Reperfusion rates following intra-arterial thrombolysis for acute ischemic stroke: the influence of the method for alteplase delivery.

BACKGROUND AND PURPOSE: Because alteplase does not penetrate thrombus effectively, this study examined whether a method thought to maximize surface distribution of alteplase on the offending thrombus during IATT would result in greater reperfusion rates in acute ischemic stroke. MATERIALS AND METHODS: Clinical information, arteriograms, and CT scans following treatment from 85 consecutive patients who underwent IATT by using alteplase within 6 hours of stroke symptom onset were reviewed. Alteplase was delivered through a microcatheter embedded within the thrombus at 1 mg per minute in all cases, and the delivery never exceeded 100 mg of alteplase. Patients who underwent microcatheter contrast injections confirming that alteplase surrounded the thrombus were compared with patients who did not. RESULTS: Greater than 50% vascular territory reperfusion occurred in 82.2% of patients who underwent IATT with the intention of optimizing alteplase delivery versus 30.0% in patients without this intention (P < .0001, Pearson correlation) with an odds ratio of 15.8 based on nominal regression analysis. Hemorrhagic complication rates between methods were similar. The mRS at 1-3 months, infarct volume, change in NIHSS score by 24 hours, and hospital discharge were positively affected by optimizing alteplase delivery. CONCLUSIONS: A method that intends to evenly distribute alteplase around a thrombus resulted in better reperfusion rates and clinical outcomes compared with methods without this intention. Other predictors positively influencing reperfusion included the presence of slow antegrade flow distal to the clot, earlier time to treatment, lower presenting NIHSS score, and proximal occlusion site.

Classification of probe-based confocal laser endomicroscopy findings in pancreaticobiliary strictures.

BACKGROUND AND STUDY AIMS: The accurate diagnosis of indeterminate pancreaticobiliary strictures presents a clinical dilemma. Probe-based confocal laser endomicroscopy (pCLE) offers real-time in vivo microscopic tissue examination that may increase sensitivity for the detection of malignancy. the objective of this study was to develop and validate a standard descriptive classification of pcle in the pancreaticobiliary system. PATIENTS AND METHODS: A total of 102 patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) with pCLE to assess indeterminate pancreaticobiliary strictures were enrolled in a multicenter registry; 89 of these patients were evaluable. Information and data on the following were collected prospectively: clinical, ERCP, tissue sampling, pCLE, and follow-up. A uniform classification of pCLE findings ("Miami Classification") was developed, consisting of a set of image interpretation criteria. Thereafter, these criteria were tested through blinded consensus review of 112 randomized pCLE videos from 47 patients, and inter-observer variability was assessed in 42 patients . RESULTS: A consensus definition of the specific criteria of biliary and pancreatic pCLE findings for indeterminate strictures was developed. Single-image interpretation criteria did not have a high enough sensitivity for predicting malignancy. However, combining two or more criteria significantly increased the sensitivity and predictive values. The characteristics most suggestive of malignancy included the following: thick white bands (>20 µm), or thick dark bands (>40 µm), or dark clumps or epithelial structures. These provided sensitivity, specificity, positive predictive value, and negative predictive value of 97%, 33%, 80%, and 80% compared with 48%, 100%, 100%, and 41% for standard tissue sampling methods. Inter-observer variability was moderate for most criteria. CONCLUSION: The Miami Classification enables a structured, uniform, and reproducible description of pancreaticobiliary pCLE. Combining individual characteristics improves the sensitivity for the detection of malignancy.

Use and perceived effectiveness of non-analgesic medical therapies for chronic pancreatitis in the United States.

BACKGROUND: Effectiveness of medical therapies in chronic pancreatitis has been described in small studies of selected patients. AIM: To describe frequency and perceived effectiveness of non-analgesic medical therapies in chronic pancreatitis patients evaluated at US referral centres. METHODS: Using data on 516 chronic pancreatitis patients enrolled prospectively in the NAPS2 Study, we evaluated how often medical therapies [pancreatic enzyme replacement therapy (PERT), vitamins/antioxidants (AO), octreotide, coeliac plexus block (CPB)] were utilized and considered useful by physicians. RESULTS: Oral PERT was commonly used (70%), more frequently in the presence of exocrine insufficiency (EI) (88% vs. 61%, P < 0.001) and pain (74% vs. 59%, P < 0.002). On multivariable analyses, predictors of PERT usage were EI (OR 5.14, 95% CI 2.87-9.18), constant (OR 3.42, 95% CI 1.93-6.04) or intermittent pain (OR 1.98, 95% CI 1.14-3.45). Efficacy of PERT was predicted only by EI (OR 2.16, 95% CI 1.36-3.42). AO were tried less often (14%) and were more effective in idiopathic and obstructive vs. alcoholic chronic pancreatitis (25% vs. 4%, P = 0.03). Other therapies were infrequently used (CPB - 5%, octreotide - 7%) with efficacy generally <50%. CONCLUSIONS: Pancreatic enzyme replacement therapy is commonly utilized, but is considered useful in only subsets of chronic pancreatitis patients. Other medical therapies are used infrequently and have limited efficacy.

Hemorrhage rates and outcomes when using up to 100 mg intra-arterial t-PA for thrombolysis in acute ischemic stroke.

This work presents a unique single center experience with intra-arterial delivery of tissue plasminogen activator (t-PA) doses as high as 100mg for thrombolysis. Hemorrhage volumes, hemorrhage rates, clinical outcomes and radiographic outcomes were assessed. Prospectively collected angiographic, clinical and laboratory information on 67 consecutive patients with acute ischemic stroke involving either the m1 segment of the middle cerebral artery, the intracranial internal carotid artery or the basilar artery were retrospectively analyzed. Patients who received more than 50 mg t-PA were compared with those patients receiving 50 mg or less. Outcome measures included: symptomatic hemorrhage, significant hemorrhage volume (greater than 25 ml), hemorrhage rate, change in National Institutes of Health stroke scale score at 24 hours and at hospital discharge, modified Rankin score at 90 days, in-hospital deaths, death within 90 days, reperfusion rate, and infarct volume. Multivariate logistic regression analysis demonstrated that t-PA dose over 50 mg was associated with higher rates of hemorrhage and larger hemorrhages. Poor pial collateral formation, poor reperfusion (less than 50% of the territory involved), and platelet count below 200 K/µL influenced hemorrhage. Limiting t-PA dose to 100mg rather than 50mg improved documented reperfusion rates from 37% to 61%. Restricting intra-arterial t-PA administration to 100mg rather than 50mg, is associated with higher overall reperfusion rates and improves overall outcomes, however, the hemorrhage rate is also elevated. Poor pial collateral formation and platelet count less than 200 K/µL may be reasons to curtail the use of higher t-PA dose to reduce hemorrhage rate.

Predictors of hemorrhage following intra-arterial thrombolysis for acute ischemic stroke: the role of pial collateral formation.

BACKGROUND AND PURPOSE: The extent of pial collateral formation during acute ischemic stroke has been shown to influence outcomes. This study examines whether angiographic assessment of pial collateral formation is predictive of hemorrhagic transformation following intra-arterial thrombolysis (IAT) for acute ischemic stroke. MATERIALS AND METHODS: Rates of any hemorrhage and significant hemorrhage (>25 mL) were reviewed in 104 consecutive patients who underwent IAT following acute ischemic stroke. The influence of the anatomic extent of pial collateral formation on the rates of hemorrhage and significant hemorrhage relative to known predictors for hemorrhagic transformation (presenting systolic blood pressure, blood glucose level, platelet level, and National Institutes of Health Stroke Scale [NIHSS] score, history of diabetes, time to treatment, age, sex, occlusion site, and extent of reperfusion) was analyzed by using logistic regression models. RESULTS: Rates of any hemorrhage and significant hemorrhage were 25.2% (26/104) and 9.7% (10/104), respectively. The rate of significant hemorrhage was 25.0% (8/32) in patients with poor pial collaterals and 2.78% (2/72) in those with good pial collaterals (P = .0004, Pearson correlation). The rate of any hemorrhage was also significantly higher in patients with poor pial collaterals (40.6% versus 18.1%; P = .0142, Pearson correlation). Logistic regression analyses revealed that pial collateral formation (odds ratio [OR] = 3.04), history of diabetes (OR = 4.83), platelets <200,000/microL (OR = 2.95), and time to treatment <3 hours (OR = 12.0) were statistically significant predictors of hemorrhage, whereas pial collateral formation (OR = 13.1) and platelets <200,000/microL (OR = 8.1) were statistically significant predictors of significant hemorrhage. CONCLUSIONS: Poor pial collateral formation is associated with higher incidence and larger size of hemorrhage following IAT.

Fibroinflammatory biliary stricture: a rare bile duct lesion masquerading as cholangiocarcinoma.

INTRODUCTION: Fibroinflammatory biliary stricture (FIBS) is a rare benign tumor-like process of the extrahepatic bile duct that masquerades as cholangiocarcinoma. METHODS: In order to distinguish this unusual entity from cancer, we performed a systematic analysis of 11 patients with FIBS. All patients presented with jaundice; six patients had coexisting autoimmune disease. Preoperative evaluation included computed tomography scan and endoscopic retrograde cholangiopancreatography with benign brush cytology. Surgical treatment included nine bile duct resections with five concurrent liver resections and two incisional biopsies. Light microscopy demonstrated fibrous lesions admixed with chronic inflammation. RESULTS AND DISCUSSION: Immunohistochemistry demonstrated smooth muscle actin expression in all lesions except one; five tumors exhibited IgG4 positive plasma cells. The lesions were negative for cytokeratin, ALK1, CD21, S100, Ki67, and p53. Six patients received postoperative immunosuppression. At 41 month median follow-up (range 15-58 months), there was no evidence of recurrent FIBS in ten patients, while one was lost to follow-up. CONCLUSION: FIBS is a rare myofibroblastic lesion with an immunohistochemical profile distinct from other epithelial and stromal neoplasms of the extrahepatic bile duct. A subset of these cases appear to represent IgG4-related sclerosing cholangitis. Because preoperative cytology is not diagnostic of FIBS, surgical resection remains the mainstay of diagnosis and treatment, while immunosuppression may reduce the risk of recurrence.

VITATOPS, the VITAmins TO prevent stroke trial: rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke (NCT00097669) (ISRCTN74743444).

BACKGROUND: Epidemiological studies suggest that raised plasma concentrations of total homocysteine (tHcy) may be a common, causal and treatable risk factor for atherothromboembolic ischaemic stroke, dementia and depression. Although tHcy can be lowered effectively with small doses of folic acid, vitamin B(12) and vitamin B(6), it is not known whether lowering tHcy, by means of B vitamin therapy, can prevent stroke and other major atherothromboembolic vascular events. AIM: To determine whether the addition of B-vitamin supplements (folic acid 2 mg, B(6) 25 mg, B(12) 500 microg) to best medical and surgical management will reduce the combined incidence of stroke, myocardial infarction (MI) and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye. DESIGN: A prospective, international, multicentre, randomised, double blind, placebo-controlled clinical trial. SETTING: One hundred and four medical centres in 20 countries on five continents. SUBJECTS: Eight thousand (6600 recruited as of 5 January, 2006) patients with recent (<7 months) stroke (ischaemic or haemorrhagic) or TIA (brain or eye). RANDOMISATION: Randomisation and data collection are performed by means of a central telephone service or secure internet site. INTERVENTION: One tablet daily of either placebo or B vitamins (folic acid 2 mg, B(6) 25 mg, B(12) 500 mug). PRIMARY OUTCOME: The composite of stroke, MI or death from any vascular cause, whichever occurs first. Outcome and serious adverse events are adjudicated blinded to treatment allocation. SECONDARY OUTCOMES: TIA, unstable angina, revascularisation procedures, dementia, depression. STATISTICAL POWER: With 8000 patients followed up for a median of 2 years and an annual incidence of the primary outcome of 8% among patients assigned placebo, the study will have at least 80% power to detect a relative reduction of 15% in the incidence of the primary outcome among patients assigned B vitamins (to 6.8%/year), applying a two-tailed level of significance of 5%. CONCLUSION: VITATOPS aims to recruit and follow-up 8000 patients between 1998 and 2008, and provide a reliable estimate of the safety and effectiveness of folic acid, vitamin B(12), and vitamin B(6) supplementation in reducing recurrent serious vascular events among a wide range of patients with TIA and stroke throughout the world.

Arteriographic demonstration of slow antegrade opacification distal to a cerebrovascular thromboembolic occlusion site as a favorable indicator for intra-arterial thrombolysis.

PURPOSE: This study sought to determine whether the angiographic demonstration of slow antegrade contrast opacification of an occluded cerebral artery distal to the thrombus (clot outline sign) on cerebral arteriograms performed immediately before thrombolytic treatment is associated with higher recanalization rates relative to patients without antegrade contrast opacification distal to the occlusion site. METHODS: The angiographic images of 100 consecutive arteriograms performed before thrombolysis in patients eligible for intra-arterial thrombolysis from May 1995 to February 2005 were reviewed. A modified Thrombolysis in Myocardial Infarction flow grade (mTIMI) was adapted to grade recanalization after cerebral thrombolysis. Clot outline sign was defined as slow antegrade contrast opacification distal to the thrombus on the delayed images of the presenting arteriogram. Logistic regression analysis for mTIMI grade included the following potential predictors: presence of outline sign, age, time to treatment, sex, site of occlusion, presenting National Institutes of Health Stroke Scale (NIHSS) score, presenting platelets, presenting systolic blood pressure, presence of pial collaterals, and admitting glucose value. RESULTS: Eighty-seven arteriograms were reviewed. Of these, 19 (22%) displayed the clot outline sign. Thirteen (69%) of 19 had clot outline sign, and 16 of 68 (29%) were not completely recanalized (mTIMI = 3); 95% with clot outline sign and 54% without were associated with either mTIMI 2 or 3 (P = .0055, Pearson correlation). Logistic regression analysis for recanalization relative to other predictors indicates that only the clot outline sign could act as a statistically significant predictor for recanalization (P = .0007). CONCLUSION: Prethrombolysis cerebral arteriograms demonstrating delayed antegrade contrast opacification distal to the occlusion site are associated with higher recanalization rates.

Multianalyte profiling of serum cytokines for detection of pancreatic cancer.

Early detection of pancreatic cancer might improve clinical outcome. Significant alterations in the levels of individual serum cytokines have been reported in pancreatic cancer. We hypothesized that a multicytokine panel could serve as biomarkers for pancreatic cancer. To evaluate the diagnostic utility of such a panel, we have utilized a novel multianalyte LabMAP profiling technology that allows simultaneous measurement of multiple markers. In this study, a panel of 31 serological markers including cytokines, chemokines, growth and angiogenic factors in combination with CA 19-9 was analyzed in sera of pancreatic cancer patients, patients with chronic pancreatitis, and matched control healthy subjects. Statistical analysis identified a multicytokine panel that was able to distinguish pancreatic cancer from healthy controls with a sensitivity of 85.7% and specificity of 92.3%, which was superior to performance of CA 19-9 alone. Importantly, a multicytokine panel allowed the discrimination of pancreatic cancer from chronic pancreatitis with high sensitivity of 98% and specificity of 96.4%. In conclusion, we demonstrated that analysis of multiple serum cytokines using a novel LabMAP technology is a promising approach for development of a diagnostic assay for pancreatic cancer.

Use of microsatellite marker loss of heterozygosity in accurate diagnosis of pancreaticobiliary malignancy from brush cytology samples.

BACKGROUND: Brush cytology of biliary strictures to diagnose pancreaticobiliary malignancy suffers from poor sensitivity. AIM: To improve the diagnostic yield of pancreaticobiliary brush cytology through analysis of tumour suppressor gene linked microsatellite marker loss of heterozygosity (LOH) and k-ras codon 12 mutation detection. METHODS: Twenty six patients with biliary strictures underwent endoscopic retrograde cholangiography with brush cytology. A panel of 12 polymorphic microsatellite markers linked to six tumour suppressor genes was developed. Genomic DNA from cell clusters acquired from brush cytology specimens and microdissected surgical malignant and normal tissue underwent polymerase chain amplification reaction (PCR). PCR products were compared for LOH and k-ras codon 12 mutations. RESULTS: Seventeen patients were confirmed to have pancreaticobiliary adenocarcinoma. Nine patients had benign strictures (eight proven surgically, one by follow up). Cytomorphological interpretation was positive for malignancy (n = 8), indeterminate (n = 10), and negative for malignancy (n = 8). Selected malignant appearing cytological cell clusters and microdissected histological samples from cancer showed abundant LOH characteristic of malignancy while brushings from nine cases without cancer carried no LOH (p<0.001). LOH and k-ras mutations profile of the cytological specimens was almost always concordant with the tissue samples. Presence of k-ras mutation predicted malignancy of pancreatic origin (p<0.001). CONCLUSION: LOH and k-ras codon 12 mutation analysis of PCR amplified DNA from biliary brush cytology discriminates reactive from malignant cells, with 100% sensitivity, specificity, and accuracy. Minor variations in LOH in brushings and in different sites within the same tumour likely reflect intratumoral mutational heterogeneity during clonal expansion of pre- and neoplastic lineages.

Endoscopic balloon dilation of gastroenteric anastomotic stricture after laparoscopic gastric bypass.

BACKGROUND AND STUDY AIMS: Laparoscopic gastric bypass is a recently introduced treatment option for morbid obesity, with promising initial results. Stenosis of the gastroenterostomy is a recognized complication. The efficacy and safety of endoscopic balloon dilation for the management of this type of anastomotic stenosis has not been studied. PATIENTS AND METHODS: 450 patients who underwent laparoscopic gastric bypass at our institution were followed prospectively. All patients had a 15 ml gastric pouch and either a 75 cm or 150 cm jejunal Roux limb depending on whether obesity was morbid (body mass index (BMI) < 50 kg/m 2) or super-morbid (BMI > 50 kg/m 2). Patients who developed symptoms compatible with stenosis of the gastrojejunostomy were referred for upper gastrointestinal endoscopy. RESULTS: 14 patients, 11 women and three men, underwent a total of 27 endoscopies, with 23 balloon dilations. Their average age was 46 years (range 33 - 59 years), average preoperative BMI was 47 kg/m 2, and they presented an average of 2.7 months after surgery (range 0.3 - 15.7 months). Of the 14 patients, 13 had a stricture of the gastrojejunostomy and one patient had edema. For initial dilation, a 15 mm hydrostatic balloon was used in 12 patients and an 18 mm balloon in two patients. There was response to treatment with the 15 mm balloon in seven of the 12 patients (58 %), and they required no further dilation; in one there was a response to a further 15 mm balloon dilation; in three patients a response to subsequent 18 mm balloon dilation; and one patient required 18 mm and 25 mm balloon dilations. The two patients treated with an initial 18 mm balloon dilation required no further dilations. The average length of follow-up after successful dilation was 18 months (range 7 - 30 months). There were no complications with any of the 23 dilations performed. CONCLUSION: Stenosis of the gastroenterostomy after laparoscopic gastric bypass occurred in 3.1 % of the patients in this series. It can be successfully and safely treated with endoscopic balloon dilation with good long-term follow-up.

Altered cerebral vasoregulation in hypertension and stroke.

BACKGROUND: Autoregulation of blood flow that maintains steady perfusion over the range of systemic blood pressure is compromised by stroke. OBJECTIVES: To determine whether cerebral vasoregulation is impaired in stroke during orthostatic stress. METHODS: Subjects included 30 control subjects, 30 with hypertension, and 20 with minor stroke and were studied using transcranial Doppler. Bilateral blood flow velocities (BFVs) from middle cerebral arteries, heart rate, blood pressure (BP), and CO2 were obtained during hyperventilation and CO2 rebreathing during supine rest and tilt at 80 degrees. Side-to-side BFV difference, vasomotor range (VMR), and cerebrovascular resistance (CVR) were calculated during normo-, hypo-, and hypercapnia. RESULTS: Mean BFVs were similar between groups in supine position but differed during tilt. BFV diminished on the stroke side during tilt with hyperventilation and CO2 rebreathing (p < 0.0001). CVR increased (p < 0.0001) and VMR decreased (p < 0.01) on the stroke side. Vasoregulation was preserved on the normal side. BFV asymmetry differentiated patients with stroke from the other groups (p < 0.0001). BFV difference between the normal vs stroke side was the largest in stroke-normotensive (n = 7) compared with stroke-hypertensive (n = 13) patients and the two other groups (p < 0.0001). BFV asymmetry in stroke was associated with lower orthostatic BP (p < 0.0001). CONCLUSIONS: Cerebral vasoregulation is impaired with minor stroke, and cerebral blood flow depends on blood pressure. Decline of blood flow velocities during orthostatic stress may pose a risk of silent hypoperfusion.

Safety of ERCP during pregnancy.

OBJECTIVES: There are few data in the literature regarding the indications, therapy, and safety of endoscopic management of pancreatico-biliary disorders during pregnancy. We report the largest single center experience with ERCP in pregnancy. METHODS: We reviewed 15 patients that underwent ERCP during pregnancy. In all patients, the pelvis was lead-shielded and the fetus was monitored by an obstetrician. Fluoroscopy was minimized and hard copy radiographs taken only when essential. RESULTS: The mean patient age was 28.9 yr (15-36 yr). The mean duration of gestation was 25 wk (12-33 wk); one patient was in the first, five in the second, and nine in the third trimester. The indications were gallstone pancreatitis (n = 6), choledocholithiasis on ultrasound (n = 5), elevated liver enzymes and a dilated bile duct on ultrasound (n = 2), abdominal pain and gallstones (n = 1), and chronic pancreatitis (n = 1). ERCP findings were bile duct stones (n = 6), patulous papilla (n = 1), bile duct debris (n = 1), normal bile duct and gallstones or gallbladder sludge (n = 3), dilated bile duct and gallstones (n = 1), normal bile duct and no gallstones (n = 2), and chronic pancreatitis (n = 1). Six patients underwent sphincterotomies and one a biliary stent insertion. One sphincterotomy was complicated by mild pancreatitis. All infants delivered to date have had Apgar-scores >8, and continuing pregnancies are uneventful. Mean fluorosocopy time was 3.2 min (SD +/- 1.8). An estimated fetal radiation exposure was 310 mrad (SD +/- 164) which is substantially below the accepted teratogenic dose. CONCLUSIONS: ERCP in pregnancy seems to be safe for both mother and fetus; however, it should be restricted to therapeutic indications with additional intraprocedure safety measures.

Effectiveness of the Ultraflex Diamond stent for the palliation of malignant biliary obstruction.

BACKGROUND AND STUDY AIMS: Endoscopically placed metallic biliary stents provide durable drainage for malignant biliary obstruction. The best-studied metal stent is the Wallstent, which has a greater duration of patency than polyethylene stents. Recently, the Ultraflex Diamond stent has been introduced, with reports from Europe which suggest efficacy similar to that of the Wallstent. We report our experience with this new metal stent and compare it with a historical cohort of Wallstent-treated patients. PATIENTS AND METHODS: Between July 1997 and July 1998 all metal stents placed for malignant biliary obstruction were Diamond stents (10 mm diameter, 6 or 8 cm length). Prospective follow-up details with regard to patient death or stent occlusion were obtained. In total, 32 patients underwent stenting, but 11 patients were excluded because of the following: death from pre-existing cholangitis (2); placement of bilateral hilar stents (2); placement of stent through occluded metal stents (3); failure to palliate jaundice due to complex hilar stricture (2) or concomitant liver failure (1); or inability to obtain follow-up (1), leaving 21 patients for analysis. Occlusion rates and stent patency were also determined retrospectively for 19 patients with malignant biliary obstruction who had Wallstents (10 mm diameter, 6.8 cm length) placed during the preceding year and for whom accurate and complete follow-up details were available. RESULTS: In the Diamond stent group there were 14 men and seven women, mean age 73. In the Wallstent group there were 11 men and eight women, mean age 66. The types of cancer, level of stricture and percentage with prior polyethylene stenting were similar in both groups. Stent occlusion occurred in 9/21 (43%), Diamond stents at a mean of 74 +/- 43 days compared with 8/19 (42%) Wallstents at a mean of 178 +/- 138 days (P < 0.04). Mean time of stent patency was 110 +/- 89 days for Diamond stents and 253 +/- 218 days for Wallstents (P < 0.01). Analysis of occlusion-free survival using a Kaplan-Meier plot showed a trend favoring the Wallstent (P = 0.12; Wilcoxon test). CONCLUSIONS: The occlusion rate and patency of Diamond stents for malignant biliary obstruction appear to be inferior to those of Wallstents and similar to reported values for polyethylene stents. Prospective randomized comparisons of Wallstents and newer self-expanding metal stents are warranted.