A subset of hereditary and sporadic colorectal carcinomas is defined by microsatellite instability (MSI), but the spectra of gene mutations have not been characterized extensively. Thirty-nine hereditary nonpolyposis colorectal cancer syndrome carcinomas (HNPCCa) and 57 sporadic right-sided colonic carcinomas (SRSCCa) were evaluated. Of HNPCCa, 95% (37/39) were MSI-positive as contrasted with 31% (18/57) of SRSCCa (P < 0.000001), but instability tended to be more widespread in SRSCCa (P = 0.08). Absence of nuclear hMSH2 mismatch repair gene product by immunohistochemistry was associated with germline hMSH2 mutation (P = 0.0007). The prevalence of K-ras proto-oncogene mutations was similar in HNPCCa and SRSCCa (30% (11/37) and 30% (16/54)), but no HNPCCa from patients with germline hMSH2 mutation had codon 13 mutation (P = 0.02), and two other HNPCCa had multiple K-ras mutations attributable to subclones. 18q allelic deletion and p53 gene product overexpression were inversely related to MSI (P = 0.0004 and P = 0.0001, respectively). Frameshift mutation of the transforming growth factor beta type II receptor gene was frequent in all MSI-positive cancers (85%, 46/54), but mutation of the E2F-4 transcription factor gene was more common in HNPCCa of patients with germline hMSH2 mutation than in those with germline bMLH1 mutation (100% (8/8) versus 40% (2/5), P = 0.04), and mutation of the Bax proapoptotic gene was more frequent in HNPCCa than in MSI-positive SRSCCa (55% (17/31) versus 13% (2/15), P = 0.01). The most common combination of mutations occurred in only 23% (8/35) of evaluable MSI-positive cancers. Our findings suggest that the accumulation of specific genetic alterations in MSI-positive colorectal cancers is markedly heterogeneous, because the occurrence of some mutations (eg, ras, E2F-4, and Bax genes), but not others (eg, transforming growth factor beta type II receptor gene), depends on the underlying basis of the mismatch repair deficiency. This genetic heterogeneity may contribute to the heterogeneous clinical and pathological features of MSI-positive cancers.

Elevated pre-procedural glucose is associated with greater risk for CI-AKI in patients without known diabetes who undergo coronary angiography in the setting of acute myocardial infarction. Measures used to prevent CI-AKI should be considered in these patients.

Background Many clinical trials use composite endpoints to reduce sample size, but the relative importance of each individual endpoint within the composite may differ between patients and researchers. Methods and Results We asked 785 cardiovascular patients and 164 clinical trial authors to assign 25 “spending weights” across 5 common adverse events comprising composite endpoints in cardiovascular trials: death, myocardial infarction (MI), stroke, coronary revascularization, and hospitalization for angina. We then calculated endpoint ratios (“ratios”) for each participant’s ratings of each nonfatal endpoint relative to death. Whereas patients assigned an average weight of 5 to death, equal or greater weight was assigned to MI (mean ratio 1.12) and stroke (ratio 1.08). In contrast, clinical trialists were much more concerned about death (average weight of 8) than MI (ratio 0.63) or stroke (ratio 0.53). Both patients and trialists considered revascularization (ratios 0.48 and 0.20, respectively) and hospitalization (ratios 0.28 and 0.13, respectively) as substantially less severe than death. Differences between patient and trialist endpoint weights persisted after adjustment for demographic and clinical characteristics (p<0.001 for all comparisons). Conclusions Neither patients nor clinical trialists weigh individual components of a composite endpoint equally. While trialists are most concerned about avoiding death, patients place equal or greater importance on reducing MI or stroke. Both groups considered revascularization and hospitalization as substantially less severe. These findings suggest that equal weights in a composite clinical endpoint do not accurately reflect the preferences of either patients or trialists.

Recanalization rates have been better than expected (50% to 65%), with improvement in neurologic status in some patients. In one study, mortality was 30% with recanalization of the ICA but was 73% in the non-recanalized patients (Flin AC, Stroke 2007;38:1274-80). In this current article, the authors' results with emergency endovascular carotid recanalization in patients with acute proximal (cervical) ICA occlusion are presented, focusing on success rates, predictors of recanalization, and neurologic and functional outcome. Inclusion criteria included a National Institutes of Health Stroke Scale (NIHSS) score Ն5, stroke onset within 8 hours of presentation, and computed tomography (CT) imaging, suggesting salvageable brain tissue. Patients with hemorrhage or evidence of a completed large ipsilateral stroke on a noncontrast CT were excluded. In all cases, occlusion of the cervical ICA was confirmed by catheter-based angiography. The authors' technique involved initially advancing a platform guide catheter into the common carotid artery just proximal to the bifurcation. They then explored the carotid artery bifurcation with a microcatheter and microwire, with subsequent advancement of a mircocatheter into the petrocavernous segment of the carotid artery. If distal patency could not be demonstrated, the procedure was aborted. If distal patency was present or could be restored, they attempted to restore flow in the cervical ICA. This series consisted of 22 patients undergoing emergency endovascular revascularization for acute stroke secondary to cervical ICA occlusion. Patients were a mean age of 65 years with a mean admission NIHSS score of 14. Recanalization was established in 17 patients (77.3%). Ten patients (45.5 %) had significant clinical improvement during the course of their hospitalization (NIHSS score improvement Ն4 points). At a median follow-up of 3 months, 50% patients had outcomes with modified Rankin scales Յ2. Age Ͼ70 years and successful recanalization predicted a good outcome (P Ͼ .01). Poor outcome was associated with ICA occlusion at all levels (cervical, petrocavernous, and intracranial) as well as atrial fibrillation. Patients with complete cervical ICA occlusion, but partial distal preservation of the ICA, were most likely to achieve benefit from the intervention, (recanalization, 88.2%; good outcome, 64.7%).Comment: The results of this review are not "what dreams are made of," but they may be better than the natural history of acute symptomatic cervical ICA occlusion. However, it is possible the patients who do the best would have done reasonably well even without interventional treatment. The approach advocated here must be tempered with knowledge of hemorrhage risk and pretreatment infarct size. The outcome was favorable in 50% of patients. However, all patients with initial complete carotid artery occlusion, including the intracranial segments, died or were severely disabled, suggesting that attempts at endovascular recanalization of the cervical ICA should be limited to patients with part...