Rebecca A Betensky

Chair of the Department of Biostatistics

Professor of Biostatistics

Professional overview

Prior to NYU, Dr. Betensky was Professor of Biostatistics at the Harvard T.H. Chan School of Public Health. She was director of the Harvard Catalyst (Clinical and Translational Science Award) Biostatistics Program; director of the Data and Statistics Core for the Massachusetts Alzheimer’s Disease Research Center; and director of the Biostatistics Neurology Core at Massachusetts General Hospital. Previously, she was the Biostatistics Program Leader for the Dana-Farber/Harvard Cancer Center.

Dr. Betensky’s research focuses on methods for the analysis of censored and truncated outcomes and covariates, which frequently arise from the subsampling of cohort studies. She has a long-time interest in clinical trials, and has written on the evaluation of biomarkers and the use and interpretation of p-values. She has collaborated extensively in studies in neurologic diseases, and serves as statistical editor for Annals of Neurology.

Dr. Betensky was awarded, and directed for 15 years, an NIH T32 training program in neurostatistics and neuroepidemiology for pre- and post-doctoral students in biostatistics and epidemiology and for clinician-scientists. She previously directed Harvard’s Biostatistics programs to promote and support diversity at all levels in the field of quantitative public health. She was also a member of the BMRD Study Section for review of NIH statistical methodology grants; on committees for the Institute of Medicine; and a co-chair of the technical advisory committee for the scientific registry of transplant recipients.

Dr. Betensky an elected Fellow of the American Statistical Association and of the International Statistical Institute, and is a past recipient of the Spiegelman Award from the American Public Health Association. She currently serves as a member of the Board of Scientific Counselors for Clinical Science and Epidemiology at the National Cancer Institute.

Education

AB, Mathematics, Harvard University, Cambridge, MA

PhD, Statistics, Stanford University, Stanford, CA

Areas of research and study

Biology

Biostatistics

Neuroepidemiology

Neurology

Neurostatistics

Translational science

Publications

Publications

Genomic and Transcriptomic Analyses of NF1-Mutant Melanoma Identify Potential Targeted Approach for Treatment

Jour, G., Illa-Bochaca, I., Ibrahim, M., Donnelly, D., Zhu, K., Miera, E. V., Vasudevaraja, V., Mezzano, V., Ramswami, S., Yeh, Y. H., Winskill, C., Betensky, R., Mehnert, J., & Osman, I. (n.d.).

Publication year

2022

Journal title

Journal of Investigative Dermatology

10.1016/j.jid.2022.07.022

Abstract

Abstract

There is currently no targeted therapy to treat NF1-mutant melanomas. In this study, we compared the genomic and transcriptomic signatures of NF1-mutant and NF1 wild-type melanoma to reveal potential treatment targets for this subset of patients. Genomic alterations were verified using qPCR, and differentially expressed genes were independently validated using The Cancer Genome Atlas data and immunohistochemistry. Digital spatial profiling with multiplex immunohistochemistry and immunofluorescence were used to validate the signatures. The efficacy of combinational regimens driven by these signatures was tested through in vitro assays using low-passage cell lines. Pathogenic NF1 mutations were identified in 27% of cases. NF1-mutant melanoma expressed higher proliferative markers MK167 and CDC20 than NF1 wild-type (P = 0.008), which was independently validated both in The Cancer Genome Atlas dataset (P = 0.01, P = 0.03) and with immunohistochemistry (P = 0.013, P = 0.036), respectively. Digital spatial profiling analysis showed upregulation of LY6E within the tumor cells (false discovery rate < 0.01, log2 fold change > 1), confirmed with multiplex immunofluorescence showing colocalization of LY6E in melanoma cells. The combination of MAPK/extracellular signal‒regulated kinase kinase and CDC20 coinhibition induced both cytotoxic and cytostatic effects, decreasing CDC20 expression in multiple NF1-mutant cell lines. In conclusion, NF1-mutant melanoma is associated with a distinct genomic and transcriptomic profile. Our data support investigating CDC20 inhibition with MAPK pathway inhibitors as a targeted regimen in this melanoma subtype.

Genomic profiling distinguishes familial multiple and sporadic multiple meningiomas

Shen, Y., Nunes, F., Stemmer-Rachamimov, A., James, M., Mohapatra, G., Plotkin, S., Betensky, R., Engler, D. A., Roy, J., Ramesh, V., & Gusella, J. F. (n.d.).

Publication year

2009

Journal title

BMC Medical Genomics

Volume

2

10.1186/1755-8794-2-42

Abstract

Abstract

Background. Meningiomas may occur either as familial tumors in two distinct disorders, familial multiple meningioma and neurofibromatosis 2 (NF2), or sporadically, as either single or multiple tumors in individuals with no family history. Meningiomas in NF2 and approximately 60% of sporadic meningiomas involve inactivation of the NF2 locus, encoding the tumor suppressor merlin on chromosome 22q. This study was undertaken to establish whether genomic profiling could distinguish familial multiple meningiomas from sporadic solitary and sporadic multiple meningiomas. Methods. We compared 73 meningiomas presenting as sporadic solitary (64), sporadic multiple (5) and familial multiple (4) tumors using genomic profiling by array comparative genomic hybridization (array CGH). Results. Sporadic solitary meningiomas revealed genomic rearrangements consistent with at least two mechanisms of tumor initiation, as unsupervised cluster analysis readily distinguished tumors with chromosome 22 deletion (associated with loss of the NF2 tumor suppressor) from those without chromosome 22 deletion. Whereas sporadic meningiomas without chromosome 22 loss exhibited fewer chromosomal imbalance events overall, tumors with chromosome 22 deletion further clustered into two major groups that largely, though not perfectly, matched with their benign (WHO Grade I) or advanced (WHO Grades II and III) histological grade, with the latter exhibiting a significantly greater degree of genomic imbalance (P < 0.001). Sporadic multiple meningiomas showed a frequency of genomic imbalance events comparable to the atypical grade solitary tumors. By contrast, familial multiple meningiomas displayed no imbalances, supporting a distinct mechanism for the origin for these tumors. Conclusion. Genomic profiling can provide an unbiased adjunct to traditional meningioma classification and provides a basis for exploring the different genetic underpinnings of tumor initiation and progression. Most importantly, the striking difference observed between sporadic and familial multiple meningiomas indicates that genomic profiling can provide valuable information for differential diagnosis of subjects with multiple meningiomas and for considering the risk for tumor occurrence in their family members.

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

Gabeau-Lacet, D., Engler, D., Gupta, S., Scangas, G. A., Betensky, R., Barker, F. G., Loeffler, J. S., Louis, D. N., & Mohapatra, G. (n.d.).

Publication year

2009

Journal title

Journal of Neuropathology and Experimental Neurology

Volume

68

Issue

10

Page(s)

1155-1165

10.1097/NEN.0b013e3181ba3952

Abstract

Abstract

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.

Glioma test array for use with formalin-fixed, paraffin-embedded tissue : Array comparative genomic hybridization correlates with loss of heterozygosity and fluorescence in situ hybridization

Mohapatra, G., Betensky, R., Miller, E. R., Carey, B., Gaumont, L. D., Engler, D. A., & Louis, D. N. (n.d.).

Publication year

2006

Journal title

Journal of Molecular Diagnostics

Volume

8

Issue

2

Page(s)

268-276

10.2353/jmoldx.2006.050109

Abstract

Abstract

Array-based comparative genomic hybridization (aCGH) is a powerful, high-throughput tool for whole genome analysis. Until recently, aCGH could only be reproducibly performed on frozen tissue samples and with significant tissue amounts. For brain tumors however, paraffin-embedded tissue blocks from small stereotactic biopsies may be the only tissue routinely available. The development of methods to analyze formalin-fixed, paraffin-embedded (FFPE) material therefore has the potential to impact molecular diagnosis in a significant way. To this end, we constructed a BAC array representing chromosomes 1, 7, 19, and X because 1p/19q deletion and EGFR gene amplification provide clinically relevant information for glioma diagnosis. We also optimized a two-step labeling procedure using an amine-modified nucleotide for generating aCGH probes. Using this approach, we analyzed a series of 28 FFPE oligodendroglial tumors for alterations of chromosomes 1, 7, and 19. We also independently assayed these tumors for 1p/19q deletion by fluorescence in situ hybridization and by loss of heterozygosity analyses. The concordance between aCGH, standard loss of heterozygosity and fluorescence in situ hybridization was nearly 100% for the chromosomes analyzed. These results suggest that aCGH could offer an improved molecular diagnostic approach for gliomas because of its ability to detect clinically relevant molecular alterations in small FFPE specimens.

Hazard regression for interval-censored data with penalized spline

Cai, T., & Betensky, R. (n.d.).

Publication year

2003

Journal title

Biometrics

Volume

59

Issue

3

Page(s)

570-579

10.1111/1541-0420.00067

Abstract

Abstract

This article introduces a new approach for estimating the hazard function for possibly interval- and right-censored survival data. We weakly parameterize the log-hazard function with a piecewise-linear spline and provide a smoothed estimate of the hazard function by maximizing the penalized likelihood through a mixed model-based approach. We also provide a method to estimate the amount of smoothing from the data. We illustrate our approach with two well-known interval- censored data sets. Extensive numerical studies are conducted to evaluate the efficacy of the new procedure.

Hazard Regression Models of Early Mortality in Trauma Centers

Clark, D. E., Qian, J., Winchell, R. J., & Betensky, R. (n.d.).

Publication year

2012

Journal title

Journal of the American College of Surgeons

Volume

215

Issue

6

Page(s)

841-849

10.1016/j.jamcollsurg.2012.08.023

Abstract

Abstract

Background: Factors affecting early hospital deaths after trauma can be different from factors affecting later hospital deaths, and the distribution of short and long prehospital times can vary among hospitals. Hazard regression (HR) models might therefore be more useful than logistic regression (LR) models for analysis of trauma mortality, especially when treatment effects at different time points are of interest. Study Design: We obtained data for trauma center patients from the 2008-2009 National Trauma Data Bank. Patients were included if they had complete data for prehospital times, hospital times, survival outcomes, age, vital signs, and severity scores. Patients were excluded if pulseless on admission, transferred in or out, or had an Injury Severity Score

High-dose methotrexate for elderly patients with primary CNS lymphoma

Zhu, J. J., Gerstner, E. R., Engler, D. A., Mrugala, M. M., Nugent, W., Nierenberg, K., Hochberg, F. H., Betensky, R., & Batchelor, T. T. (n.d.).

Publication year

2009

Journal title

Neuro-Oncology

Volume

11

Issue

2

Page(s)

211-215

10.1215/15228517-2008-067

Abstract

Abstract

The introduction of methotrexate (MTX)-based chemotherapy has improved median survival for patients with primary CNS lymphoma (PCNSL). Older age is a negative prognostic marker in patients with PCNSL and may increase the likelihood of MTX toxicity. We studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. We identified 31 patients at our institution diagnosed with PCNSL at age ≥70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m2) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrastenhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survival were 7.1 months and 37 months, respectively. Grade IIV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL.

Histology-based expression profiling yields novel prognostic markers in human glioblastoma

Dong, S., Nutt, C. L., Betensky, R., Stemmer-Rachamimov, A. O., Denko, N. C., Ligon, K. L., Rowitch, D. H., & Louis, D. N. (n.d.).

Publication year

2005

Journal title

Journal of Neuropathology and Experimental Neurology

Volume

64

Issue

11

Page(s)

948-955

10.1097/01.jnen.0000186940.14779.90

Abstract

Abstract

Although the prognosis for patients with glioblastoma is poor, survival is variable, with some patients surviving longer than others. For this reason, there has been longstanding interest in the identification of prognostic markers for glioblastoma. We hypothesized that specific histologic features known to correlate with malignancy most likely express molecules that are directly related to the aggressive behavior of these tumors. We further hypothesized that such molecules could be used as biomarkers to predict behavior in a manner that might add prognostic power to sole histologic observation of the feature. We reasoned that perinecrotic tumor cell palisading, which denotes the most aggressive forms of malignant gliomas, would be a striking histologic feature on which to test this hypothesis. We therefore used laser capture microdissection and oligonucleotide arrays to detect molecules differentially expressed in perinecrotic palisades. A set of RNAs (including POFUT2, PTDSR, PLOD2, ATF5, and HK2) that were differentially expressed in 3 initially studied, microdissected glioblastomas also provided prognostic information in an independent set of 28 glioblastomas that did not all have perinecrotic palisades. On validation in a second, larger independent series, this approach could be applied to other human glioma types to derive tissue biomarkers that could offer ancillary prognostic and predictive information alongside standard histopathologic examination.

Histopathological-molecular genetic correlations in referral pathologist-diagnosed low-grade "oligodendroglioma"

Betensky, R., Sasaki, H., Zlatescu, M. C., Betensky, R. A., Johnk, L. B., Cutone, A. N., Cairncross, J. G., & Louis, D. N. (n.d.).

Publication year

2002

Journal title

Journal of Neuropathology and Experimental Neurology

Volume

61

Issue

1

Page(s)

58-63

10.1093/jnen/61.1.58

Abstract

Abstract

Allelic loss of chromosome 1p predicts increased chemosensitivity and better survival in oligodendroglial tumors. Clinical testing for 1p loss in oligodendroglial tumors at our hospital has allowed us to postulate that certain histological appearances are associated with 1p allelic status. Forty-four cases received for genetic testing were diagnosed by referring pathologists as pure low-grade oligodendroglioma. Central neuropathological review divided the series equally into 22 cases with classical oligodendroglioma histology and 22 with more astrocytic features. Molecular genetic analyses demonstrated 1p loss in 19 of 22 classic oligodendrogliomas (86%) and maintenance of both 1p alleles in 16 of 22 gliomas with astrocytic features (73%). No glial fibrillary acidic protein-positive cell type (gliofibrillary oligodendrocyte, minigemistocyte, cellular processes) was associated with 1p allelic status. Fourteen of the 44 cases were treated with chemotherapy at tumor progression: 3 "astrocytic" gliomas with 1p loss responded to PCV chemotherapy and 2 classic oligodendrogliomas that maintained both 1p alleles included a responder and a non-responder. These results suggest that histological appearance correctly predicts genotype in approximately 80% of low-grade gliomas, but that tumor genotype more closely predicts chemosensitivity. As a result, such objective molecular genetic analyses should be incorporated into patient management and into clinical trials of low-grade diffuse gliomas.

Hospital Acquired Pneumonia Is Linked to Right Hemispheric Peri-Insular Stroke

Kemmling, A., Lev, M. H., Payabvash, S., Betensky, R., Qian, J., Masrur, S., & Schwamm, L. H. (n.d.).

Publication year

2013

Journal title

PloS one

Volume

8

Issue

8

10.1371/journal.pone.0071141

Abstract

Abstract

Purpose:Hospital acquired pneumonia (HAP) is a major complication of stroke. We sought to determine associations between infarction of specific brain regions and HAP.Methods:215 consecutive acute stroke patients with HAP (2003-2009) were carefully matched with 215 non-pneumonia controls by gender, then NIHSS, then age. Admission imaging and binary masks of infarction were registered to MNI-152 space. Regional atlas and voxel-based log-odds were calculated to assess the relationship between infarct location and the likelihood of HAP. An independently validated penalized conditional logistic regression model was used to identify HAP associated imaging regions.Results:The HAP and control patients were well matched by gender (100%), age (95% within 5-years), NIHSS (98% within 1-point), infarct size, dysphagia, and six other clinical variables. Right hemispheric infarcts were more frequent in patients with HAP versus controls (43.3% vs. 34.0%, p = 0.054), whereas left hemispheric infarcts were more frequent in controls (56.7% vs. 44.7%, p = 0.012); there was no significant difference between groups in the rate of brainstem strokes (p = 1.0). Of the 10 most infarcted regions, only right insular cortex volume was different in HAP versus controls (20 vs. 12 ml, p = 0.02). In univariate analyses, the highest log-odds regions for pneumonia were right hemisphere, cerebellum, and brainstem. The best performing multivariate model selected 7 brain regions of infarction and 2 infarct volume-based variables independently associated with HAP.Conclusions:HAP is associated with right hemispheric peri-insular stroke. These associations may be related to autonomic modulation of immune mechanisms, supporting recent hypotheses of stroke mediated immune suppression.

Hospital volume versus outcome : An unusual example of bivariate association

Betensky, R., Christian, C. K., Gustafson, M. L., Daley, J., & Zinner, M. J. (n.d.).

Publication year

2006

Journal title

Biometrics

Volume

62

Issue

2

Page(s)

598-604

10.1111/j.1541-0420.2005.00449.x

Abstract

Abstract

The Leapfrog Group, a consortium of more than 100 large employers, purchasing coalitions, and states that collectively provide health insurance to more than 33 million people, convened in 2000 with the goal of using market forces to improve the quality of healthcare. The resulting Leapfrog initiative suggested selective referral of complex procedures to high-volume hospitals and set volume thresholds for five procedures. This was based on the hypothesis that low-volume hospitals have higher mortality, which can be viewed in simplified statistical terms as the hypothesis that the binomial p is a decreasing function of n. The analysis of the correlation between hospitals' standardized mortality ratios (SMR, i.e., the ratio of observed to expected deaths) and hospitals' procedural volumes is revealing about the volume/mortality hypothesis. This presents an unusual pedagogic example in which the detection of correlation in the presence of nonlinear dependence is of primary interest, and thus the Pearson correlation is ideally suited. The frequently preferred nonparametric measures of bivariate association are inappropriate as they are unable to discriminate between correlation and dependence.

Human miRNome profiling identifies microRNAs differentially present in the urine after kidney injury

Ramachandran, K., Saikumar, J., Bijol, V., Koyner, J. L., Qian, J., Betensky, R., Waikar, S. S., & Vaidya, V. S. (n.d.).

Publication year

2013

Journal title

Clinical Chemistry

Volume

59

Issue

12

Page(s)

1742-1752

10.1373/clinchem.2013.210245

Abstract

Abstract

BACKGROUND: Extracellular microRNAs (miRNAs) have been proposed as potentially robust and stable biomarkers of various disease conditions. The primary objective of this study was to identify miRNAs differentially occurring in the urine that could serve as potential biomarkers of acute kidney injury (AKI), because traditional AKI markers have limitations with respect to sensitivity, specificity, and timeliness of diagnosis. METHODS: We profiled 1809 miRNAs in pooled urine samples from 6 patients with AKI and from 6 healthy controls. We measured the 378 stably detectable miRNAs in the 12 samples individually and selected the top 7 miRNAs that were most different in the urine of patients with AKI compared with the non-AKI control individuals. These miRNAs were assessed in a larger cohort of patients with AKI (n = 98: 71 AKI patients in the intensive care unit (ICU) and 27 kidney transplantation patients with biopsy-proven tubular injury) and patients without AKI (n = 97: 74 healthy volunteers and 23 ICU patients without AKI). RESULTS: We identified 4 miRNAs capable of significantly differentiating patients with AKI from individuals without AKI: miR-21 (P = 0.0005), miR-200c (P < 0.0001), miR-423 (P = 0.001), and miR-4640 (P = 0.0355). The combined cross-validated area under the ROC curve for these 4 miRNAs was 0.91. The imprecision with respect to miRNA isolation and reverse transcription efficiency was

Hypothesis Tests for Neyman's Bias in Case–Control Studies

Betensky, R., Swanson, D. M., Anderson, C. D., & Betensky, R. A. (n.d.).

Publication year

2018

Journal title

Journal of Applied Statistics

Volume

45

Issue

11

Page(s)

1956-1977

10.1080/02664763.2017.1401053

Abstract

Abstract

Survival bias is a long recognized problem in case–control studies, and many varieties of bias can come under this umbrella term. We focus on one of them, termed Neyman's bias or ‘prevalence–incidence bias’. It occurs in case–control studies when exposure affects both disease and disease-induced mortality, and we give a formula for the observed, biased odds ratio under such conditions. We compare our result with previous investigations into this phenomenon and consider models under which this bias may or may not be important. Finally, we propose three hypothesis tests to identify when Neyman's bias may be present in case–control studies. We apply these tests to three data sets, one of stroke mortality, another of brain tumors, and the last of atrial fibrillation, and find some evidence of Neyman's bias in the former two cases, but not the last case.

Identification of tissue contamination by polymorphic deletion probe fluorescence in situ hybridization

Chiang, S., Yip, S., Betensky, R., Batten, J. M., Misdraji, J., & Iafrate, A. J. (n.d.).

Publication year

2012

Journal title

American Journal of Surgical Pathology

Volume

36

Issue

10

Page(s)

1464-1471

10.1097/PAS.0b013e31826247a2

Abstract

Abstract

Potential sources of error in surgical pathology include specimen misidentification, unidentified tissue, and tissue contamination of paraffin blocks and slides. Current molecular approaches to characterize unidentified or misidentified tissue include fluorescence in situ hybridization identification of sex chromosomes (XY FISH) and microsatellite analysis. Polymorphic deletion probe (PDP) FISH, a novel FISH assay based on copy number variants, can distinguish between cells and tissues from 2 individuals in situ, independent of gender. Using a panel of 3 PDPs, we compared the genotypes of potential tissue contaminants (n=19) and unidentified tissues (n=6) with patient tissues to determine the utility of PDP FISH in resolving specimen identity. XY FISH was added to increase the informative potential of the assay, and microsatellite analysis was used as a gold standard to confirm PDP FISH results. PDP FISH distinguished between putative contaminants and patient tissues in 13 of 14 cases and indicated a high likelihood of 2 tissues originating from the same source in 11 of 11 cases. The assay has a sensitivity and specificity of 86% [6/7, exact 95% confidence interval (CI): 42%, 97%] and 100% (9/9, exact 1-sided 97.5% CI: 68%, 100%), respectively, and a positive predictive value and negative predictive value of 100% (6/6, exact 1-sided 97.5% CI: 54%, 100%) and 90% (9/10, exact 95% CI: 55%, 98%), respectively. PDP FISH is an accurate and practical molecular assay for the genetic characterization of potential tissue contaminants and unidentified tissues, especially in the setting of small sample size, and permits concomitant assessment of morphology.

Imaging correlates of molecular signatures in oligodendrogliomas

Megyesi, J. F., Kachur, E., Lee, D. H., Zlatescu, M. C., Betensky, R., Forsyth, P. A., Okada, Y., Sasaki, H., Mizoguchi, M., Louis, D. N., & Cairncross, J. G. (n.d.).

Publication year

2004

Journal title

Clinical Cancer Research

Volume

10

Issue

13

Page(s)

4303-4306

10.1158/1078-0432.CCR-04-0209

Abstract

Abstract

Molecular subsets of oligodendroglioma behave in biologically distinct ways. Their locations in the brain, rates of growth, and responses to therapy differ with their genotypes. Retrospectively, we inquired whether allelic loss of chromosomal arms 1p and 19q, an early molecular event and favorable prognostic marker in oligodendrogliomas, were reflected in their appearance on magnetic resonance imaging. Loss of 1p and 19q was associated with an indistinct border on T1 images and mixed intensity signal on T1 and T2. Loss of 1p and 19q was also associated with paramagnetic susceptibility effect and with calcification, a common histopathological finding in oligodendrogliomas. These data encourage prospective evaluation of molecular alterations and magnetic resonance imaging characteristics of glial neoplasms.

Immunoglobulin gene rearrangement analysis in cerebrospinal fluid of patients with lymphoproliferative processes

Baehring, J. M., Hochberg, F. H., Betensky, R., Longtine, J., & Sklar, J. (n.d.).

Publication year

2006

Journal title

Journal of the Neurological Sciences

Volume

247

Issue

2

Page(s)

208-216

10.1016/j.jns.2006.05.044

Abstract

Abstract

Objective: To determine the sensitivity and specificity of clonal immunoglobulin heavy chain gene rearrangement (IGHR) analysis in the distinction of benign and malignant lymphoproliferative diseases. Methods: A retrospective analysis was conducted of patients in whom a malignant lymphoproliferative process was suspected. Cells of CSF samples were collected by centrifugation, resuspended in 100 μl of the supernatant and boiled. A 10 μl aliquot of this lysate served as template for semi-nested polymerase chain reaction using variable and joining region consensus primers. PCR products were analyzed by polyacrylamide gel electrophoresis. Cytopathological diagnosis and flow cytometry results were recorded. Sensitivity and specificity of IGHR analysis, cytopathology and flow cytometry were calculated. Results: Eleven patients (12 specimens) had involvement of leptomeninges at the time of lumbar puncture. Another 25 cases (27 specimens) had normal CSF findings or were diagnosed with benign lymphoproliferative conditions. Sensitivity of CSF cytopathology, flow cytometry and IGHR analysis were 0.27 [95% confidence interval 0.06, 0.61], 0.1 [0.003, 0.45] and 0.58 [0.28, 0.85]. Specificity was 1 [0.86, 1], 0.95 [0.77, 1.0] and 0.85 [0.66, 0.96]. Interpretation: IGHR analysis appears to be a useful addition to morphological and flow cytometry analysis of cerebrospinal fluid in the evaluation of CNS lymphoproliferative processes.

Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas

Patil, S., Perry, A., MacCollin, M., Dong, S., Betensky, R., Yeh, T. H., Gutmann, D. H., & Stemmer-Rachamimov, A. O. (n.d.).

Publication year

2008

Journal title

Brain Pathology

Volume

18

Issue

4

Page(s)

517-519

10.1111/j.1750-3639.2008.00155.x

Abstract

Abstract

The INI1/SMARCB1 protein product (INI1), a component of a transcription complex, was recently implicated in the pathogenesis of schwannomas in two members of a single family with familial schwannomatosis. Tumors were found to have both constitutional and somatic mutations of the SMARCB1 gene and showed a mosaic pattern of loss of INI1 expression by immunohistochemistry, suggesting a tumor composition of mixed null and haploinsufficient cells. To determine if this finding could be extended to all tumors arising in familial schwannomatosis, and how it compares with other multiple schwannoma syndromes [sporadic schwannomatosis and neurofibromatosis 2 (NF2)] as well as to sporadic, solitary schwannomas, we performed an immunohistochemistry analysis on 45 schwannomas from patients with multiple schwannoma syndromes and on 38 solitary, sporadic schwannomas from non-syndromic patients. A mosaic pattern of INI1 expression was seen in 93% of tumors from familial schwannomatosis patients, 55% of tumors from sporadic schwannomatosis, 83% of NF2-associated tumors and only 5% of solitary, sporadic schwannomas. These results confirm a role for INI1/SMARCB1 in multiple schwannoma syndromes and suggest that a different pathway of tumorigenesis occurs in solitary, sporadic tumors.

Immunophenotypic and viral (human papillomavirus) correlates of vulvar seborrheic keratosis

Bai, H., Cviko, A., Granter, S., Yuan, L., Betensky, R., & Crum, C. P. (n.d.).

Publication year

2003

Journal title

Human Pathology

Volume

34

Issue

6

Page(s)

559-564

10.1016/S0046-8177(03)00184-9

Abstract

Abstract

Human papillomavirus (HPV) infections of the genital mucosa classically present as warts (condylomata) and are traditionally defined by the presence of viral cytopathic effect (koilocytosis). In recent years, HPV has been detected in vulvar epithelial changes lacking koilocytosis, including squamous papillomas and lesions closely resembling seborrheic keratosis (SK). The purpose of this study was to determine the frequency and type of HPV associated with vulvar SK (VSK) and to compare expression of biomarkers (p16, Mib-1, and cyclin E) in these lesions. Sixty-seven biopsy specimens, including 25 VSKs, 10 nondiagnostic vulvar acanthoses, 12 fibroepithelial polyps (FEPs), and 20 nongenital cutaneous SKs (CSKs), were studied. Biopsy specimens were typed for HPV by polymerase chain reaction and immunostained with Mib-1, cyclin E, and p16INK4 antibodies. Eighteen of 25 VSKs (72%), 0 of 10 nondiagnostic vulvar acanthuses (0%; P = 0.0001), 2 of 12 FEPs (16.7%; P = 0.004), and 3 of 20 CSKs (15%; P = 0.0002) scored HPV positive. Increased Mib-1 staining was significantly more common in VSKs than in other vulvar lesions, but not in CSKs; increased p16 and cyclin E staining was not more common. VSKs are morphologically and immunophenotypically similar to CSKs but distinct by their association with HPV. Unlike the cervix, p16 and cyclin E will not consistently distinguish VSKs from HPV-negative lesions due to underexpression in low-risk HPV infections (p16) and less-restricted expression in vulvar lesions (cyclin E). Whether CSKs are associated with other forms of HPV infection remains to be determined.

Immunophenotyping of pediatric brain tumors : correlating immune infiltrate with histology, mutational load, and survival and assessing clonal T cell response

Plant, A. S., Koyama, S., Sinai, C., Solomon, I. H., Griffin, G. K., Ligon, K. L., Bandopadhayay, P., Betensky, R., Emerson, R., Dranoff, G., Kieran, M. W., & Ritz, J. (n.d.).

Publication year

2018

Journal title

Journal of Neuro-Oncology

Volume

137

Issue

2

Page(s)

269-278

10.1007/s11060-017-2737-9

Abstract

Abstract

There is little known regarding the immune infiltrate present in pediatric brain tumors and how this compares to what is known about histologically similar adult tumors and its correlation with survival. Here, we provide a descriptive analysis of the immune infiltrate of 22 fresh pediatric brain tumor tissue samples of mixed diagnoses and 40 peripheral blood samples. Samples were analyzed using a flow cytometry panel containing markers for immune cell subtypes, costimulatory markers, inhibitory signals, and markers of activation. This was compared to the standard method of immunohistochemistry (IHC) for immune markers for 89 primary pediatric brain tumors. Both flow cytometry and IHC data did not correlate with the grade of tumor or mutational load and IHC data was not significantly associated with survival for either low grade or high grade gliomas. There is a trend towards a more immunosuppressive phenotype in higher grade tumors with more regulatory T cells present in these tumor types. Both PD1 and PDL1 were present in only a small percentage of the tumor infiltrate. T cell receptor sequencing revealed up to 10% clonality of T cells in tumor infiltrates and no significant difference in clonality between low and high grade gliomas. We have shown the immune infiltrate of pediatric brain tumors does not appear to correlate with grade or survival for a small sample of patients. Further research and larger studies are needed to fully understand the interaction of pediatric brain tumors and the immune system.

Imperfect gold standards for biomarker evaluation

Waikar, S. S., Betensky, R., Emerson, S. C., & Bonventre, J. V. (n.d.).

Publication year

2013

Journal title

Clinical Trials

Volume

10

Issue

5

Page(s)

696-700

10.1177/1740774513497540

Abstract

Abstract

Background Serum creatinine has been used as the diagnostic test for acute kidney injury (AKI) for decades despite having imperfect sensitivity and specificity. Novel tubular injury biomarkers may revolutionize the diagnosis of KI; however, even if a novel tubular injury biomarker is 100% sensitive and 100% specific, it may appear inaccurate when using serum creatinine as the gold standard. Conclusions In general, the apparent diagnostic performance of a biomarker depends not only on its ability to detect injury but also on disease prevalence and the sensitivity and specificity of the imperfect gold standard. Apparent errors in diagnosis using a new biomarker may be a reflection of errors in the imperfect gold standard itself rather than poor performance of the biomarker. Clinical Trials 2013; 10: 696700. http://ctj.sagepub.com.

Imperfect gold standards for kidney injury biomarker evaluation

Waikar, S. S., Betensky, R., Emerson, S. C., & Bonventre, J. V. (n.d.).

Publication year

2012

Journal title

Journal of the American Society of Nephrology

Volume

23

Issue

1

Page(s)

13-21

10.1681/ASN.2010111124

Abstract

Abstract

Clinicians have used serumcreatinine in diagnostic testing for acute kidney injury for decades, despite its imperfect sensitivity and specificity. Novel tubular injury biomarkers may revolutionize the diagnosis of acute kidney injury; however, even if a novel tubular injury biomarker is 100% sensitive and 100% specific, itmay appear inaccurate when using serum creatinine as the gold standard. Acute kidney injury, as defined by serum creatinine, may not reflect tubular injury, and the absence of changes in serum creatinine does not assure the absence of tubular injury. In general, the apparent diagnostic performance of a biomarker depends not only on its ability to detect injury, but also on disease prevalence and the sensitivity and specificity of the imperfect gold standard. Assuming that, at a certain cutoff value, serum creatinine is 80% sensitive and 90% specific and disease prevalence is 10%, a new perfect biomarker with a true 100% sensitivity may seem to have only 47% sensitivity compared with serum creatinine as the gold standard. Minimizing misclassification by using more strict criteria to diagnose acute kidney injury will reduce the error when evaluating the performance of a biomarker under investigation. Apparent diagnostic errors using a new biomarkermay be a reflection of errors in the imperfect gold standard itself, rather than poor performance of the biomarker. The results of this study suggest that small changes in serum creatinine alone should not be used to define acute kidney injury in biomarker or interventional studies.

Improved design of prodromal Alzheimer's disease trials through cohort enrichment and surrogate endpoints

Macklin, E. A., Blacker, D., Hyman, B. T., & Betensky, R. (n.d.).

Publication year

2013

Journal title

Journal of Alzheimer&#39;s Disease

Volume

36

Issue

3

Page(s)

475-486

10.3233/JAD-122212

Abstract

Abstract

Alzheimer's disease (AD) trials initiated during or before the prodrome are costly and lengthy because patients are enrolled long before clinical symptoms are apparent, when disease progression is slow. We hypothesized that design of such trials could be improved by: 1) selecting individuals at moderate near-term risk of progression to AD dementia (the current clinical standard) and 2) by using short-term surrogate endpoints that predict progression to AD dementia. We used a longitudinal cohort of older, initially non-demented, community-dwelling participants (n = 358) to derive selection criteria and surrogate endpoints and tested them in an independent national data set (n = 6,243). To identify a 'mid-risk' subgroup, we applied conditional tree-based survival models to Clinical Dementia Rating (CDR) scale scores and common neuropsychological tests. In the validation cohort, a time-to-AD dementia trial applying these mid-risk selection criteria to a pool of all non-demented individuals could achieve equivalent power with 47% fewer participants than enrolling at random from that pool. We evaluated surrogate endpoints measureable over two years of follow-up based on cross-validated concordance between predictions from Cox models and observed time to AD dementia. The best performing surrogate, rate of change in CDR sum-of-boxes, did not reduce the trial duration required for equivalent power using estimates from the validation cohort, but alternative surrogates with better ability to predict time to AD dementia should be able to do so. The approach tested here might improve efficiency of prodromal AD trials using other potential measures and could be generalized to other diseases with long prodromal phases.

In situ analysis of integrin and growth factor receptor signaling pathways in human glioblastomas suggests overlapping relationships with focal adhesion kinase activation

Riemenschneider, M. J., Mueller, W., Betensky, R., Mohapatra, G., & Louis, D. N. (n.d.).

Publication year

2005

Journal title

American Journal of Pathology

Volume

167

Issue

5

Page(s)

1379-1387

10.1016/S0002-9440(10)61225-4

Abstract

Abstract

Deregulated integrin signaling is common in cancers, including glioblastoma. Integrin binding and growth factor receptor signaling activate focal adhesion kinase (FAK) and subsequently up-regulate extracellular regelated kinases (ERK-1/2), leading to cell-cycle progression and cell migration. Most studies of this pathway have used in vitro systems or tumor lysate-based approaches. We examined these pathways primarily in situ using a panel of 30 glioblastomas and gene expression arrays, immunohistochemistry, and fluorescence in situ hybridization, emphasizing the histological distribution of molecular changes. Within individual tumors, increased expression of FAK, p-FAK, paxillin, ERK-1/2, and p-ERK-1/2 occurred in regions of elevated EGFK and/or PDGFRA expression. Moreover, FAK activation levels correlated with EGFR and PDGFRA expression, and p-FAK and EGFR expression co-localized at the single-cell level. In addition, integrin expression was enriched in EGFR/PDGFRA-overexpressing areas but was more regionally confined than FAK, p-FAK, and paxillin. Integrins β8 and α5β1 were most commonly expressed, often in a perinecrotic or perivascular pattern. Taken together, our data suggest that growth factor receptor overexpression facilitates alterations in the integrin signaling pathway. Thus, FAK may act in gliobiastoma as a downstream target of growth factor signaling, with integrals enhancing the impact of such signaling in the tumor microenvironment.

Increased blood-brain barrier permeability following COVID-19 and its correlation with Alzheimer’s biomarkers

Sun, Z., Boutajangout, A., Masurkar, A., Jiang, L., Thawani, S., Vedvyas, A., Debure, L., Ahmed, W., Betensky, R., Wisniewski, T., & Ge, Y. (n.d.).

Abstract

Abstract

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Influence of unrecognized molecular heterogeneity on randomized clinical trials

Betensky, R., Louis, D. N., & Cairncross, J. G. (n.d.).

Publication year

2002

Journal title

Journal of Clinical Oncology

Volume

20

Issue

10

Page(s)

2495-2499

10.1200/JCO.2002.06.140

Abstract

Abstract

Purpose: In solid tumor oncology, decisions regarding treatment and eligibility for trials are governed by histologic diagnosis. Despite this reliance on histology and the assumption that histology defines the disease, underlying molecular heterogeneity likely differentiates among patients' outcomes. Patients and Methods: To illustrate how unrecognized molecular heterogeneity might obscure a truly effective new therapy for cancer, we analyzed the planning assumptions and results of a hypothetical randomized controlled trial of chemoradiotherapy for a cancer found to be drug sensitive in preliminary phase II studies. Results: Randomized controlled trials of effective cancer therapies can be falsely negative if therapeutic benefit is overestimated during study design because of enrichment of phase II trials for treatment-sensitive subtypes, a beneficial effect in responding patients is diluted by large numbers of nonresponding patients, or a beneficial effect in responders is reversed by a negative effect in nonresponders. Conclusion: Molecular heterogeneity, if it confers different risks to patients and is unaccounted for in the design of a randomized study, can result in a clinical trial that is underpowered and fails to detect a truly effective new therapy for cancer