George A. Scangas

A Role for BRCA1 in Uterine Leiomyosarcoma

Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy with a low survival rate. Currently, there is no effective treatment for ULMS. Infrequent occurrences of human ULMS hamper the understanding of the initiation and progression of the disease, thereby limiting the ability to develop efficient therapies. To elucidate the roles of the p53 and BRCA1 tumor suppressor genes in gynecologic malignancies, we generated mice in which p53 and/or BRCA1 can be conditionally deleted using anti-Müllerian hormone type II receptor (Amhr2)-driven Cre recombinase. We showed that conditional deletion of p53 in mice results in the development of uterine tumors that resemble human ULMS and that concurrent deletion of p53 and BRCA1 significantly accelerates the progression of these tumors. This finding led to our hypothesis that BRCA1 may play a role in human ULMS development. Consistent with this hypothesis, we showed that the BRCA1 protein is absent in 29% of human ULMS and that BRCA1 promoter methylation is the likely mechanism of BRCA1 downregulation. These data indicate that the loss of BRCA1 function may be an important step in the progression of ULMS. Our findings provide a rationale for investigating therapies that target BRCA1 deficiency in ULMS.

Cytometric fingerprinting: Quantitative characterization of multivariate distributions

Recent technological advances in flow cytometry instrumentation provide the basis for high‐dimensionality and high‐throughput biological experimentation in a heterogeneous cellular context. Concomitant advances in scalable computational algorithms are necessary to better utilize the information that is contained in these high‐complexity experiments. The development of such tools has the potential to expand the utility of flow cytometric analysis from a predominantly hypothesis‐driven mode to one of discovery, or hypothesis‐generating research. A new method of analysis of flow cytometric data called Cytometric Fingerprinting (CF) has been developed. CF captures the set of multivariate probability distribution functions corresponding to list‐mode data and then “flattens” them into a computationally efficient fingerprint representation that facilitates quantitative comparisons of samples. An experimental and synthetic data were generated to act as reference sets for evaluating CF. Without the introduction of prior knowledge, CF was able to “discover” the location and concentration of spiked cells in ungated analyses over a concentration range covering four orders of magnitude, to a lower limit on the order of 10 spiked events in a background of 100,000 events. We describe a new method for quantitative analysis of list‐mode cytometric data. CF includes a novel algorithm for space subdivision that improves estimation of the probability density function by dividing space into nonrectangular polytopes. Additionally it renders a multidimensional distribution in the form of a one‐dimensional multiresolution hierarchical fingerprint that creates a computationally efficient representation of high dimensionality distribution functions. CF supports both the generation and testing of hypotheses, eliminates sources of operator bias, and provides an increased level of automation of data analysis.

Genomic profiling of atypical meningiomas associates gain of 1q with poor clinical outcome

Atypical meningiomas exhibit heterogeneous clinical outcomes. It is unclear which atypical meningiomas require aggressive multimodality treatment with surgery and radiation therapy versus surgery alone to prevent recurrence. Detailed molecular-genetic characterization of these neoplasms is necessary to understand their pathogenesis and identify clinically relevant genetic markers. Oligonucleotide array comparative genomic hybridization was used to identify frequent genetic alterations in 47 primary atypical meningiomas resected at Massachusetts General Hospital between August 1987 and September 2006. Eighty-five percent of samples exhibited loss of 22q, including the neurofibromatosis type 2 gene. The second most frequent regions of loss were confined to the short arm of chromosome 1, particularly 1p33-p36.2 (70%) and 1p13.2 (64%). Other frequent regions of loss, detected in more than 50% of samples, included 14q, 10q, 8q, 7p, 21q, 19, 9q34, and 4p16. Frequent regions of gain were detected along 1q (59%), 17q (44%), 9q34 (30%), and 7q36 (26%). Univariate marker-by-marker analysis of all frequently identified copy number alterations showed potential correlation between gain of 1q and shorter progression-free survival. Given the heterogeneous treatment outcomes of atypical meningioma, investigation of large-scale and focal genomic alterations in multi-institutional efforts may help clarify molecular-genetic signatures of clinical use.

EQ-5D-derived health utility values in patients undergoing surgery for chronic rhinosinusitis.

Health utility value (HUV) is an index used to measure health‐related quality of life for the valuation and comparison of treatments. The Euroqol 5‐Dimension (EQ‐5D) questionnaire is a widely used method for determining HUV, but it has not been applied for this purpose in patients with chronic rhinosinusitis (CRS) who undergo sinus surgery.

The natural history and clinical characteristics of paranasal sinus mucoceles: a clinical review

A retrospective data analysis at a university tertiary referral center was conducted to characterize the natural history, clinical characteristics, management principles, and outcomes of paranasal sinus mucoceles.

Emergency department presentation for uncomplicated acute rhinosinusitis is associated with poor access to healthcare

Uncomplicated acute rhinosinusitis (ARS) is most appropriately managed in an outpatient clinic setting. Some ARS patients present to emergency departments (EDs) for care. We investigates factors associated with ARS presentation to EDs versus outpatient settings.

Genome-wide comparison of paired fresh frozen and formalin-fixed paraffin-embedded gliomas by custom BAC and oligonucleotide array comparative genomic hybridization: facilitating analysis of archival gliomas

Array comparative genomic hybridization (aCGH) is a powerful tool for detecting DNA copy number alterations (CNA). Because diffuse malignant gliomas are often sampled by small biopsies, formalin-fixed paraffin-embedded (FFPE) blocks are often the only tissue available for genetic analysis; FFPE tissues are also needed to study the intratumoral heterogeneity that characterizes these neoplasms. In this paper, we present a combination of evaluations and technical advances that provide strong support for the ready use of oligonucleotide aCGH on FFPE diffuse gliomas. We first compared aCGH using bacterial artificial chromosome (BAC) arrays in 45 paired frozen and FFPE gliomas, and demonstrate a high concordance rate between FFPE and frozen DNA in an individual clone-level analysis of sensitivity and specificity, assuring that under certain array conditions, frozen and FFPE DNA can perform nearly identically. However, because oligonucleotide arrays offer advantages to BAC arrays in genomic coverage and practical availability, we next developed a method of labeling DNA from FFPE tissue that allows efficient hybridization to oligonucleotide arrays. To demonstrate utility in FFPE tissues, we applied this approach to biphasic anaplastic oligoastrocytomas and demonstrate CNA differences between DNA obtained from the two components. Therefore, BAC and oligonucleotide aCGH can be sensitive and specific tools for detecting CNAs in FFPE DNA, and novel labeling techniques enable the routine use of oligonucleotide arrays for FFPE DNA. In combination, these advances should facilitate genome-wide analysis of rare, small and/or histologically heterogeneous gliomas from FFPE tissues.

Disparity between popular (Internet) and scientific illness concepts of carpal tunnel syndrome causation.

PURPOSE To determine whether there are notable disparities between popular (Internet) and scientific (Index Medicus) theories of carpal tunnel syndrome (CTS) causation. METHODS Reports from 3 sources were evaluated with regard to support for etiological theories of CTS: 1) patient-oriented information on CTS from the Internet, 2) recent physician-oriented information on CTS from medical journals indexed on Index Medicus, and 3) articles addressing the etiology of CTS from the 1997 National Institute for Occupational Safety and Health report. Multiple logistic regression analyses evaluated differences in etiological theories from the 3 sources. RESULTS Internet sites implicated vitamin B(6) deficiency, tenosynovitis, and typing or computer use as causes for idiopathic CTS considerably more often and genetic predisposition considerably less often than recent Index Medicus scientific reports and reports reviewed by the National Institute for Occupational Safety and Health. CONCLUSIONS There are notable disparities between popular (Internet) and scientific (Index Medicus) theories of CTS causation.

Cost utility analysis of endoscopic sinus surgery for chronic rhinosinusitis.

The purpose of this work was to evaluate the cost‐effectiveness of endoscopic sinus surgery (ESS) compared to medical therapy for patients with chronic rhinosinusitis (CRS).

Socioeconomic determinants of overnight and weekend emergency department use for acute rhinosinusitis

Prior work has shown Medicaid and self‐pay insurance status is associated with emergency department (ED), rather than outpatient clinic, presentation for uncomplicated acute rhinosinusitis (ARS). We investigate whether the disparate use of ED resources for this nonemergent condition by patients with Medicaid and self‐pay insurance can be attributed to presentation overnight or on weekends.