BackgroundIntracranial atherosclerotic disease tends to affect multiple arterial segments. Using whole‐brain vessel wall imaging, we sought to study the differences in plaque features among various types of plaques in patients with a recent unilateral anterior circulation ischemic stroke.Methods and ResultsSixty‐one patients with unilateral anterior circulation ischemic stroke were referred to undergo whole‐brain vessel wall imaging (before and after contrast) within 1 month of symptom onset for intracranial atherosclerotic disease evaluations. Each plaque was classified as a culprit, probably culprit, or nonculprit lesion, according to its likelihood of causing the stroke. The associations between plaque features (thickening pattern, plaque‐wall contrast ratio, high signal on T1‐weighted images, plaque contrast enhancement ratio, enhancement grade, and enhancement pattern) and culprit lesions were estimated using mixed multivariable logistic regression after adjustment for maximum wall thickness. In 52 patients without motion corruption in whole‐brain vessel wall imaging, a total of 178 intracranial plaques in the anterior circulation were identified, including 52 culprit lesions (29.2%), 51 probably culprit lesions (28.7%), and 75 nonculprit lesions (42.1%). High signal on T1‐weighted images (adjusted odds ratio, 9.1; 95% confidence interval, 1.9–44.1; P=0.006), grade 2 (enhancement ratio of plaque ≥ enhancement ratio of pituitary) contrast enhancement (adjusted odds ratio, 17.4; 95% confidence interval, 1.8–164.9; P=0.013), and type 2 (≥50% cross‐sectional wall involvement) enhancement pattern (adjusted odds ratio, 10.1; 95% confidence interval, 1.3–82.2; P=0.030) were independently associated with culprit lesions.ConclusionsHigh signal on T1‐weighted images, grade 2 contrast enhancement, and type 2 enhancement pattern are associated with cerebrovascular ischemic events, which may provide valuable insights into risk stratification.

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BackgroundOne of the potentially important applications of three-dimensional (3D) intracranial vessel wall (IVW) cardiovascular magnetic resonance (CMR) is to monitor disease progression and regression via quantitative measurement of IVW morphology during medical management or drug development. However, a prerequisite for this application is to validate that IVW morphologic measurements based on the modality are reliable. In this study we performed comprehensive reliability analysis for the recently proposed whole-brain IVW CMR technique.MethodsThirty-four healthy subjects and 10 patients with known intracranial atherosclerotic disease underwent repeat whole-brain IVW CMR scans. In 19 of the 34 subjects, two-dimensional (2D) turbo spin-echo (TSE) scan was performed to serve as a reference for the assessment of vessel dimensions. Lumen and wall volume, normalized wall index, mean and maximum wall thickness were measured in both 3D and 2D IVW CMR images. Scan-rescan, intra-observer, and inter-observer reproducibility of 3D IVW CMR in the quantification of IVW or plaque dimensions were respectively assessed in volunteers and patients as well as for different healthy subjectsub-groups (i.e. < 50 and ≥ 50 years). The agreement in vessel wall and lumen measurements between the 3D technique and the 2D TSE method was also investigated. In addition, the sample size required for future longitudinal clinical studies was calculated.ResultsThe intra-class correlation coefficient (ICC) and Bland-Altman plots indicated excellent reproducibility and inter-method agreement for all morphologic measurements (All ICCs > 0.75). In addition, all ICCs of patients were equal to or higher than that of healthy subjects except maximum wall thickness. In volunteers, all ICCs of the age group of ≥50 years were equal to or higher than that of the age group of < 50 years. Normalized wall index and mean and maximum wall thickness were significantly larger in the age group of ≥50 years. To detect 5% - 20% difference between placebo and treatment groups, normalized wall index requires the smallest sample size while lumen volume requires the highest sample size.ConclusionsWhole-brain 3D IVW CMR is a reliable imaging method for the quantification of intracranial vessel dimensions and could potentially be useful for monitoring plaque progression and regression.Electronic supplementary materialThe online version of this article (10.1186/s12968-018-0453-z) contains supplementary material, which is available to authorized users.

Background The National Cancer Institute Moonshot research initiative calls for improvements in the analysis and reporting of treatment toxicity to advise key stakeholders on treatment tolerability and inform regulatory and clinical decision making. This study illustrates alternative approaches to toxicity evaluation using the National Surgical Adjuvant Breast and Bowel Project R-04 clinical trial as an example. Methods National Surgical Adjuvant Breast and Bowel Project R-04 was a neoadjuvant chemoradiation trial in stage II–III rectal cancer patients. A 2 x 2 factorial design was used to evaluate whether the addition of oxaliplatin (Oxa) to 5-fluorouracil (5FU) or capecitabine (Cape) with radiation therapy improved local-regional tumor control. The toxicity index (TI), which accounts for the frequency and severity of toxicities, was compared across treatments using multivariable probabilistic index models, where Pr A &lt; B indicates the probability that higher values of TI were observed for A when compared with B. Baseline age, sex, performance status, body mass index, surgery type, and stage were evaluated as independent risk factors. Results A total of 4560 toxicities from 1558 patients were analyzed. Results from adjusted probabilistic index models indicate that oxaliplatin-containing regimens had statistically significant (P &lt; .001) probability (Pr) for higher TI compared with regimens without oxaliplatin (Pr 5FU &lt; 5FU + Oxa = 0.619, 95% confidence interval [CI] = 0.560 to 0.674; Pr 5FU &lt; Cape + Oxa = 0.627, 95% CI = 0.568 to 0.682; Pr Cape &lt; 5FU + Oxa = 0.587, 95% 0.527 to 0.644; and Pr Cape &lt; Cape + Oxa = 0.596, 95% 0.536 to 0.653). When compared with other existing toxicity analysis methods, TI provided greater power to detect differences between treatments. Conclusions This article uses standard data collected in a cancer clinical trial to introduce descriptive and analytic methods that account for the additional burden of multiple toxicities. These methods may provide a more accurate description of a patient’s treatment experience that could lead to individualized dosing for better toxicity control. Future research will evaluate the generalizability of these findings in trials with similar drugs.

Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues—such as incomplete mechanistic knowledge and faulty clinical trial design—a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.

BackgroundIt is important to know the causes of dyspepsia to establish the therapeutic approach. Dyspepsia is a frequent syndrome in our country, where there are restrictions to endoscopy and high prevalence of Helicobacter pylori (H. pylori) infection. This study aimed to assess the endoscopic findings of the syndrome, in an outpatient screening clinic of a tertiary hospital in São Paulo.MethodsOutpatients with uninvestigated dyspepsia, according to Rome III criteria, answered a dyspepsia questionnaire and underwent esophagogastroduodenoscopy. The Rapid Urease Test was applied to fragments of the antral mucosa and epidemiological data were collected from the studied population. Organic dyspepsia findings were analyzed with different variables to verify statistically significant associations.ResultsThree hundred and six patients were included and 282 were analyzed in the study. The mean age was 44 years and women comprised 65% of the sample. Forty-five percent of the patients reported alarm symptoms. Functional dyspepsia was found in 66% of the patients (20% with normal endoscopy results and 46% with gastritis), 18% had GERD and 13% had ulcers (duodenal in 9% and gastric in 4%). Four cases of gastric adenocarcinoma were identified (1.4%), one without alarm characteristics, 1 case of adenocarcinoma of the distal esophagus and 1 case of gastric lymphoma. The prevalence of H. pylori was 54% and infection, age and smoking status were associated with organic dyspepsia. The age of 48 years was indicative of alarm signs.ConclusionsThe endoscopic diagnosis of uninvestigated dyspepsia in our setting showed a predominance of functional disease, whereas cancer was an uncommon finding, despite the high prevalence of H. pylori. Organic dyspepsia was associated with infection, age and smoking status.

Background Liver transplantation (LT) is the treatment of choice for patients with unresectable early hepatocellular carcinoma (HCC). Post-LT HCC recurrence rates range from 8 to 20% and still impact on overall survival (OS). The aim of our study was to evaluate the impact of HCC recurrence on post-LT survival and analyze prognostic factors among those patients with recurrence. Patients and methods We carried out a national, multicenter, retrospective cohort study in Brazil. Medical records of 1119 LT recipients with HCC were collected. Data from patients with post-LT HCC recurrence were analyzed and correlated with post-relapse survival. Results OS of the 1119 patients included in the study was 63% over 5 years. Post-LT HCC recurrence occurred in 86 (8%) patients. The mean time to recurrence was 12 months. Sites of recurrence were extrahepatic in 55%, hepatic in 27%, and both hepatic and extrahepatic in 18%. Recurrence treatment was performed in 50 (64%) cases, mostly with sorafenib. Post-relapse survival rates were 34% at 1 year and 13% at 5 years. Univariable analysis identified α-fetoprotein more than 1000 ng/ml at relapse, recurrence treatment, extrahepatic location, and time to recurrence more than 2 years as prognostic factors. In multivariable analysis, recurrence treatment, extrahepatic location, and time to recurrence more than 2 years were independent predictors of better survival. Conclusion In a large Brazilian cohort of LT recipients with HCC, post-LT HCC recurrence occurred in 8% and impacted significantly on the OS. Patients with early recurrence presented a worse prognosis. However, treatment of recurrence improved outcomes, highlighting the importance of early diagnosis.

Background: Effective treatment options for nonresectable hepatic carcinoma (HC) in dogs are limited.Hypothesis/Objective: Objectives were to report outcomes, complications, and tumor responses via computed tomography (CT) assessment after drug-eluting bead transarterial chemoembolization (DEB-TACE) for nonresectable HC in dogs. The authors hypothesized that major complications would be uncommon and short-term CT assessment would demonstrate stable disease or partial response.Animals: Client-owned dogs (n = 16) with nonresectable HC.Methods: Prospective, single-arm clinical trial. Drug-eluting bead transarterial chemoembolization was performed to varying levels of blood flow stasis. Computed tomography imaging was compared before and approximately 12 weeks after initial treatment.Results: Drug-eluting bead transarterial chemoembolization was successfully administered in all attempts. Based on percent change in elliptical tumor volume response (mL), stable disease (8/13; 62%) was the most common outcome followed by partial response (3/13; 23%) and progressive disease (2/13; 15%) with a median of 74 days (range, 39-125) after initial treatment. Median tumor volume (mL) after DEB-TACE decreased in volume by 13% (range, 56% decrease to 77% increase). Mild complications consistent with postembolization syndrome occurred after 7/27 (26%) treatments. Major complications occurred after 3/27 (11%) treatments: hepatic abscess/