Citations

The recent “Advanced Neuroimaging for Acute Stroke Treatment” meeting on September 7 and 8, 2007 in Washington DC, brought together stroke neurologists, neuroradiologists, emergency physicians, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Biomedical Imaging and Bioengineering (NIBIB), industry representatives, and members of the US Food and Drug Administration (FDA) to discuss the role of advanced neuroimaging in acute stroke treatment. The goals of the meeting were to assess state-of-the-art practice in terms of acute stroke imaging research and to propose specific recommendations regarding: (1) the standardization of perfusion and penumbral imaging techniques, (2) the validation of the accuracy and clinical utility of imaging markers of the ischemic penumbra, (3) the validation of imaging biomarkers relevant to clinical outcomes, and (4) the creation of a central repository to achieve these goals. The present article summarizes these recommendations and examines practical steps to achieve them.

Abstract Background: Guidelines for treatment of acute coronary syndrome (ACS) recommend observing a rise or fall in cardiac troponin (cTn) concentrations for assessing acute injury. It is unknown whether a rising pattern presages a more adverse long-term prognosis than elevations that do not change. The present study assessed whether a rising pattern of cardiac biomarkers was more prognostic than simple elevations. Methods: We measured N-terminal pro-brain natriuretic peptide (NT-proBNP) (Roche), cTnT (Roche) and cTnI (Beckman Coulter) in 212 ACS patients. These biomarkers were measured in coincident EDTA and heparin plasma samples available from at least 2 different time points, an early first specimen obtained a median of 2 hours after onset of symptoms, interquartile range (IQR) 2–4 hours, and a later second specimen obtained at 9 hours, IQR 9–9 hours. The cTn concentration in the second specimen was used to classify myocardial necrosis (cTnI >0.04 ug/L; cTnT >0.01 ug/L). Outcomes [death, myocardial infarction (MI), heart failure (HF)] were obtained >8 years after the initial presentation. For patients with myocardial necrosis and a cTn concentration ratio (second/first measured concentrations) ≥1.00, the concentration ratios and the absolute concentrations in the second specimen were used to assess prognosis after 4 years. Results: In myocardial necrosis, the relative change (cTn2/cTn1) was greater for cTnI than for cTnT (P <0.01), whereas the relative change in NT-proBNP was the same regardless of which troponin was used to classify necrosis (P = 0.71). The concentration ratio for cTnI, cTnT, and NT-proBNP was not useful for risk stratification (i.e., death/MI/HF; P ≥0.15). Conclusions: A rise in cardiac troponin or NT-proBNP concentration in ACS patients presenting early after onset of pain is not helpful for long-term prognosis.

OBJECTIVE— Little is known about the capacity, mechanisms, or timing of growth in β-cell mass in humans. We sought to establish if the predominant expansion of β-cell mass in humans occurs in early childhood and if, as in rodents, this coincides with relatively abundant β-cell replication. We also sought to establish if there is a secondary growth in β-cell mass coincident with the accelerated somatic growth in adolescence. RESEARCH DESIGN AND METHODS— To address these questions, pancreas volume was determined from abdominal computer tomographies in 135 children aged 4 weeks to 20 years, and morphometric analyses were performed in human pancreatic tissue obtained at autopsy from 46 children aged 2 weeks to 21 years. RESULTS— We report that 1) β-cell mass expands by severalfold from birth to adulthood, 2) islets grow in size rather than in number during this transition, 3) the relative rate of β-cell growth is highest in infancy and gradually declines thereafter to adulthood with no secondary accelerated growth phase during adolescence, 4) β-cell mass (and presumably growth) is highly variable between individuals, and 5) a high rate of β-cell replication is coincident with the major postnatal expansion of β-cell mass. CONCLUSIONS— These data imply that regulation of β-cell replication during infancy plays a major role in β-cell mass in adult humans.

Abstract Inactivating mutations in several genes that encode components of the DNA repair machinery have been associated with an increased risk of breast cancer. To assess whether alterations in other DNA repair genes contribute to breast cancer and to further determine the relevance of these genes to pancreatic cancer, we performed mutational analysis of 32 DNA double-strand break repair genes in genomic DNA from 38 breast tumors, 48 pancreatic tumors, and 10 non-BRCA1/BRCA2 hereditary breast cancer patients. A total of 494 coding exons were screened by denatured high-performance liquid chromatography and direct DNA sequencing. Two inactivating mutations were identified in breast tumor samples, a germline single-nucleotide deletion in POLQ (c.3605delT) and a somatic nonsense change in PRKDC (c.2408C>A, p.Ser803X). Two germline-inactivating mutations in RAD50 (c.1875C>G, p.Tyr625X and IVS14+1G>A) were also detected in separate pancreatic tumor samples. In addition, 35 novel nonsynonymous amino acid substitutions, resulting from two in-frame deletions and 33 single nucleotide alterations, were identified. Seven of these were predicted to influence protein function. A separate analysis of the CLSPN c.3839C>T (rs35490896) variant that was observed more frequently in breast tumors than in pancreatic tumors or normal controls failed to detect a significant association with breast cancer risk in a Mayo Clinic breast cancer case-control study. In conclusion, this screen of DNA repair genes implicates PRKDC and POLQ as candidate tumor suppressor genes involved in breast cancer and suggests that inactivating mutations in RAD50 predispose to pancreatic cancer as well as breast cancer. [Cancer Res 2008;68(4):971–5]

Purpose To assess cardiac safety and potential cardiac risk factors associated with trastuzumab in the NCCTG N9831 Intergroup adjuvant breast cancer trial. Patients and Methods Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide (AC) followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or paclitaxel plus trastuzumab then trastuzumab alone (arm C). Left ventricular ejection fraction (LVEF) was evaluated at registration and 3, 6, 9, and 18 to 21 months. Results Of 2,992 patients completing AC, 5.0% had LVEF decreases disallowing trastuzumab (decrease below normal: 2.4%, decrease > 15%: 2.6%). There were 1,944 patients with satisfactory or no LVEF evaluation who proceeded to post-AC therapy. Cardiac events (congestive heart failure [CHF] or cardiac death [CD]): arm A, n = 3 (2 CHF, 1 CD); arm B, n = 19 (18 CHF, 1 CD); arm C, n = 19 (all CHF); 3-year cumulative incidence: 0.3%, 2.8%, and 3.3%, respectively. Cardiac function improved in most CHF cases following trastuzumab discontinuation and cardiac medication. Factors associated with increased risk of a cardiac event in arms B and C: older age (P < .003), prior/current antihypertensive agents (P = .005), and lower registration LVEF (P = .033). Incidence of asymptomatic LVEF decreases requiring holding trastuzumab was 8% to 10%; LVEF recovered and trastuzumab was restarted in approximately 50%. Conclusion The cumulative incidence of post-AC cardiac events at 3 years was higher in the trastuzumab-containing arms versus the control arm, but by less than 4%. Older age, lower registration LVEF, and antihypertensive medications are associated with increased risk of cardiac dysfunction in patients receiving trastuzumab following AC.

Purpose We conducted a pediatric phase I trial of the vascular endothelial growth factor (VEGF)–neutralizing antibody bevacizumab (BV). Primary aims included estimating the maximum-tolerated dose (MTD) and determining the dose-limiting toxicities (DLTs), pharmacokinetics, and biologic effects of BV in children with cancer. Patients and Methods BV (5, 10, 15 mg/kg) was administered intravenously every 2 weeks in 28-day courses to children with refractory solid tumors. Results Twenty-one patients enrolled, 20 (median age, 13 years) were eligible, and 18 completed one course and were fully assessable for toxicity. A total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Treatment was well tolerated with no DLTs observed. Non-DLTs included infusional reaction, rash, mucositis, proteinuria, and lymphopenia. Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for Adverse Events (CTCAEv3) pediatric-specific criteria for hypertension were observed. There was no hemorrhage or thrombosis. Growth perturbation was not detected in a limited sample over the first course. The serum exposure to BV as measured by area under the concentration-time curve (AUC) seemed to increase in proportion to dose. The median clearance of BV was 4.1 mL/d/kg (range, 3.1 to 15.5 mL/d/kg), and the median half-life was 11.8 days (range, 4.4 to 14.6 days). No objective responses were observed. Exploratory analyses on circulating endothelial mobilization and viability are consistent with the available adult data. Conclusion BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.