Occult malignancy in patients with suspected paraneoplastic neurologic syndromes: value of positron emission tomography in diagnosis.

OBJECTIVE: To determine the value of positron emission tomography (PET) in diagnosing occult malignancies in patients with paraneoplastic neurologic syndromes (PNSs) at Mayo Clinic's site in Rochester, MN. PATIENTS AND METHODS: We retrospectively reviewed the medical charts of all 107 patients who underwent PET from January 1, 2000, to July 31, 2006, for the indication of suspected PNS. Three patients did not meet inclusion criteria. PET results were considered positive if increased fludeoxyglucose F 18 uptake indicated malignancy (24 patients). Results from computed tomography were interpreted as positive if any suspect lesion was consistent with malignancy (26 patients). RESULTS: One hundred four patients with PNS were identified from the PET central database; 73 patients had at least 1 positive result for paraneoplastic antibody, and 31 had antibody-negative PNS. Malignancy was confirmed pathologically in 10 patients, of whom 8 had positive PET results. There were 2 cases of confirmed malignancy (fallopian tube adenocarcinoma and spindle cell uterine carcinoma) for which PET results were negative. Two patients with positive PET results declined biopsy. Computed tomography was able to identify 3 of the 10 malignancies detected. Five cases of malignancy were detected only by PET. All patients with confirmed malignancy had positive results for at least 1 paraneoplastic antibody. One patient with positive results for PNS antibody and negative PET results was diagnosed as having small cell carcinoma on a follow-up PET scan after 27 months. PET had sensitivity, specificity, positive predictive value, and negative predictive value of 80%, 67%, 53%, and 88%, respectively. CONCLUSION: PET scan was shown to be more sensitive than computed tomography for detecting occult malignancy (confirmed by positive test results for autoantibody) among patients with suspected PNS. The greatest clinical utility of PET could be in its high negative predictive value.

Increased shear stress with upregulation of VEGF-A and its receptors and MMP-2, MMP-9, and TIMP-1 in venous stenosis of hemodialysis grafts.

Venous injury and subsequent venous stenosis formation are responsible for hemodialysis graft failure. Our hypothesis is that these pathological changes are in part related to changes in wall shear stress (WSS) that results in the activation of matrix regulatory proteins causing subsequent venous stenosis formation. In the present study, we examined the serial changes in WSS, blood flow, and luminal vessel area that occur subsequent to the placement of a hemodialysis graft in a porcine model of chronic renal insufficiency. We then determined the corresponding histological, morphometric, and kinetic changes of several matrix regulatory proteins including VEGF-A, its receptors, matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and TIMP-2. WSS was estimated by obtaining blood flow and luminal vessel area by performing phase-contrast MRI with magnetic resonance angiography in 21 animals at 1 day after graft placement and prior to death on day 3 (n = 7), day 7 (n = 7), and day 14 (n = 7). At all time points, the mean WSS at the vein-to-graft anastomosis was significantly higher than that at the control vein (P < 0.05). WSS had a bimodal distribution with peaks on days 1 and 7 followed by a significant reduction in WSS by day 14 (P < 0.05 compared with day 7) and a decrease in luminal vessel area compared with control vessels. By day 3, there was a significant increase in VEGF-A and pro-MMP-9 followed by, on day 7, increased pro-MMP-2, active MMP-2, and VEGF receptor (VEGFR)-2 (P < 0.05) and, by day 14, increased VEGFR-1 and TIMP-1 (P < 0.05) at the vein-to-graft anastomosis compared with control vessels. Over time, the neointima thickened and was composed primarily of alpha-smooth muscle actin-positive cells with increased cellular proliferation. Our data suggest that hemodialysis graft placement leads to early increases in WSS, VEGF-A, and pro-MMP-9 followed by subsequent increases in pro-MMP-2, active MMP-2, VEGFR-1, VEGFR-2, and TIMP-1, which may contribute to the development of venous stenosis.

Adventitial remodeling with increased matrix metalloproteinase-2 activity in a porcine arteriovenous polytetrafluoroethylene grafts.

BACKGROUND: We hypothesized the source of early proliferating cells contributing to venous stenosis formation in a porcine hemodialysis grafts is the adventitia and media, and migration of these cells is greatest within the first two weeks following graft placement, resulting in increased matrix metalloproteinase-2 (MMP-2) activity. METHODS: Polytetrafluoroethylene grafts from the iliac artery to the ipsilateral iliac vein were placed in 23 pigs and 5-Bromo-2'-deoxyuridine (BrdU) was given at 24 and 48 hours after surgery to assess cell proliferation and migration. Angiography and magnetic resonance angiography was performed. Animals were euthanized on day three (N= 6), day seven, (N= 5), day 14 (N= 6), and days 19 to 26 (N= 6) after graft placement, and stenotic tissue and unaffected contralateral iliac vein were removed for zymography and immunostaining. RESULTS: Migration of cells derived from the adventitia and media peaked at day 14. Adventitial diameter of the stenotic vein decreased, while the intima to media ratio increased. MMP-2 activity peaks at day seven in the adventitia and days 19 to 26 in the intima. CONCLUSION: These results confirm our hypothesis that the source of cells resulting in venous stenosis formation is derived from the adventitia and media, with cell migration being greatest within the first two weeks after graft placement with translocation of these cells into the intima at four weeks. MMP-2 activity peaks at day seven in the adventitia and again at days 19 to 26 in the intima. A key to limiting venous stenosis formation may lie in inhibiting MMP-2 by adventitial and medial targeting.