new therapeutic strategy for treating pulmonary fibrosis.

Background Inhibition of leukocyte adhesion can reduce myocardial infarct size in animals. This study was designed to define the safety and efficacy of a recombinant, humanized, monoclonal antibody to the CD18 subunit of the β2 integrin adhesion receptors (rhuMAb CD18), in reducing infarct size in patients treated with a thrombolytic agent. Methods and Results The Limitation of Myocardial Infarction following Thrombolysis in Acute Myocardial Infarction Study (LIMIT AMI) was a randomized, double-blind, placebo-controlled, multicenter study conducted in 60 centers in the United States and Canada. A total of 394 subjects who presented within 12 hours of symptom onset with ECG findings (ST-segment elevation) consistent with AMI were treated with recombinant tissue plasminogen activator and were also given an intravenous bolus of 0.5 or 2.0 mg/kg rhuMAb CD18 or placebo. Coronary angiography was performed at 90 minutes, 12-lead ECGs were obtained at baseline, 90, and 180 minutes, and resting sestamibi scans were performed at ≥120 hours. Adjunctive angioplasty and use of glycoprotein IIb/IIIa antiplatelet agents at the time of angiography were discretionary. There were no treatment effects on coronary blood flow, infarct size, or the rate of ECG ST-segment elevation resolution, despite the expected induction of peripheral leukocytosis. A slight trend toward an increase in bacterial infections was observed with rhuMAb CD18 ( P =0.33). Conclusions RhuMAb CD18 was well tolerated but not effective in modifying cardiac end points.

Hemangiopericytomas are rare tumors of vascular origin most commonly found in the extremities or retroperitoneal area. When they originate from the nasal cavity and paranasal sinuses, they tend to be less aggressive and generally do not metastasize. The term “hemangiopericytoma-like lesion” has been coined for sinonasal hemangiopericytomas that display more benign histologic and growth characteristics than do those located elsewhere. Fifteen cases of hemangiopericytoma of the nasal cavity and paranasal sinuses were reviewed over the period 1951 to 1990; included are follow-up data on cases reported earlier from this institution. The clinical course, management, and outcome was evaluated and correlated with the histologic characteristics of the tumors. The recurrence rate in our series was 13.3%; the mean follow-up was 11 years. No patients died of their disease or had evidence of metastatic disease. This clinicopathologic review suggests that sinonasal hemangiopericytomas should not be classified as “hemangiopericytoma-like” lesions; rather, they should be expected to have significant local recurrence rates with low rates of distant metastasis and mortality. Long-term follow-up is essential as there can be local recurrence after many years.

Abstract Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. This study is registered at http://clinicaltrials.gov (Study ID NCT00048230).

AbstractThe AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1416–21)

The coexistence of urologic malignancy (UM) and abdominal aortic aneurysm (AAA) is rare. Simultaneous treatment may increase morbidity, whereas staged operations delay necessary treatment. We reviewed our experience to develop guidelines for evaluation and management. Clinical data of all patients diagnosed between 1980 and 1998 with both AAA and UM, who also had staged or simultaneous surgical treatment were reviewed. Four thousand forty-seven patients underwent AAA repair during the study period at our institution. Of these, 18 (0.44%) patients, 16 men and two women (mean age: 74 years, range: 61 to 92) had UM. UM was discovered incidentally in nine patients with AAA with computed tomography (CT) scan (7) and ultrasonography (2). In one patient with AAA, hematuria raised the suspicion of UM. Eight patients were diagnosed with AAA during evaluation of UM by CT scan or ultrasound (7) or during laparotomy (1). Initial signs and symptoms included abdominal pain (33%), gross hematuria (33%), and urinary tract infections (17%), although 33% were asymptomatic. The AAA was symptomatic at first examination in three (17%) patients, 14 (78%) patients had hypertension, and two (11%) had renal insufficiency (overall mean serum creatinine: 1.6, range: 0.8 to 3.7). Mean AAA diameter was 5.8 cm (range: 3.8 to 8 cm). Aortography documented significant contralateral renal artery disease in two patients. Twelve patients underwent simultaneous AAA repair and resection of UM; the operations were staged in six (AAA repair first in 2, nephrectomy first in 4). One patient required emergent repair of a ruptured AAA three days after nephrectomy. UM was treated with nephrectomy in 17 patients, and with bilateral ureterectomy and cystectomy in one. A straight aortic graft was implanted in seven patients, a bifurcated graft in ten, and one had extra-anatomic reconstruction. Two patients required reconstruction of the contralateral renal artery. The 30-day mortality rate was 0% after staged and 6% after simultaneous repair (p= >0.1). Major perioperative complications occurred more frequently after simultaneous (42%) than after staged repair (33%), although the difference was not significant (p= >0.1). Two patients developed postoperative renal failure. Seventeen patients were followed for an average of 3.9 years (14 days to 10.8 years). Three (17%) patients died of recurrent cancer at 1, 10.7, and 10.8 years after surgery. Patients with resectable UM have satisfactory long-term survival, which justifies aggressive treatment of concomitant AAA. Aortography in these patients is suggested to exclude contralateral renal artery disease. Complications were frequent, but simultaneous repair did not increase morbidity or mortality significantly. The risk of AAA rupture after nephrectomy, need to correct contralateral renal artery disease at the time of nephrectomy, and disadvantage of delaying treatment of UM are compelling reasons to favor simultaneous treatment of AAA and UM.

The purpose of this study was to examine the technical aspects of intraoperative duplex ultrasound (DUS) following carotid endarterectomy (CEA), suggest criteria to differentiate significant lesions requiring immediate surgical revision from normal or benign defects, and evaluate how frequently intraoperative DUS provides useful or unsuspected information. A retrospective study was performed on all patients who had both CEA and intraoperative carotid DUS between January 1,1990. and January 1,1995. A total of 155 DUS examinations were performed in 149 patients. Findings were grouped into three categories: normal; minor/insignificant lesions; and hemodynamically significant lesions based on the presence or absence of elevated peak systolic velocities, visible stenosis/thrombus, or intimal flap/dissection. Postoperative status was correlated with intraoperative DUS findings. Ninety-one (59%) examinations performed on 87 patients produced normal findings. Forty-seven (30%) examinations performed on 45 patients showed minor abnormalities consisting of insignificant residual plaque, residual external carotid artery stenoses, small intimal flaps, elevated velocities with no associated anatomic lesion, or an arterial kink. Fourteen patients (9%) had significant findings requiring immediate surgical revision. These consisted of large intimal flaps or dissection in six patients, marked residual plaque and significant stenosis in five patients, thrombus in two patients, and a kink in one patient. Three additional patients ( 2 %) had significant findings but were not revised for various reasons. No significant difference was identified in morbidity or mortality rates between those patients with normal findings, those patients with minor technical defects, and those patients with significant abnormalities undergoing immediate surgical revision. However, two of three patients who had significant abnormalities within the common carotid artery that were not revised suffered perioperative ipsilateral strokes. Intraoperative DUS is a safe and accurate method to assess the technical adequacy of CEA. Intraoperative DUS showed significant lesions in 11% of patients. Identification and immediate repair of significant technical defects may decrease perioperative complication rate and long-term restenosis rate.

Purpose The clinical significance of epidermal growth factor receptor variant III (EGFRvIII) expression in glioblastoma multiforme (GBM) and its relationship with other key molecular markers are not clear. We sought to evaluate the clinical significance of GBM subtypes as defined by EGFRvIII status. Patients and Methods The expression of EGFRvIII was assessed by immunohistochemistry in 649 patients with newly diagnosed GBM. These data were then examined in conjunction with the expression of phospho-intermediates (in a subset of these patients) of downstream AKT and Ras pathways and YKL-40 as well as with known clinical risk factors, including the Radiation Therapy Oncology Group's recursive partitioning analysis (RTOG-RPA) class. Results The RTOG-RPA class was highly predictive of survival in EGFRvIII-negative patients but much less predictive in EGFRvIII-positive patients. These findings were seen in both an initial test set (n = 268) and a larger validation set (n = 381). Similarly, activation of the AKT/MAPK pathways and YKL-40 positivity were predictive of poor outcome in EGFRvIII-negative patients but not in EGFRvIII-positive patients. Pair-wise combinations of markers identified EGFRvIII and YKL-40 as prognostically important. In particular, outcome in patients with EGFRvIII-negative/YKL-40–negative tumors was significantly better than the outcome in patients with the other three combinations of these two markers. Conclusion Established prognostic factors in GBM were not predictive of outcome in the EGFRvIII-positive subset, although this requires confirmation in independent data sets. GBMs negative for both EGFRvIII and YKL-40 show less aggressive behavior.