Citations

SUMMARY Chromosomally integrated human herpesvirus 6 (ciHHV‐6) is a condition in which the complete HHV‐6 genome is integrated into the host germ line genome and is vertically transmitted in a Mendelian manner. The condition is found in less than 1% of controls in the USA and UK, but has been found at a somewhat higher prevalence in transplant recipients and other patient populations in several small studies. HHV‐6 levels in whole blood that exceed 5.5 log10 copies/ml are strongly suggestive of ciHHV‐6. Monitoring DNA load in plasma and serum is unreliable, both for identifying and for monitoring subjects with ciHHV‐6 due to cell lysis and release of cellular DNA. High HHV‐6 DNA loads associated with ciHHV‐6 can lead to erroneous diagnosis of active infection. Transplant recipients with ciHHV‐6 may be at increased risk for bacterial infection and graft rejection. ciHHV‐6 can be induced to a state of active viral replication in vitro . It is not known whether ciHHV‐6 individuals are put at clinical risk by the use of drugs that have been associated with HHV‐6 reactivation in vivo or in vitro . Nonetheless, we urge careful observation when use of such drugs is indicated in individuals known to have ciHHV‐6. Little is known about whether individuals with ciHHV‐6 develop immune tolerance for viral proteins. Further research is needed to determine the role of ciHHV‐6 in disease. Copyright © 2011 John Wiley & Sons, Ltd.

The temporal lobe is a common focus for epilepsy. Temporal lobe epilepsy in infants and children differs from the relatively homogeneous syndrome seen in adults in several important clinical and pathological ways. Seizure semiology varies by age, and the ictal EEG pattern may be less clear cut than what is seen in adults. Additionally, the occurrence of intractable seizures in the developing brain may impact neurocognitive function remote from the temporal area. While many children will respond favorably to medical therapy, those with focal imaging abnormalities including cortical dysplasia, hippocampal sclerosis, or low-grade tumors are likely to be intractable. Expedient workup and surgical intervention in these medically intractable cases are needed to maximize long-term developmental outcome.

Abstract Background: BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers. Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made. Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2). Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers. Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 20(8); 1690–702. ©2011 AACR.

Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow for detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state‐of‐the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory, and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real‐world situations so as to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally, and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

There is controversy regarding the application of angioplasty to patients with multivessel disease in whom all significant stenoses are not dilated. We analyzed the outcomes of 286 patients with multivessel disease and prior successful angioplasty at a mean follow-up duration of 26.2 months. End points analyzed included death, myocardial infarction, late revascularization, and angina pectoris. After successful angioplasty, 127 patients had no residual stenoses of 70% or greater (group 1) and 159 patients had one or more residual stenoses of 70% or greater (group 2). Because there were significant differences in baseline risk factors between the two groups, a logistic regression model was used to make the necessary adjustments in the analysis. Adjusted estimates of the risk of death, death/myocardial infarction, or presence of angina pectoris did not differ between the two groups. Group 2 patients, however, had more coronary artery bypass surgery during follow-up, while those in group 1 had more second PTCA procedures. Results suggest that angioplasty can be safely applied to patients with multivessel disease, even when all significant stenoses are not dilated.

Abstract Activation of the Sonic hedgehog (Shh) pathway and increased expression of Gli1 play an important role in proliferation and transformation of granule cell progenitors (GCP) in the developing cerebellum. Medulloblastomas arising from cerebellar GCPs are frequently driven by Shh pathway–activating mutations; however, molecular mechanisms of Shh pathway dysregulation and transformation of neural progenitors remain poorly defined. We report that the transcription factor and oncogene Snail1 (Sna1) is directly induced by Shh pathway activity in GCPs, murine medulloblastomas, and human medulloblastoma cells. Enforced expression of Sna1 was sufficient to induce GCPs and medulloblastoma cell proliferation in the absence of Shh/Gli1 exposure. In addition, enforced expression of Sna1 increased transformation of medulloblastoma cells in vitro and in vivo. Analysis of potential Sna1 targets in neural cells revealed a novel Sna1 target, N-Myc, a transcription factor known to play a role in Shh-mediated GCP proliferation and medulloblastoma formation. We found that Sna1 directly induced transcription of N-Myc in human medulloblastoma cells and that depletion of N-Myc ablated the Sna1-induced proliferation and transformation. Taken together, these results provide further insight into the mechanism of Shh-induced transformation of neural progenitor cells and suggest that induction of Sna1 may serve to amplify the oncogenic potential of Shh pathway activation through N-Myc induction. Cancer Res; 71(15); 5336–45. ©2011 AACR.

Purpose Preoperative aromatase inhibitor (AI) treatment promotes breast-conserving surgery (BCS) for estrogen receptor (ER) –positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations. Patients and Methods Three hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis. Results On the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P = .004). Conclusion Neoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with > 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling.