Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1.

The tumor microenvironment is emerging as an important target for cancer therapy. Fibroblasts (Fbs) within the tumor stroma are critically involved in promoting tumor growth and angiogenesis through secretion of soluble factors, synthesis of extracellular matrix and direct cell-cell interaction. In this work, we aim to alter the biological activity of stromal Fbs by modulating the Notch1 signaling pathway. We show that Fbs engineered to constitutively activate the Notch1 pathway significantly inhibit melanoma growth and tumor angiogenesis. We determine that the inhibitory effect of 'Notch-engineered' Fbs is mediated by increased secretion of Wnt-induced secreted protein-1 (WISP-1) as the effects of Notch1 activation in Fbs are reversed by shRNA-mediated blockade of WISP-1. When 'Notch-engineered' Fbs are co-grafted with melanoma cells in SCID mice, shRNA-mediated blockade of WISP-1 reverses the tumor-suppressive phenotype of the 'Notch-engineered' Fbs, significantly increases melanoma growth and tumor angiogenesis. Consistent with these findings, supplement of recombinant WISP-1 protein inhibits melanoma cell growth in vitro. In addition, WISP-1 is modestly expressed in melanoma-activated Fbs but highly expressed in inactivated Fbs. Evaluation of human melanoma skin biopsies indicates that expression of WISP-1 is significantly lower in melanoma nests and surrounding areas filled with infiltrated immune cells than in the adjacent dermis unaffected by the melanoma. Overall, our study shows that constitutive activation of the Notch1 pathway confers Fbs with a suppressive phenotype to melanoma growth, partially through WISP-1. Thus, targeting tumor stromal Fbs by activating Notch signaling and/or increasing WISP-1 may represent a novel therapeutic approach to combat melanoma.

Structural MRI of carotid artery atherosclerotic lesion burden and characterization of hemispheric cerebral blood flow before and after carotid endarterectomy.

Collateral circulation plays a major role in maintaining cerebral blood flow (CBF) in patients with internal carotid artery (ICA) stenosis. CBF can remain normal despite severe ICA stenosis, making the benefit of carotid endarterectomy (CEA) or stenting difficult to assess. Before and after surgery, we assessed CBF supplied through the ipsilateral (stenotic) or contralateral ICA individually with a novel hemisphere-selective arterial spin-labeling (ASL) perfusion MR technique. We further explored the relationship between CBF and ICA obstruction ratio (OR) acquired with a multislice black-blood imaging sequence. For patients with unilateral ICA stenosis (n = 19), conventional bilateral labeling did not reveal interhemispheric differences. With unilateral labeling, CBF in the middle cerebral artery (MCA) territory on the surgical side from the ipsilateral supply (53.7 +/- 3.3 ml/100 g/min) was lower than CBF in the contralateral MCA territory from the contralateral supply (58.5 +/- 2.7 ml/100 g/min), although not statistically significant (p = 0.09). The ipsilateral MCA territory received significant (p = 0.02) contralateral supply (7.0 +/- 2.7 ml/100 g/min), while ipsilateral supply to the contralateral side was not reciprocated. After surgery (n = 11), ipsilateral supply to the MCA territory increased from 57.3 +/- 5.7 to 67.3 +/- 5.4 ml/100 g/min (p = 0.03), and contralateral supply to the ipsilateral MCA territory decreased. The best predictor of increased CBF on the side of surgery was normalized presurgical ipsilateral supply (r(2) = 0.62, p = 0.004). OR was less predictive of change, although the change in normalized contralateral supply was negatively correlated with OR(excess) (=OR(ipsilateral) - OR(contralateral)) (r(2) = 0.58, p = 0.006). The results demonstrate the effect of carotid artery stenosis on blood supply to the cerebral hemispheres, as well as the relative role of collateral pathways before surgery and redistribution of blood flow through these pathways after surgery. Unilateral ASL may better predict hemodynamic surgical outcome (measured by improved perfusion) than ICA OR.

Impact of exclusion criteria on patient selection for endovascular abdominal aortic aneurysm repair.

PURPOSE: Wide-ranging predictions have been made about the usefulness of endovascular repair for patients with abdominal aortic aneurysms (AAAs). The availability of US Food and Drug Administration-approved devices has removed the restrictions on patient selection, which had been controlled by device trials. This study examined the applicability of endovascular AAA repair and identified the anatomic barriers to successful endovascular AAA repair that should guide future device development. METHODS: All patients who came to our institution for infrarenal AAA repair between April 1998 and June 2000 were offered evaluation for endovascular repair. Thin-cut spiral computed tomography scans and arteriograms were obtained on all patients, and their anatomic characteristics were prospectively entered into a database. A wide selection of available devices allowed the treatment of diverse AAA anatomic features. RESULTS: A total of 307 patients were examined (264 men, 43 women). Of these, 204 patients (66%; 185 men, 19 women) underwent endovascular repair, and 103 patients (34%, 79 men, 24 women) were rejected. Reasons for exclusion included short aneurysm neck (56, 54%), inadequate access because of small iliac arteries (48, 47%), wide aneurysm neck (41, 40%), presence of bilateral common iliac aneurysms extending to the hypogastric artery (22, 21%), excessive neck angulation (14, 14%), extensive mural thrombus in the aneurysm neck (10, 10%), extreme tortuosity of the iliac arteries (10, 10%), accessory renal arteries originating from the AAA (6, 6%), malignancy discovered during the examination (5, 5%), and death during the examination interval (2, 2%). Rejected patients had an average of 1.9 exclusion criteria (range, 1 to 4). A disproportionate number of women were excluded because of anatomic findings (P = .0009). Although 80% of patients who were at low risk for surgery qualified for endovascular repair, only 49% of our patients who were at high risk for surgery were acceptable candidates (P < .001). Of the 103 patients who were excluded, 34 (33%) underwent open surgical repair, and the remaining 69 (67%) were deemed to be unfit for open surgery. Three patients (1.4%) failed endograft placement because of inadequate vascular access. CONCLUSION: Most infrarenal AAAs (66%) can be treated with endovascular devices currently available commercially or through US Food and Drug Administration-approved clinical trials. However, patients who are at high risk for surgery and might benefit most from endovascular repair are less likely to qualify for the procedure (49%). Men (70%) are more likely than women (40%) to meet the anatomic criteria for endografting. Difficulties with vascular access and attachment site geometry predominate as reasons for exclusion. Our findings suggest that smaller profile devices, which can negotiate small and tortuous iliac arteries, are needed. Proximal and distal attachment site problems require devices that can accommodate wide and angulated attachment necks and achieve short seal zones.

Endovascular AAA repair in patients with renal insufficiency: strategies for reducing adverse renal events.

Vascular imaging, usually employing nephrotoxic contrast agents is relied upon for all aspects of endovascular AAA repair causing some to consider renal insufficiency a relative contraindication. We sought to determine if endovascular AAA evaluation and repair could be successfully accomplished by minimally or non-nephrotoxic modalities. Records and results for 98 consecutive patients undergoing endovascular AAA repair were reviewed. Patients requiring dialysis preoperatively were excluded (N=3). The average volume of iodinated contrast agent employed for intraoperative imaging was 152 cc (35-420 cc). Twenty patients (20%) had baseline renal insufficiency (serum creatinine > or =1.3 mg/dl). A rise in serum creatinine above baseline was observed in 23 (24%) patients following repair; for 15 (16%) this was permanent. Creatinine rise occurred in patients with both normal (15) and abnormal (8) baseline values (P=0.09). Rise in creatinine was independent of contrast volume employed and of the use of infrarenal vs suprarenal device fixation (P>0.05). Two (2%) patients required permanent dialysis, one of which had a normal baseline creatinine and unclear etiology for renal failure, the other had a baseline creatinine of 2 and required device placement over an accessory renal artery. Strategies to minimize the use of nephrotoxic contrast for patients with renal insufficiency included the use of MRA, rather than contrast-CT for pre and postoperative imaging (7, 35%) and use of Gadolinium rather than iodinated contrast for performance of intraoperative arteriography (5, 25%). Endovascular grafts were successfully designed and implanted based upon MRA as the sole preoperative imaging modality in every case in which it was attempted (7). Mortality was not significantly different between those with and without abnormal baseline renal function (P>0.05). Adverse events (access failures, arterial injuries, blood loss, endoleaks) were not significantly correlated with baseline renal insufficiency, rise in creatinine from baseline, use of MRA or intraoperative Gadolinium angiography (P>0.05).Pre- and postoperative evaluation and performance of endovascular AAA repair can be accomplished in patients with renal insufficiency without increasing the rate of mortality or adverse events employing a strategy which minimizes the use of nephrotoxic contrast agents, relying upon Gadolinium arteriography and MRA. Endovascular grafts can be successfully planned and followed employing MRA as the sole imaging modality.

The role of magnetic resonance angiography for endoprosthetic design.

OBJECTIVES: Many patients with aortic aneurysms have renal insufficiency and may be at increased risk when conventional imaging modalities (contrast-enhanced computed tomography and arteriography) are used for aortic endograft design. Our objective was to determine if magnetic resonance angiography (MRA) could be used as the sole imaging modality for endoprosthetic design. METHODS: A total of 96 consecutive patients who underwent endovascular repair of thoracic (5) and abdominal (91) aortic aneurysms (April 1998-December 1999) were included in this study. Data were collected prospectively. Gadolinium-enhanced MRA was used preoperatively in place of conventional imaging if renal insufficiency or a history of severe contrast reaction was present. The control group underwent conventional imaging. Endografts used included Ancure, AneuRx, and Talent. RESULTS: Fourteen patients (14.6%) had their endografts designed solely with MRA. Intraoperative access failure; proximal and distal extensions (unplanned); conversion to open, aborted procedures; and endoleaks occurred with equal frequency in both the MRA-designed and control groups (16.7% vs 18.3%, respectively; P =.33). Despite baseline renal insufficiency, there was no significant rise in the creatinine level after endograft implantation in patients with an MRA design (preoperative level, 1.8; postoperative level, 1.9; P =.5). CONCLUSION: MRA may be successfully used as the sole modality for aortic endograft design. The use of MRA for this purpose is noninvasive and minimizes nephrotoxic risk.

Failure of endovascular abdominal aortic aneurysm graft limbs.

OBJECTIVE: Endovascular abdominal aortic aneurysm (AAA) grafts are subject to subsequent failure of endograft limbs. We sought to determine what device-related factors could be identified that might contribute to limb failure. METHODS: We reviewed the records of patients who had undergone endovascular AAA repair and femorofemoral bypass grafting at a single institution. RESULTS: Endovascular AAA repair was performed in 173 patients. There were 137 bifurcated endografts and 36 aortomonoiliac grafts combined with femorofemoral bypass grafts, yielding a total population of 310 aortic graft limbs and 36 femorofemoral grafts. Thirty-nine additional patients underwent femorofemoral bypass grafting for occlusive disease. The cumulative primary patency of all endografts performed for AAA was 92% at 21 months. Secondary patency was achieved for all failed endograft limbs. There were 24 aortic graft limb "failures" that required intervention: seven limbs underwent thrombosis requiring revision; kinked limbs requiring stenting either at the time of graft placement (17) or subsequently (7) were identified. Fully supported endograft limbs had better primary patency (97% at 18 months) than unsupported limbs (69% at 18 months, P <.001). The aortomonoiliac grafts with femorofemoral bypass grafts tended to have better patency (97% at 18 months) than bifurcated endografts (90% at 18 months), but this did not reach statistical significance (P =.28, not significant). Femorofemoral grafts performed for occlusive disease were found to have somewhat lower patency than those performed for AAA (83% vs 92% at 18 months of follow-up, P =.37, not significant). CONCLUSIONS: Fully supported AAA endografts provide superior endograft limb patency compared with unsupported designs. Consideration should be given to routine stenting of all unsupported endograft limbs. Aortomonoiliac grafts and bifurcated grafts provide similar results for endograft limb patency. Femorofemoral bypass grafts performed in conjunction with aortomonoiliac grafts for AAA disease provide excellent short-term patency.

Gender-related differences in infrarenal aortic aneurysm morphologic features: issues relevant to Ancure and Talent endografts.

PURPOSE: The purpose of this study was to determine whether gender-related anatomic variables may reduce applicability of aortic endografting in women. METHODS: Data on all patients evaluated at our institution for endovascular repair of their abdominal aortic aneurysm were collected prospectively. Ancure (Endovascular Technologies (EVT)/Guidant Corporation, Menlo Park, Calif) and Talent (World Medical/Medtronic Corporation, Sunrise, Fla) endografts were used. Preoperative imaging included contrast-enhanced computed tomography and arteriography or magnetic resonance angiography. RESULTS: One hundred forty-one patients were evaluated (April 1998-December 1999), 19 women (13.5%) and 122 men (86.5%). Unsuitable anatomy resulted in rejection of 63.2% of the women versus only 33.6% of the men (P = .026). Maximum aneurysm diameter in women and men were similar (women, 56.94 +/- 8.23 mm; men, 59.29 +/- 13.22 mm; P = .5). The incidence of iliac artery tortuosity was similar across gender (women, 36.8%; men, 54.9%; P = .2). The narrowest diameter of the larger external iliac artery in women was significantly smaller (7.29 +/- 2.37 mm) than in men (8.62 +/- 2.07 mm; P = .02). The proximal neck length was significantly shorter in women (10.79 +/- 12.5 mm) than in men (20.47 +/- 19.5 mm; P = .02). The proximal neck width was significantly wider in women (30.5 +/- 2.4 mm) than in men (27.5 +/- 2.5 mm; P = .013). Proximal neck angulation (>60 degrees) was seen in a significantly higher proportion of women (21%) than men (3.3%; P = .012). Of the patients accepted for endografting, a significantly higher proportion of women required an iliofemoral conduit for access (women, 28.6%; men, 1.2%; P = .016). CONCLUSION: Gender-related differences in infrarenal aortic aneurysm morphologic features may preclude widespread applicability of aortic endografting in women, as seen by our experience with the Ancure and Talent devices. In addition to a significantly reduced iliac artery size, women are more likely to have a shorter, more dilated, more angulated proximal aortic neck.

Aneurysm sac pressure measurements after endovascular repair of abdominal aortic aneurysms.

OBJECTIVES: The goal of endovascular grafting of abdominal aortic aneurysms (AAAs) is to exclude the aneurysm sac from systemic pressure and thereby decrease the risk of rupture. Unlike conventional open surgery, branch vessels in the sac (eg, lumbar artery and inferior mesenteric artery [IMA]) are not ligated and can potentially transmit pressure. The purpose of our investigation was to evaluate the feasibility of various interventional techniques for measuring pressure within the aneurysm sac in patients who had undergone endovascular repair of AAAs. METHODS: Sac pressure measurements were performed in 21 patients who had undergone stent graft repair of AAAs. Seventeen of 21 patients had endoleaks demonstrated on 30-day computed tomographic (CT) scans. Access to the aneurysm sac in these patients was through direct translumbar sac puncture (5 patients), through a patent IMA accessed via the superior mesenteric artery (SMA) (9 patients), or by direct cannulation around attachment sites (3 patients). Four patients had perioperative pressure measurements obtained through catheters positioned along side of the endovascular graft at the time of its deployment. Two of these catheters were left in position for 30 hours during which time CT and conventional angiography were performed. Pressures were determined with standard arterial-line pressure transduction techniques and compared with systemic pressure in each patient. RESULTS: Elevated sac pressure was found in all patients. The sac pressure in patients with endoleaks was found to be systemic (15 patients) or near systemic (2 patients) and all had pulsatile waveforms. Elevated sac pressures were also found in patients without CT or angiographic evidence of endoleak (2 patients). Injection of the sacs in two of these patients revealed a patent lumbar artery and an IMA. CONCLUSIONS: It is possible to measure pressures from within the aneurysm sac in patients with stent grafts with a variety of techniques. Patients may continue to have pressurized AAA sacs despite endovascular AAA repair. Endoleaks transmit pulsatile pressure into the aneurysm sac regardless of the type. It is possible to have systemic sac pressures without evidence of endoleaks on CT or angiography.

Limb kinking in supported and unsupported abdominal aortic stent-grafts.

PURPOSE: The occurrence of kinking of stent-graft limbs depends on the patient's anatomy and the device used. The purpose of this investigation was to determine the rates of limb kinking in supported and unsupported aortic stent-grafts. MATERIALS AND METHODS: The authors performed a retrospective review of patients undergoing placement of either a Guidant Ancure/EGS or Medtronic Talent aortic stent-graft for the treatment of abdominal aortic aneurysm as part of separate phase II and phase III clinical trials. The records of 91 consecutive patients with 149 limbs were reviewed. The type and configuration of each device and any procedure performed specifically relating to limb patency was recorded. An analysis was then performed comparing the rates of kinking in supported and unsupported groups. A review of the literature was also performed. RESULTS: Overall, there was kinking in 18 of 149 limbs (12%). In the supported stent-graft group, 48 bifurcated and 26 aortomonoiliac grafts were placed, with a total of 122 limbs at risk. Six limbs (5%) in five patients required intervention as a result of limb kinking. Stents were placed intraoperatively in two limbs (2%) and postoperatively in four limbs (3%) for thrombosis or severe stenosis. In the unsupported group, 12 bifurcated and three aortomonoiliac grafts were placed, with a total of 27 limbs at risk. Twelve limbs (44%) in eight patients required some type of intervention as a result of limb kinking. Stents were placed intraoperatively in seven limbs (26%) and postoperatively in five limbs (19%) for thrombosis or severe stenosis. Rates of limb kinking were significantly different between the supported and unsupported groups (P < .0001). CONCLUSIONS: The use of supported versus unsupported stent-grafts impacts the occurrence of limb kinking. A direct comparison of the groups suggests that an unsupported stent-graft will be more than 15 times more likely than a supported system to require intervention because of kinking.

Safety of coil embolization of the internal iliac artery in endovascular grafting of abdominal aortic aneurysms.

PURPOSE: During endovascular grafting of an abdominal aortic aneurysm (AAA), iliac limb extension to the external iliac artery may be indicated when the common iliac artery is ectatic or aneurysmal. Preliminary or concomitant coil embolization of the internal iliac artery (IIA) is thus necessary to prevent potential reflux and endoleak. We sought to determine the safety of hypogastric flow interruption in this setting. METHODS: We retrospectively reviewed 156 patients who underwent stent-graft AAA repair at two institutions between February 1, 1998, and January 31, 1999. Coil embolization of one or both IIAs was undertaken when the diameter of the common iliac artery was more than 20 mm to enable limb endograft extension to the external iliac artery. Bilateral procedures were staged. RESULTS: Thirty-nine (25%) of 156 patients were selected for coil embolization of one (n = 28) or both (n = 11) IIAs. The interventions were performed before (n = 31) or during (n = 8) the stent-graft procedure. Complications included groin hematomas in 3 patients, iliac artery dissection in 1, failure to catheterize the IIA in 2, and transient rise in the serum creatinine level in 3. One patient had erectile dysfunction, and five patients (13%) had buttock claudication after unilateral occlusion. Serious ischemic complications were not observed. CONCLUSION: Coil embolization of one or both IIAs appears to be safe in the setting of endovascular grafting of AAA. Buttock claudication is a relatively significant problem and may limit applicability of this strategy to patients who are unfit for standard open repair.

Relationship between preoperative patency of the inferior mesenteric artery and subsequent occurrence of type II endoleak in patients undergoing endovascular repair of abdominal aortic aneurysms.

OBJECTIVES: The purpose of this study was (1) to find out whether preoperative inferior mesenteric artery (IMA) patency (on radiographic imaging) predicts IMA-related endoleaks after endovascular repair of infrarenal abdominal aortic aneurysms, (2) to determine feasibility of measuring aneurysm sac pressures in patients with endoleaks, and (3) to report early evidence of effective endovascular obliteration of IMA endoleaks. METHODS: We studied 76 consecutive cases of infrarenal aortic aneurysms that were repaired with an endovascular approach (March 1998-April 1999). RESULTS: There were 13 (17%) endoleaks persistent 30 days after the procedure. Eleven (85%) of these 13 were IMA-related endoleaks, which were documented with selective superior mesenteric artery angiography. The preoperative finding (on computed tomographic scan) of a patent IMA does not always predict an IMA-related endoleak, but results in a statistically and clinically significant higher ratio of patients with IMA-related endoleaks in the immediate postoperative period (24% versus 3%, P <.035). In eight of the 11 patients with persistent IMA-related endoleaks, measurement of intra-aneurysm sac pressures was possible, and six of these patients had systemic pressures within the excluded aneurysm sac. Nine (82%) of 11 IMA-related endoleaks were successfully obliterated by means of selective IMA embolization. CONCLUSIONS: Many endoleaks are caused by a patent IMA, and this can result in persistence of systemic pressure within the aneurysm sac. The preoperative finding (on computed tomographic scan) of a patent IMA is a predictor of increased rates of IMA endoleaks, and IMA endoleaks can be successfully obliterated through endovascular procedures, after endovascular abdominal aortic aneurysm repair.

Diagnosis and treatment of inferior mesenteric arterial endoleaks after endovascular repair of abdominal aortic aneurysms.

PURPOSE: To review the incidence and repair of inferior mesenteric arterial (IMA) type II endoleaks after endovascular repair of abdominal aortic aneurysms. MATERIALS AND METHODS: Fifty patients who underwent endovascular repair of abdominal aortic aneurysms were examined. If an endoleak was identified at 30-day postoperative computed tomography, conventional arteriography was performed to identify and eliminate its source. After the exclusion of attachment site leaks, a catheter was placed selectively in the superior mesenteric artery (SMA). If retrograde filling of the IMA and aneurysm was identified, coil embolization was attempted through the SMA and middle colic artery. Intrasac pressures were measured at embolization. RESULTS: Eight of 50 patients (16%) had type II endoleaks that were attributed to retrograde flow in the IMA. Intrasac measurements demonstrated systemic pressure in six patients and one-half systemic pressure in two patients. The IMA was embolized through the SMA and left colic artery in seven patients and through the translumbar aorta in one patient. CONCLUSION: Retrograde flow in the IMA is responsible for many type II endoleaks. Systemic pressures are transmitted into the aneurysm sac from the IMA. The IMA can be embolized successfully with an SMA approach in most patients.

Emergency repair of thoracoabdominal aortic aneurysms with immediate presentation.

OBJECTIVE: The objective of this report was the study of the clinical outcome of emergently repaired thoracoabdominal aortic aneurysms (TAAAs). METHODS: We retrospectively reviewed our experience with TAAA repairs from 1990 to 1998. During this interval, 110 TAAA procedures were performed, 33 (30%) of which were for immediate presentations. The chi(2) test and regression analysis were used for the analysis of mortality, paraplegia, and renal failure (hemodialysis) rates and of factors that predict these complications, respectively. RESULTS: There were no significant differences between the elective and immediate presentations with respect to the use of adjunctive procedures (lumbar drain, hypothermia, and bypass grafting). The overall mortality rate was 13%. There were no statistically significant differences between the 30-day mortality rates or the complication rates in elective versus immediate presentations. Subgroup analysis results showed a significantly higher in-hospital mortality rate in type II TAAA with immediate presentation and free rupture presentation as compared with the overall mortality rate (50% vs 13%, P <.05, and 67% vs 13%, P <.01, respectively). Multiple regression analysis results identified the use of bypass grafting (atrial-femoral or cardiopulmonary) and lumbar drain and shorter bypass grafting time as significant predictors of decreased overall mortality (P <.05). The mortality rates were not significantly different among aneurysm types and were not significantly decreased with the use of hypothermia. Paraplegia (5%) and renal failure (9%) rates were not predicted with aneurysm type, immediate versus elective presentation, or the adjunctive use of hypothermia, lumbar drain, or bypass grafting. CONCLUSION: The emergency repair of TAAA with immediate presentation can be performed with mortality and morbidity rates that approach those of elective presentations, except in the setting of free rupture or symptomatic type II TAAA. Adjunctive circulatory management techniques and lumbar drains may reduce mortality in TAAA repair.

Perigraft air, fever, and leukocytosis after endovascular repair of abdominal aortic aneurysms.

BACKGROUND: The postimplantation syndrome of fever and leukocytosis after endovascular repair of infrarenal aortic aneurysms has not been previously characterized and its etiology is not known. METHODS: We studied the first 12 patients who underwent successful endovascular repair of infrarenal aortic aneurysms with Dacron-covered stent-grafts, as part of an ongoing phase II clinical trial. Sepsis syndrome evaluations (physical examination, urinalysis, chest radiograph, urine cultures, and blood cultures) were performed for all patients with postoperative temperature (T) greater than 101.4 degrees F. Computed tomography scans of the abdomen were performed, as part of the clinical protocol, on postoperative days 2 and 30. RESULTS: Fever (T > 101.4 degrees F) was seen in 8 of 12 (67%) patients (P < 05). An additional 2 of 12 (17%) patients had low-grade fevers (100.3 degrees F, 100.6 degrees F). Only 2 of 12 (17%) patients remained afebrile postoperatively. Leukocytosis with counts over 11,000 white blood cells (WBC)/dL was observed in 7 of 12 (58%) patients (P < 05). Sepsis evaluations failed to identify any source of infection in 11 of 12 (97%) patients. Computed tomography scan evidence of perigraft air was noted in 8 of 12 (67%) patients. All patients were afebrile, had normal white blood cell counts, and were discharged within 1 week postoperatively. There has been no evidence of graft infection after 1 to 6 months of follow-up. CONCLUSIONS: Fever and leukocytosis after stent-graft repair of aortic aneurysms does not represent evidence of systemic or graft infection and is not clearly related to nonspecific causes of postoperative fever and leukocytosis. Moreover, the finding of early postoperative perigraft air is not necessarily an indication of graft infection even when concurrently present with fever and leukocytosis.

Magnetic resonance angiography of lower-extremity arterial disease.

Improvements in vascular technique have expanded the treatment options for patients with severe occlusive peripheral vascular disease. The decision to perform a major revascularization procedure in patients who are often at high risk for cardiovascular morbidity and mortality depends on the risk-benefit ratio. Detailed and accurate vascular imaging is essential and evaluating the likelihood of a successful revascularization with subsequent limb salvage. Although contrast angiography has been the time-honored reference standard imaging technique, the method is an invasive procedure with limitations and risks. MRA is a new, noninvasive vascular imaging technique that may now be added to the imaging options with the potential for improved sensitivity for finding patent runoff vessels, avoidance of morbidity, and cost equivalent to that of conventional contrast angiography. Magnetic resonance angiography is a rapidly developing and exciting new vascular imaging technique. As with any new technique, it is imperative that individual centers validate their MRA results and interpretations against the time-honored standard, which continues to be contrast arteriography. Several studies now indicate that MRA can be a cost-effective outpatient imaging technique sufficient for planning and successfully performing peripheral bypass procedures. As developments in hardware, software, and non-nephrotoxic contrast agents continue to increase, applicability of MRA in vascular surgery will continue to expand. Predictably, MRA will have a major role in the future of vascular imaging, and it is likely to supplant the need for conventional contrast angiography in the majority of patients.

Butyrate inhibits deoxycholate-induced increase in colonic mucosal DNA and protein synthesis in vivo.

PURPOSE: Crypt surface hyperproliferation is an intermediate biomarker of colon cancer risk. In vitro studies indicate that the short-chain fatty acid and antineoplastic agent butyrate may reverse the crypt surface hyperproliferation induced by the secondary bile acid and tumor promoter, deoxycholate. We hypothesized that butyrate may reverse deoxycholate-induced crypt surface proliferation in vivo. METHODS: Thirty-one Sprague-Dawley rats (250-300 g) underwent surgical isolation of the colon and 24-hour luminal instillation of either sodium chloride, butyrate, deoxycholate, or butyrate plus deoxycholate (all solutions, 2 ml; pH 7; total sodium = 20 mM). Study variables included colon weight, mucosal DNA, mucosal protein, and proliferating cell nuclear antigen immunohistochemistry, labeling of which was determined in five crypt compartments from base to surface (12 crypts per rat). Labeling indexes were calculated as proliferating cell nuclear antigen immunohistochemistry-labeled cells divided by total counted cells in the whole colonic crypt and each of five crypt compartments. The phi(h) value (an index of premalignant risk) was calculated as the ratio of labeled cells in the two surface compartments divided by the total labeled cells. RESULTS: Deoxycholate significantly increased colon wet weight, mucosal protein, total crypt labeling indexes, crypt surface labeling indexes, and the phi(h) value and raised the mucosal DNA content. Butyrate alone slightly reduced total mucosal DNA and protein content. The combination of butyrate plus deoxycholate significantly decreased mucosal DNA and tended to reduce mucosal protein compared with deoxycholate alone. In contrast to prior in vitro findings, butyrate plus deoxycholate did not reverse the deoxycholate-induced surface hyperproliferative changes as measured by proliferating cell nuclear antigen labeling. CONCLUSIONS: Because co-treatment with butyrate plus deoxycholate inhibits deoxycholate-induced increases in total mucosal DNA and protein content, we conclude that butyrate may play a role in maintaining the proliferative balance of the colonic mucosa, in vivo. However, co-treatment with butyrate plus deoxycholate does not reverse the deoxycholate-induced increases in colon weight and proliferating cell nuclear antigen labeling indexes under the studied experimental conditions.

Deoxycholate inhibits in vivo butyrate-mediated BrDU labeling of the colonic crypt.

The short-chain fatty acid butyrate (NaBu) selectively increases colonic crypt base proliferation and inhibits "premalignant" crypt surface hyperproliferation while the secondary bile acid deoxycholate (DCA) induces surface hyperproliferation, in vitro. We hypothesized that NaBu and DCA have similar selective and antagonistic effects on the colonic crypt proliferative pattern, in vivo. Fifty-six adult SD rats underwent surgical isolation of the colon and 24-hr intraluminal instillation with physiological (10 mM) and pharmacological (25 mM) levels of butyrate alone or combined with a physiological DCA level (5 microM). Bromodeoxyuridine-labeling indices (LI) were determined as labeled cells divided by total cells, for the whole crypt and five crypt compartments from base to surface. Treatment with NaBu increased total LI when compared to NaCl. This effect was significant only at the crypt base. Both doses of NaBu resulted in similar LI with no further response at the higher concentration. In contrast to prior in vitro studies, DCA alone at this concentration did not affect LI, but when combined with NaBu, DCA inhibited the effects of NaBu at the crypt base and surface. The conclusions are: (1) the in vivo proliferative effects of NaBu are selective to the crypt base, (2) an in vivo low physiological DCA level does not promote crypt surface hyperproliferation but does inhibit butyrate's proliferative effect, and (3) NaBu and DCA interact in a complex and antagonistic manner to selectively modulate crypt base and surface proliferation, in the rat colon, in vivo. These findings may have clinical relevance since colonic levels of NaBu and DCA are affected by diet.

Butyrate and the colonocyte. Production, absorption, metabolism, and therapeutic implications.

Butyrate, a SCFA generated by microbial fermentation of dietary substrates, is produced in the colon of humans and may influence colonic disease. It is possible to manipulate the diet in order to enhance levels of butyrate in various regions of the large intestine. Butyrate is absorbed by colonocytes in the proximal colon via passive diffusion and by active transport mechanisms which are linked to various ion exchange transporters. In the distal colon, the main mechanism of absorption is passive diffusion of the lipid-soluble form. Butyrate and other SCFA are important for the absorption of electrolytes by the large intestine and may play a role in preventing certain types of diarrhea. The mechanism by which butyrate and other SCFA exerts control over fluid and electrolyte fluxes in the colon is not well delineated though it may occur through an energy generated fuel effect, the up-regulation of various electrolyte transport systems, as well as possible effects on neuroendocrine factors. Butyrate has been shown to have beneficial effects on some colonic pathologies. This SCFA may be protective against colorectal neoplasia. Butyrate regulates colonic motility, increases colonic blood flow and may enhance colonic anastomosis healing. Butyrate may reduce the symptoms from ulcerative colitis and diversion colitis and it may prevent the progression of colitis in general. Further investigations are needed to confirm these findings in controlled, randomized, double blinded clinical studies.