Citations

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.

Abstract Primary central nervous system (CNS) lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the CNS. A genome-wide gene expression comparison between PCNSL and non-CNS DLBCL was performed, the latter consisting of both nodal and extranodal DLBCL (nDLBCL and enDLBCL), to identify a “CNS signature.” Pathway analysis with the program SigPathway revealed that PCNSL is characterized notably by significant differential expression of multiple extracellular matrix (ECM) and adhesion-related pathways. The most significantly up-regulated gene is the ECM-related osteopontin (SPP1). Expression at the protein level of ECM-related SPP1 and CHI3L1 in PCNSL cells was demonstrated by immunohistochemistry. The alterations in gene expression can be interpreted within several biologic contexts with implications for PCNSL, including CNS tropism (ECM and adhesion-related pathways, SPP1, DDR1), B-cell migration (CXCL13, SPP1), activated B-cell subtype (MUM1), lymphoproliferation (SPP1, TCL1A, CHI3L1), aggressive clinical behavior (SPP1, CHI3L1, MUM1), and aggressive metastatic cancer phenotype (SPP1, CHI3L1). The gene expression signature discovered in our study may represent a true “CNS signature” because we contrasted PCNSL with wide-spectrum non-CNS DLBCL on a genomic scale and performed an in-depth bioinformatic analysis.

AbstractBackground: Newborn screening for maple syrup urine disease (MSUD) relies on finding increased concentrations of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine by tandem mass spectrometry (MS/MS). d-Alloisoleucine (allo-Ile) is the only pathognomonic marker of MSUD, but it cannot be identified by existing screening methods because it is not differentiated from isobaric amino acids. Furthermore, newborns receiving total parenteral nutrition often have increased concentrations of BCAAs. To improve the specificity of newborn screening for MSUD and to reduce the number of diet-related false-positive results, we developed a LC-MS/MS method for quantifying allo-Ile.Methods: Allo-Ile and other BCAAs were extracted from a 3/16-inch dried blood spot punch with methanol/H2O, dried under nitrogen, and reconstituted into mobile phase. Quantitative LC-MS/MS analysis of allo-Ile, its isomers, and isotopically labeled internal standards was achieved within 15 min. To determine a reference interval for BCAAs including allo-Ile, we analyzed 541 dried blood spots. We also measured allo-Ile in blinded samples from 16 MSUD patients and 21 controls and compared results to an HPLC method.Results: Intra- and interassay imprecision (mean CVs) for allo-Ile, leucine, isoleucine, and valine ranged from 1.8% to 7.4%, and recovery ranged from 91% to 129%. All 16 MSUD patients were correctly identified.Conclusions: The LC-MS/MS method can reliably measure allo-Ile in dried blood spots for the diagnosis of MSUD. Applied to newborn screening as a second-tier test, it will reduce false-positive results, which produce family anxiety and increase follow-up costs. The assay also appears suitable for use in monitoring treatment of MSUD patients.

Background and Purpose— Recombinant-activated factor VII (rFVIIa) is an investigational treatment for intracerebral hemorrhage (ICH). We have evaluated the drug’s treatment effect based on time to treatment. Methods— ICH patients treated up to 4 hours from symptom onset were divided based on time to treatment: ≤3 hours (3H) and 3 to 4 hours (4H). Head CT was done at baseline and 24 hours. Outcome measures included: ICH growth at 24 hours, mortality, favorable outcome and discharge disposition. A cohort of nontreated matched ICH patients was used to asses the clinical efficacy. Results— Forty-six patients were treated with rFVIIa: 24 in the 3H group (range 70 to 180 minutes), 22 in the 4H group (range 181 to 300). One hundred and forty-eight patients formed the control group. Mean baseline ICH volume was 8.8 mL for 3H and 10.1 mL for 4H. Mean 24-hour volume was 9.3 mL for 3H (absolute increase 1.05 mL, relative increase 11.9%) and 11.5 mL for 4H (absolute increase 1.1 mL, relative increase 10.9%); P =0.47 is for the difference in relative increase. Mortality was 12.5% for 3H group, 13.6% for 4H, and 13.1% for the control. In the 3H group, 58.3% were discharged with a poor outcome, compared with 54.5% in 4H and 54.1% in the control. Thrombotic adverse events occurred in 11.1% of patients treated with rFVIIa. Conclusions— In our off-label with rFVIIa, we did not find evidence of a treatment effect based on time to treatment. Other criteria should be sought to identify patients who might benefit clinically from rFVIIa.

Abstract Context: The process of epiphyseal fusion during puberty is regulated by estrogen, even in males. Objective: Our objective was to investigate whether anastrozole, a potent aromatase inhibitor, could delay bone age acceleration and increase predicted adult height in adolescent boys with GH deficiency. Methods: Fifty-two adolescent males with GH deficiency treated with GH were randomized to cotreatment with anastrozole or placebo daily for up to 36 months. Results: Fifty subjects completed 12 months, 41 completed 24 months, and 28 completed 36 months. Linear growth was comparable between groups; however, there was a significantly slower increase in bone age advancement from baseline in the anastrozole group vs. placebo group after 2 yr (+1.8 ± 0.1 vs. +2.7 ± 0.1 yr, P &lt; 0.0001) and after 3 yr (+2.5 ± 0.2 vs. +4.1 ± 0.1 yr, P &lt; 0.0001). This resulted in a net increase in predicted adult height of +4.5 ± 1.2 cm in the anastrozole group at 24 months and +6.7 ± 1.4 cm at 36 months as compared with a 1-cm gain at both time points in the placebo group. Estradiol and estrone concentrations increased less in the anastrozole group compared with placebo group. All boys on the aromatase inhibitor had normal tempo of virilization. Safety data, including glucose, and plasma lipid concentrations were comparable between groups. Conclusions: Anastrozole increases adult height potential of adolescent boys on GH therapy while maintaining normal pubertal progression after 2–3 yr. This treatment offers an alternative in promoting growth in GH-deficient boys in puberty. Long-term follow up is needed to elucidate fully the safety and efficacy of this approach.

Abstract The frequency of colorectal cancer (CRC) among the Alaska Native people is the highest of any ethnic group in the United States. In this study, CRC from 329 Alaska Native people (165 Eskimo, 111 Indians, and 53 Aleut) were evaluated for evidence of defective DNA mismatch repair (MMR) by testing tumors for altered protein expression (hMLH1, hMSH2, and hMSH6) and for the presence of microsatellite instability. Of the 329 samples tested, 46 (14%) showed both microsatellite instability and altered protein expression; 42 (91%) with a loss of hMLH1, 3 (7%) hMSH2, and 1 (2%) hMLH1/hMSH6. Tumors with loss of hMLH1 were further evaluated for hMLH1 promoter hypermethylation and for the presence of the BRAF-V600E mutation. Among cases tested, all 19 (100%) tumors among the Eskimo patients showed hMLH1 promoter hypermethylation, whereas this was the case for only 3 of the 7 (42%) tumors among the Aleut (P = 0.002) and 5 of the 10 (50%) tumors from the Indians (P = 0.002). The majority of hypermethylated cases (23 of 27) tested positive for the V600E alteration. Of the nine tumors from the Aleut and Indian patients that did not exhibit hMLH1 hypermethylation, eight tested negative for V600E. Overall, the frequency of defective MMR among the three groups was not statistically different (P = 0.75). However, the data suggest that the pathogenesis of CRC may differ between the three groups. The CRC with defective MMR among the Eskimo sample fit the typical profile for hMLH1-related cancer associated with sporadic CRC, whereas the pattern in the Aleut and Indian suggests the possibility that germ line hMLH1 mutations may be present. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2344–50)

Background— Cardiac troponin T (cTnT) and B-type natriuretic peptide (BNP) have been used to estimate prognosis in heart failure; however, most studies have evaluated decompensated patients with single measurements. To determine if there are advantages to serial measurements, we evaluated stable chronic heart failure patients every 3 months for 2 years. Methods and Results— A cohort of 190 New York Heart Association class III–IV heart failure patients was prospectively enrolled from June 2001 to January 2004. Primary end points were death, cardiac transplantation, or hospitalization. At study enrollment cTnT was <0.01 ng/mL in 87 (45.8%) patients, 0.01 to 0.03 ng/mL in 50 (26.3%) patients, and >0.03 ng/mL in 53 (27.9%) patients. An increase in cTnT above normal (<0.01 ng/mL) carried a 3.4-fold increased risk ( P =0.019). Further increases (≥20%) from an elevated level worsened the overall risk (hazard ratio, 5.09; P <0.001). BNP was elevated (>95th percentile for age and gender normal population) in 122 (64.2%) patients. An elevation of BNP from normal at any time during the study was associated with a poor outcome, but, once elevated, further changes in BNP (increases or decreases) remained associated with the same risk (hazard ratio, 5.09; P <0.001). Combined elevations of cTnT (>0.03 ng/mL) and BNP defined the highest risk group (hazard ratio, 8.58; P <0.001). Conclusions— Elevations of cTnT or BNP from normal detected at any time during clinical follow-up in ambulatory patients with chronic heart failure are highly associated with an increased risk of events. Further increases in cTnT contribute to additional risk. Combined elevations of cTnT and BNP contribute the highest risk. The ability to monitor changes by serial measurements adds substantially to the assessment of risk in this patient population.

The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid-β protein (Aβ), which forms amyloid plaques in Alzheimer's disease (AD), secreted APPα (sAPPα) which enhances memory, and the APP intracellular domain (AICD), which has been implicated in the regulation of gene transcription and calcium signaling. The β-site APP cleaving enzyme 1 (BACE1) cleaves APP in an activity-dependent manner to form Aβ, AICD, and secreted APPβ. Because this neural activity was shown to diminish synaptic transmission in vitro [Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R (2003) Neuron 37:925–937], the prevailing notion has been that this pathway diminishes synaptic function. Here we investigated the role of this pathway in vivo . We studied transgenic mice overproducing APP that do not develop AD pathology or memory deficits but instead exhibit enhanced spatial memory. We showed enhanced synaptic plasticity in the hippocampus that depends on prior synaptic activity. We found that the enhanced memory and synaptic plasticity are abolished by the ablation of one or both copies of the BACE1 gene, leading to a significant decrease in AICD but not of any other APP cleavage products. In contrast to the previously described negative effect of BACE1-mediated cleavage of APP on synaptic function in vitro , our in vivo work indicates that BACE1-mediated cleavage of APP can facilitate learning, memory, and synaptic plasticity.