Citations

Abstract Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes. Patients and Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts. Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median Cmax and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS. Conclusions: This combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.

AbstractIntroductionWe conducted Japanese Alzheimer's Disease Neuroimaging Initiative (J‐ADNI) and compared the basic characteristics and progression profiles with those of ADNI in North America.MethodsA total of 537 Japanese subjects with normal cognition, late amnestic mild cognitive impairment (LMCI), or mild Alzheimer's disease (AD) were enrolled using the same criteria as ADNI. Rates of changes in representative cognitive or functional measures were compared for amyloid positron emission tomography‐ or cerebrospinal fluid amyloid β(1–42)‐positive LMCI and mild AD between J‐ADNI and ADNI.ResultsAmyloid positivity rates were significantly higher in normal cognition of ADNI but at similar levels in LMCI and mild AD between J‐ADNI and ADNI. Profiles of decline in cognitive or functional measures in amyloid‐positive LMCI in J‐ADNI (n = 75) and ADNI (n = 269) were remarkably similar, whereas those in mild AD were milder in J‐ADNI (n = 73) compared with ADNI (n = 230).DiscussionThese results support the feasibility of bridging of clinical trials in the prodromal stage of AD between Asia and western countries.

AimsDespite efforts to standardise grading of prostate cancer, even among experts there is still a considerable variation in grading practices. In this study we describe the use of Pathology Imagebase, a novel reference image library, for setting an international standard in prostate cancer grading.Methods and resultsThe International Society of Urological Pathology (ISUP) recently launched a reference image database supervised by experts. A panel of 24 international experts in prostate pathology reviewed independently microphotographs of 90 cases of prostate needle biopsies with cancer. A linear weighted kappa of 0.67 (95% confidence interval = 0.62–0.72) and consensus was reached in 50 cases. The interobserver weighted kappa varied from 0.48 to 0.89. The highest level of agreement was seen for Gleason score (GS) 3 + 3 = 6 (ISUP grade 1), while higher grades and particularly GS 4 + 3 = 7 (ISUP grade 3) showed considerable disagreement. Once a two‐thirds majority was reached, images were moved automatically into a public database available for all ISUP members at www.isupweb.org. Non‐members are able to access a limited number of cases.ConclusionsIt is anticipated that the database will assist pathologists to calibrate their grading and, hence, decrease interobserver variability. It will also help to identify instances where definitions of grades need to be clarified.

Abstract Background and study aims A novel intragastric trocar placed using a percutaneous endoscopic gastrostomy technique enables the use of laparoscopic tools and procedures, including tissue stapling, cutting, suturing, and retraction. The aim of this porcine study was to determine long-term success of crossing full-thickness sutures in closure of the tract upon trocar withdrawal. Methods 10 trocars were placed in 5 animals. Each animal underwent a standardized tissue resection using a 5-mm stapler under gastroscopic guidance, and two full-thickness, absorbable, crossing sutures were used to close the trocar tracts. The animals were monitored for 35 days and then euthanized for necropsy. Results All five animals survived without sign of infection or distress. Nine of the 10 trocar sites healed completely without any adverse findings. A single site developed a gastrocutaneous fistula. On necropsy, there was no evidence of intra-abdominal infection or abscess. Conclusions Full-thickness crossing sutures appeared to be effective in long-term closure of an intragastric trocar tract. Given the ease of placement and success of this simple closure method, this device may prove clinically useful to the endoscopist performing complex procedures in the endoscopy suite.

Abstract Background: The utility of alpha-fetoprotein (AFP) for hepatocellular carcinoma (HCC) surveillance is controversial. We aimed to identify factors associated with elevated AFP and define the patients for whom AFP is effective for surveillance. Methods: Data from the NCI Early Detection Research Network phase II HCC biomarker study (233 early-stage HCC and 412 cirrhotic patients) were analyzed. We analyzed 110 early-stage HCC and 362 cirrhotic hepatitis C virus (HCV) patients for external validation. Sensitivity, specificity, and area under the ROC curve (AUC) for HCC were calculated. Results: HCV etiology, non-White race, and serum alanine transaminase (ALT) predicted elevated AFP in cirrhotics. Non-White race and ALT predicted elevated AFP in HCC patients. Higher AUC of AFP for HCC was noted in patients with HBV (0.85) and alcohol (0.84), whereas it was lower in patients with hepatitis C virus (HCV; 0.80) and nonviral/alcohol etiology (0.76). The AUC was higher in HCV patients with serum ALT ≤40 U/L than patients with serum ALT >40 U/L (0.91 vs. 0.75, P < 0.01). At 90% specificity, the sensitivity of AFP increased from 44% to 74% in Whites with HCV and from 50% to 85% in non-Whites with HCV. There was a trend toward higher AUC in HCV patients with serum ALT ≤40 U/L than those with serum ALT >40 U/L (0.79 vs. 0.69, P = 0.10) in the validation cohort. Conclusions: The satisfactory performance of AFP in HCV patients with normal ALT should be further validated. Impact: The AFP may serve as a valuable surveillance test in HCV patients with normal ALT. Cancer Epidemiol Biomarkers Prev; 26(7); 1085–92. ©2017 AACR.

Background— Left atrial (LA) compliance and contractility influence left ventricular stroke volume. We hypothesized that diminished LA compliance and contractile function occur early during the development of heart failure with preserved ejection fraction (HFpEF) and impair overall cardiac performance. Methods and Results— Cardiac magnetic resonance imaging, echocardiography, left ventricular and LA pressure-volume studies, and tissue analyses were performed in a model of early HFpEF (elderly dogs, renal wrap-induced hypertension, exogenous aldosterone; n=9) and young control dogs (sham surgery; n=13). Early HFpEF was associated with LA enlargement, cardiomyocyte hypertrophy, and enhanced LA contractile function (median active emptying fraction 16% [95% confidence interval, 13–24]% versus 12 [10–14]%, P =0.008; end-systolic pressure-volume relationship slope 2.4 [1.9–3.2]mm Hg/mL HFpEF versus 1.5 [1.2–2.2]mm Hg/mL controls, P =0.01). However, atrioventricular coupling was impaired and the curvilinear LA end-reservoir pressure-volume relationship was shifted upward/leftward in HFpEF (LA stiffness constant [β LA ] 0.16 [0.11–0.18]mm Hg/mL versus 0.06 [0.04–0.10]mm Hg/mL controls; P =0.002), indicating reduced LA compliance. Impaired atrioventricular coupling and lower LA compliance correlated with lower left ventricular stroke volume. Total fibrosis and titin isoform composition were similar between groups; however, titin was hyperphosphorylated in HFpEF and correlated with β LA . LA microvascular reactivity was diminished in HFpEF versus controls. LA microvascular density tended to be lower in HFpEF and inversely correlated with β LA . Conclusions— In early-stage hypertensive HFpEF, LA cardiomyocyte hypertrophy, titin hyperphosphorylation, and microvascular dysfunction occur in association with increased systolic and diastolic LA chamber stiffness, impaired atrioventricular coupling, and decreased left ventricular stroke volume. These data indicate that maladaptive LA remodeling occurs early during HFpEF development, supporting a concept of global myocardial remodeling.

PurposeTo evaluate the effect of imaging sequence (spin‐echo echo‐planar imaging [EPI] and gradient‐echo [GRE]) and postprocessing method (two‐dimensional [2D] and 3D inversion algorithms) on liver MR elastography (MRE) and to validate the diagnostic performance of EPI‐MRE3D versus conventional GRE‐MRE2D for liver fibrosis staging.Materials and MethodsThree MRE methods (EPI‐MRE3D, EPI‐MRE2D, and GRE‐MRE2D) were performed on soft and mildly stiff phantoms and 58 patients with chronic liver disease using a 3 Tesla clinical MRI scanner, and stiffness values were compared among the three methods. A validation study comprised 73 patients with histological liver fibrosis (F0–4, METAVIR system). Areas under the receiver operating characteristic curves (AUCs) and accuracies for diagnosing significant fibrosis (F3–4) and cirrhosis (F4) were compared between EPI‐MRE3D and GRE‐MRE2D.ResultsStiffness values of the soft and mildly stiff phantoms were 2.4 kPa and 4.0 kPa by EPI‐MRE3D; 2.6 kPa and 4.2 kPa by EPI‐MRE2D; and 2.7 kPa and 4.2 kPa by GRE‐MRE2D. In patients, EPI‐MRE3D provided significantly lower stiffness values than other methods (P < 0.001). However, there was no significant difference between GRE‐MRE2D and EPI‐MRE2D (P = 0.12). The AUCs and accuracies of EPI‐MRE3D and GRE‐MRE2D were statistically equivalent in the diagnoses of significant fibrosis (F3–4) and cirrhosis (F4) (all P < 0.005).ConclusionEPI‐MRE3D showed modestly lower liver stiffness values than conventional GRE‐MRE2D. The diagnostic performances of EPI‐MRE3D and GRE‐MRE2D were equivalent for liver fibrosis staging.Level of Evidence: 3J. Magn. Reson. Imaging 2017;45:1163–1170