The PARP inhibitor ABT-888 potentiates dacarbazine-induced cell death in carcinoids.

Monoagent DNA-alkylating chemotherapies like dacarbazine are among a paucity of medical treatments for advanced carcinoid tumors, but are limited by host toxicity and intrinsic chemoresistance through the base excision repair (BER) pathway via poly (ADP-ribose) polymerase (PARP). Hence, inhibitors of PARP may potentiate DNA-damaging agents by blocking BER and DNA restoration. We show that the PARP inhibitor ABT-888 (Veliparib) enhances the cytotoxic effects of dacarbazine in carcinoids. Two human carcinoid cell lines (BON and H727) treated with a combination of ABT-888 and dacarbazine resulted in synergistic growth inhibition signified by combination indices <1 on the Chou-Talalay scale. ABT-888 administered prior to varying dacarbazine doses promoted the suppression of neuroendocrine biomarkers of malignancy, ASCL1 and chromogranin A, as shown by western analysis. Ataxia telangiectasia mitogen factor phosphorylation and p21Waf1/Cip1 activation, indicative of DNA damage, were increased by ABT-888 when combined with dacarbazine treatment, suggesting BER pathway attenuation by ABT-888. PE Annexin V/7-AAD staining and sorting revealed a profound induction of apoptosis following combination treatment, which was further confirmed by increased PARP cleavage. These results demonstrate that ABT-888 synergizes dacarbazine treatment in carcinoids. Therefore, ABT-888 may help treat carcinoids unresponsive or refractory to mainstay therapies.

Aortic Arch Morphology and Aortic Length in Patients with Dissection, Traumatic, and Aneurysmal Disease.

OBJECTIVES: To assess aortic arch morphology and aortic length in patients with dissection, traumatic injury, and aneurysm undergoing TEVAR, and to identify characteristics specific to different pathologies. METHOD: This was a retrospective analysis of the aortic arch morphology and aortic length of dissection, traumatic injury, and aneurysmal patients. Computed tomography imaging was evaluated of 210 patients (49 dissection, 99 traumatic injury, 62 aneurysm) enrolled in three trials that received the conformable GORE TAG thoracic endoprosthesis. The mean age of trauma patients was 43 ± 19.6 years, 57 ± 11.7 years for dissection and 72 ± 9.6 years for aneurysm patients. A standardized protocol was used to measure aortic arch diameter, length, and take-off angle and clockface orientation of branch vessels. Differences in arch anatomy and length were assessed using ANOVA and independent t tests. RESULTS: Of the 210 arches evaluated, 22% had arch vessel common trunk configurations. The aortic diameter and the distance from the left main coronary (LMC) to the left common carotid (LCC) were greater in dissection patients than in trauma or aneurysm patients (p < .001). Aortic diameter in aneurysm patients was greater compared with trauma patients (p < .05). The distances from the branch vessels to the celiac artery (CA) were greater in dissection and aneurysm patients than in trauma patients (p < .001). The take-off angle of the innominate (I), LCCA, and left subclavian (LS) were greater, between 19% and 36%, in trauma patients than in dissection and aneurysm patients (p < .001). Clockface orientation of the arch vessels varies between pathologies. CONCLUSIONS: Arch anatomy has significant morphologic differences when comparing aortic pathologies. Describing these differences in a large sample of patients is beneficial for device designs and patient selection.

Milrinone improves lung compliance in patients receiving mechanical ventilation for cardiogenic pulmonary edema.

BACKGROUND: Cardiogenic pulmonary edema is a frequent cause of respiratory failure. We investigated whether milrinone improved lung compliance. METHODS: We selected 10 patients with respiratory failure due to severe cardiogenic pulmonary edema to receive mechanical ventilation. Patients were administered a bolus injection of milrinone (50 microg kg-1) over 10 min, followed by continuous intravenous infusion (0.5 microg kg-1 min-1). Lung compliance, blood gas values, hemodynamic parameters, and sample plasma milrinone levels were assessed over 120 min after the onset of the continuous infusion of milrinone. RESULTS: Ten min following milrinone infusion, dynamic compliance (Cdyn) and static compliance (Cst) increased from 37 +/- 12 to 42 +/- 12 ml cmH2O-1 and from 40 +/- 13 to 45 +/- 12 ml cmH2O-1, respectively (P < 0.01). Plasma milrinone levels reached a therapeutic level for vasodilator and positive inotropic effect at 10 min after milrinone infusion. A significant decrease in mean pulmonary artery pressure and pulmonary artery wedge pressure occurred simultaneously with an increase in respiratory system compliance. However, an increase in cardiac index was observed later than these changes. There were significant correlations between the mean pulmonary artery pressure and Cdyn (r = -0.39, P < 0.01) and Cst (r = -0.38, P < 0.01). CONCLUSIONS: Milrinone-induced improvement in lung compliance along with an improvement of hemodynamics was found together with an inverse relationship between compliance and mean pulmonary artery pressure.

Morphometric analysis of the popliteal artery for endovascular treatment.

This study intended to determine the precise diameter of the popliteal artery in patients at risk for popliteal aneurysms. Accurate sizing is necessary to develop devices for endovascular treatment of popliteal aneurysms. Fifty-four patients with abdominal aortic aneurysms (AAAs) had computed tomography (CT) scans of the popliteal arteries. Age- and gender-matched control subjects were measured by ultrasound. NIH Image was used to measure the minor diameter at the adductor hiatus (proximal) and femoral condyles (midpopliteal artery). There were 4 unsuspected popliteal aneurysms (7.4%). The proximal popliteal artery was ectatic in these patients: 13.4 +/- 5.2 mm. Proximal and midpopliteal arteries were significantly larger in the other patients with AAAs compared with controls: 9.6 +/- 1.8 mm vs 7.9 +/- 1.1 mm at the hiatus (p<0.001) and 10.2 +/- 2 mm vs 7.9 +/- 0.9 mm at the condyles (p<0.001). The popliteal artery was focally larger in patients with AAAs without popliteal aneurysms. The popliteal artery was larger in men compared with women; 9.8 +/- 1.8 mm vs 8.8 +/- 1.9 mm at the hiatus (p=0.024) and 10.5 +/- 1.9 mm vs 9.0 +/- 2.4 mm at the condyles (p=0.005). The proximal popliteal artery was 2 mm larger in patients at risk for popliteal aneurysms and 5 mm larger in patients with popliteal aneurysms compared to controls. Focal ectasia of the midpopliteal artery was common. Planning for endovascular treatment of popliteal aneurysms must incorporate this striking enlargement.

Is bilateral ultrasound scanning of the legs necessary for patients with unilateral symptoms of deep vein thrombosis?

PURPOSE: The purpose of this study was to determine the necessity of bilateral lower-extremity venous duplex ultrasound scanning in patients with unilateral symptoms of deep vein thrombosis (DVT). PATIENTS AND METHODS: A retrospective review of 1080 bilateral venous duplex scans was performed. Patients were randomly selected from a total of 7922 studied between May 1998 and May 2000. Data on patient age, sex, comorbidity, and the reason for ultrasound scan were compiled. Forty percent (435/1080) of patients presented with unilateral symptoms of lower-extremity DVT. This group was further analyzed according to their status as inpatients or outpatients. RESULTS: DVT was diagnosed in 26.9% (117/435) of the patients. Of the inpatients found to have DVT, the thrombus was confined to the symptomatic leg in 23.8% (38/159), thrombus was present just in the asymptomatic leg in 8/159 (5.0%), and thrombus was found in both legs in 8/159 (5.0%). In the outpatient group, thrombus was confined to the symptomatic leg in 21.0% (58/276) and found in both legs in 1.8% (5/276). None of the 276 outpatients had DVT isolated in the asymptomatic leg. CONCLUSION: Routine bilateral lower-extremity venous duplex studies are not necessary in outpatients presenting with unilateral symptoms. In many outpatients, a single-limb study will suffice. If a patient is found to have a DVT on the symptomatic side, then we believe that a bilateral study is indicated. We do believe that routine bilateral scanning of inpatients remains justified. This algorithm may save technician time and increase vascular laboratory efficiency.

Mesenteric venous thrombosis: a changing clinical entity.

OBJECTIVE: Mesenteric venous thrombosis (MVT) and its clinical spectrum have become better defined following improvements in diagnostic imaging. Historically, MVT has been described as a morbid clinical entity, but this may not necessarily be true. Often, an underlying disease process that predisposes a patient to MVT can be found and potentially treated. This study was designed to evaluate the diagnostics and management of MVT and to review long-term results of treatment. PATIENTS: Thirty-one patients in whom MVT was diagnosed between 1985 and 1999 were retrospectively reviewed. Survivors were contacted for follow-up. There were 15 men and 16 women. Ages ranged from 22 to 80 years (mean, 49.1 years). Thirteen patients had documented hypercoagulability, 10 had a history of previous abdominal surgery, 6 had a prior thrombotic episode, and 4 had a history of cancer. MVT presented as abdominal pain (84%), diarrhea (42%), and nausea/vomiting (32%). Computed tomography (CT) was considered diagnostic in 18 (90%) of 20 patients who underwent the test. CT diagnosed MVT in 15 (100%) of 15 patients presenting with vague abdominal pain or diarrhea. Angiography demonstrated MVT in only five (55.5%) of nine patients. RESULTS: Seven of 31 patients died within 30 days (< 30-day mortality rate, 23%). Twenty-two patients (72%) were initially treated with heparin. Nine patients were not heparinized: four of them died, and two were later given warfarin sodium (Coumadin). Of the 31 patients, only one received lytic therapy. Three patients became symptom free without anticoagulation. Ten patients (32%) underwent bowel resection. Overall, 19 (79%) of 24 survivors were treated with long-term warfarin therapy. Long-term follow-up was obtained in 24 patients (mean, 57.7 months). Twenty-one (88%) of 24 survived in follow-up. CONCLUSION: The diagnosis of MVT should be suspected when acute abdominal symptoms develop in patients with prior thrombotic episodes or a documented coagulopathy. CT scanning appears to be the primary diagnostic test of choice. Anticoagulation is recommended. If diagnosed and treated early, MVT is not likely to progress to gangrenous bowel. Recent mortality rates for MVT are lower than previously published, perhaps because of earlier diagnosis and aggressive treatment or possibly because we now readily diagnose a more benign form of the disease, which is due to widespread use of CT scanning.

Screening and surveillance for abdominal aortic aneurysms: who needs it and when.

Early detection of abdominal aortic aneurysms potentially can save many lives by preventing aneurysm rupture. Screening programs, however, have yet to be proven as an efficient means of accomplishing this goal and improving overall life expectancy. Until more information is available, selective high-risk screening may be the only viable option. Recently, 2 large prospective studies have better defined the utility of screening programs and have provided guidelines for the safe nonoperative management of small aneurysms. Using ultrasound surveillance, these can be followed up at 3- to 12-month intervals, depending on their size, with operative intervention reserved for aneurysms that enlarge rapidly, become symptomatic, or reach 5.5 cm in diameter.

Identification and implications of transgraft microleaks after endovascular repair of aortic aneurysms.

PURPOSE: The purpose of this report is to describe an interesting cause of endoleak and detail-specific techniques for identifying small transgraft defects, which we have termed microleaks. METHODS: Four patients underwent endovascular repair of abdominal aortic aneurysms with modular nitinol/polyester endoprostheses and were studied after 6 to 30 months. All patients were enrolled in standard follow-up radiographic surveillance protocols. RESULTS: Three of the four abdominal aortic aneurysms continued to expand after endograft repair. Standard computed tomography imaging with precontrast, dynamic contrast, and delayed imaging frequently identifies endoleak, although it fails to precisely identify microleaks as the source. Color flow duplex ultrasound scan was performed on three patients and perigraft "jets," small areas of color flow adjacent to the endograft, were identified in all. Microleaks were identified in one patient who underwent digital subtraction arteriography with directed efforts to completely opacify the prosthesis lumen and multiple oblique projections. In another patient, contrast arteriography with balloon occlusion of the distal endograft clearly depicted midgraft microleaks that might otherwise be mistaken for graft porosity or cuff junction endoleaks. No microleaks were diagnosed on angiograms when these directed efforts were not performed. Aneurysm exploration before aortic clamping provided conclusive determination of the presence of blood flow through the wall of the endoprosthesis in two patients. CONCLUSIONS: Microleaks occur up to 2.5 years after endovascular repair of aortic aneurysms. Although computed tomography demonstrates the presence of an endoleak in these patients, the exact site of origin usually remains obscure. Doppler ultrasound scan and directed arteriography appear to be of greater utility for identifying the presence and location of microleaks. Balloon occlusion arteriography and aneurysm exploration without arterial clamping provide definitive evidence of microleaks. Although the clinical significance of microleaks remains unclear, long-term monitoring of patients is imperative to diagnose and treat these and other modes of endograft failure before they progress to aneurysm rupture.

Bedside vena cava filter placement guided with intravascular ultrasound.

OBJECTIVE: The purpose of this study was to report a feasibility trial approved by the Institutional Review Board for insertion of inferior vena cava (IVC) filters with intravascular ultrasound (IVUS) guidance in the intensive care unit. METHODS: Between October 1998 and May 2000, 26 patients (15 men, 11 women; age range, 22-86 years; mean, 55 years) were enrolled. Eight patients (31%) underwent prophylactic filter placement, and 18 patients (69%) had venous thromboembolism (deep venous thrombosis = 16, pulmonary embolism = 2) with contraindications to anticoagulation. A single groin puncture was used for IVUS and filter placement. Location of major branch veins, thrombosis, and caval diameter were readily demonstrated without the use of radiocontrast agents. Mapping of the IVC permitted assessment of ideal filter location. Postprocedure radiographs (23 of 26) were obtained to document filter position. Seventeen of 26 had follow-up lower extremity duplex studies. RESULTS: Twenty-four (92%) of 26 patients underwent successful filter deployment. The two other patients had filters subsequently placed by means of traditional fluoroscopic techniques. One femoral vein insertion site thrombosis resolved after a month. One patient experienced symptomatic caval thrombosis thought to be caused by thrombus trapping 55 days after the procedure. No pulmonary emboli occurred after filter placement. One patient's death was unrelated to vena cava filter placement. The hospital charge for bedside filters was $3623 compared with $4165 (P =.281) for fluoroscopic placement. CONCLUSION: Bedside insertion of an IVC filter with IVUS guidance is feasible and may be an effective alternative in the intensive care unit. No additional costs were incurred in this small series. Protocol refinements should reduce the incidence of complications. The results of this study support the need for further evaluation comparing it with standard techniques.

Familial nasal NK/T-cell lymphoma and pesticide use.

Familial occurrence of nasal NK/T-cell lymphoma (NNKTCL) in pesticide users is presented. The proband (71 years old, male) and son (39 years old) were both diagnosed with NNKTCL within interval of 26 months. Laboratory data showed slight anemia, with no abnormal cells in peripheral blood. They and their wives were farmers and used large amounts of pesticides (fungicides and insecticides) in the hothouse. NNKTCL did not develop in the wives. Proband's father was diagnosed with malignant lymphoma of the neck and died of the disease. Genetic analyses of the peripheral blood leukocytes and tumor tissues did not show p53 and k-ras gene mutations and microsatellite instability. Metaphase cells from peripheral blood leukocytes bore specific marker chromosomes (father, 44XY,-14,-17,-18,-22,+2mar; son, 46XY,-17,+1mar). Environmental exposures to pesticides in conjunction with familial or genetic factors might increase the risk for NNKTCL.

Postoperative radiotherapy for squamous cell carcinoma of the maxillary sinus: analysis of local control and late complications.

This retrospective study was conducted to analyze the local control and late complications in patients with squamous cell carcinoma of the maxillary sinus treated with postoperative radiation therapy following surgery. Between 1979 and 1998, 41 patients with squamous cell carcinoma of the maxillary sinus were treated with postoperative irradiation following partial or total maxillectomy. Tumor classification according to the TNM classification of the International Union Against Cancer (1997) was T2 in 6 patients, T3 in 21 patients, and T4 in 14 patients. Fourteen patients had negative surgical margins, 23 had microscopically positive margins, and 4 had grossly positive margins. Sixteen patients received preoperative intraarterial chemotherapy. The total dose to the primary tumor bed was 40-70 Gy (median: 54 Gy) with a fraction size of 2 Gy. The median follow-up time of the surviving patients was 93 months (range: 25-179 months). Local recurrence was observed in 17 patients (41%), and the 5-year actuarial overall survival and local control rates were 48% and 55%, respectively. In the univariate analysis, surgical margin status and total dose each had a statistically significant impact on local recurrence. For the patients with negative surgical margins, 8 of 9 (89%) patients achieved local control with a dose of 50-54 Gy, while 7 of 10 (70%) patients with microscopically positive margins achieved local control with a dose of 60-64 Gy. There were 11 late complications found in 9 patients; bone necrosis in 2, soft tissue necrosis in 2, trisumus: 2, cellulitis in 1, retinopathy in 1, and vision impairment in 3 patients. A total dose of 60 Gy or more was administered in all patients who suffered late complications except for 2 patients with vision impairment. These results indicated that an optimal dose of postoperative irradiation according to the surgical margin status was necessary to achieve local control for squamous cell carcinoma of the maxillary sinus following surgery. For patients with negative surgical margins, a total dose of 50-54 Gy in conventional fractionation was appropriate to achieve local control as well as to reduce late complications. On the other hand, a dose of 60 Gy or more was required for the patients with microscopic positive margins.

Update on the bifurcated EXCLUDER endoprosthesis: phase I results.

Many devices are being investigated for treatment of infrarenal abdominal aortic aneurysms. This report describes the particular characteristics of a next generation modular endograft and the Phase I results in 29 patients. Larger comparative studies are in progress to assess the safety and efficacy of this new design.

Incidental asymptomatic cerebral aneurysms in patients with extracranial cerebrovascular disease: is this a case against carotid endarterectomy without arteriography?

As less arteriography is performed before carotid surgery, concern arises about missing occult cerebral aneurysms and possible adverse outcomes. A study was conducted by the divisions of vascular surgery and neurosurgery of Northwestern University Medical School to evaluate the frequency of incidental cerebral aneurysms and outcomes of patients with extracranial cerebrovascular disease and asymptomatic cerebral aneurysms. From October 1995, through March 1997, 200 patients underwent intracranial and extracranial cerebrovascular angiography for evaluation of extracranial disease. Demographic data, symptoms, data of vascular lesions, surgical treatment and outcomes of stroke and death were recorded prospectively. Two patients (1%) had asymptomatic cerebral aneurysms found on angiography. Six more patients were referred with a known asymptomatic cerebral aneurysm with extracranial disease during this same period. Of these eight patients, five underwent extracranial vascular reconstruction surgery and seven received treatment for their aneurysms. There were two stroke complications, both occurred after treatment of a basilar artery aneurysm. One of these patients died. No aneurysms ruptured following 203 extracranial revascularizations during this same period. On the basis of the low prevalence of diagnosing coincidental cerebral aneurysms during work-up of extracranial disease, as well as the lack of evidence that carotid surgery predisposes to aneurysm rupture in these patients in both our study and the literature review, it is concluded that coexisting extracranial disease and asymptomatic cerebral aneurysms do not pose a case against carotid surgery without routine arteriography. However, arteriography should be considered in selected groups of patients where the yield of intracranial aneurysms is high; these include patients with a familial history of cerebral aneurysms, autosomal dominant polycystic kidney disease, extracranial internal carotid artery medial fibrodysplasia, Takayasu's arteritis, alpha1-antitripsin deficiency and atypical clinical presentations, including headache.

Filter placement by ultrasound technique at the bedside.

Vena cava filtration devices are commonly inserted for the prevention of fatal pulmonary emboli. Several imaging methods are used today to direct device placement. Bedside insertion has several advantages, particularly in the critically ill patient. Imaging techniques include bedside fluoroscopy, transperitoneal ultrasound, and intravascular ultrasound. We have now successfully placed 10 transfemoral vena cava filters by use of intravascular ultrasound at the patient's bedside. This appears to be a feasible method for filter insertion.

Minor cardiac troponin T release in patients undergoing coronary artery bypass graft surgery on a beating heart.

OBJECTIVES: To determine whether and to what extent coronary artery bypass graft (CABG) surgery without extracorporeal circulation is associated with cardiac troponin T (TnT) release. DESIGN: Prospective study. SETTING: A single university hospital. PARTICIPANTS: Twenty-three patients scheduled for minimally invasive CABG surgery. Sixteen patients received one coronary anastomosis, and seven received two. INTERVENTIONS: TnT and creatine kinase-MB (CK-MB) levels were determined immediately before induction of anesthesia (baseline) and at 0, 12, and 24 hours after surgery. Hemodynamic measurements were made, and 5-lead electrocardiograms with continuous automated ST-segment trends were analyzed. MEASUREMENTS AND MAIN RESULTS: All patients had a good cardiac outcome. Median cumulative coronary artery occlusion time was 27 minutes (range, 10 to 49 minutes). TnT levels were undetectable in 91.3% of patients at baseline when a detection limit of 0.01 ng/mL was employed. TnT and CK-MB showed significant elevations at 12 and 24 hours versus baseline. Postoperatively, TnT was detectable in 91.3% of patients, and 17.4% suffered minor myocardial damage, as evidenced by an abnormal increase in TnT greater than 0.2 ng/mL, excluding those exhibiting myocardial infarction. ST segment changes developed in seven patients, persisting for 13.0 minutes (range, 9.5 to 15.8 minutes) and disappearing immediately after coronary artery clamp release. There were no significant correlations between cumulative coronary occlusion time and peak TnT or CK-MB levels. CONCLUSIONS: TnT was detected after surgery in most patients, and significant TnT levels indicative of myocardial injury (>0.2 ng/mL) were detected in only 17% of patients, probably as a result of brief periods of coronary artery occlusion.

Transrectal ultrasound assessment of murine aorta and iliac arteries.

Recent research in arterial aneurysm formation has focused on animal model development. Mice are an ideal experimental organism due to their short life cycle, prolific progeny, and extensively studied genome. Most experiments require the sacrifice of the mice to observe and assess any morphological changes. Noninvasive or minimally invasive imaging is limited due to the relatively small size of the structures. The development of such a technique, therefore, is especially useful for allowing repeated measurement without sacrificing the mice. We introduce a novel technique of imaging and measuring the aorta, the aorta/inferior vena cava complex, and the right and the left common iliac artery/vein complex by the use of an intravascular ultrasound catheter. The catheter is inserted through the anus and rectum and into the sigmoid and left colon, where the aorta can be observed to fluctuate at approximately 500 beats/min. The aortic bifurcation can also be observed. The diameters of the aorta and the inferior vena cava were measured first with the transrectal ultrasound technique and then with direct visualization upon laparotomy for 10 mice. This revealed a percentage error between 13.7 and 14.2% for this novel technique. Fifteen more sets of vessel measurements were also made with 8 male and 7 female mice. The results demonstrated a correlation between vessel size and body weight in male but not female mice and suggested an intersex difference in vessel growth rate. We conclude that transrectal ultrasound is a useful tool in imaging and measuring the murine aorta and its bifurcation.