Publications by authors named "Arati Desai"

29 Publications

  • Page 1 of 1

Association of plasma cell-free DNA with survival in patients with IDH wild-type glioblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab011. Epub 2021 Jan 16.

Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Background: We aimed to determine whether plasma cell-free DNA (cfDNA) concentration is associated with survival in patients with isocitrate dehydrogenase () wild-type glioblastoma (GBM).

Methods: Pre-operative and post-chemoradiotherapy blood samples were prospectively collected from patients with newly diagnosed wild-type GBM. Patients underwent surgical resection or biopsy and received adjuvant radiotherapy with concomitant temozolomide. Cell-free DNA (cfDNA) was isolated from plasma and quantified using SYBR Green-based q polymerase chain reaction (qPCR).

Results: Sixty-two patients were enrolled and categorized into high vs. low cfDNA groups relative to the pre-operative median value (25.2 ng/mL, range 5.7-153.0 ng/mL). High pre-operative cfDNA concentration was associated with inferior PFS (median progression-free survival (PFS), 3.4 vs. 7.7 months; log-rank = .004; hazard ratio [HR], 2.19; 95% CI, 1.26-3.81) and overall survival (OS) (median OS, 8.0 vs. 13.9 months; log-rank = .01; HR, 2.43; 95% CI, 1.19-4.95). After adjusting for risk factors, including O-methylguanine-DNA methyltransferase () promoter methylation status, pre-operative cfDNA remained independently associated with PFS (HR, 2.70; 95% CI, 1.50-4.83; .001) and OS (HR, 2.65; 95% CI, 1.25-5.59; = .01). Post-hoc analysis of change in cfDNA post-chemoradiotherapy compared to pre-surgery ( = 24) showed increasing cfDNA concentration was associated with worse PFS (median, 2.7 vs. 6.0 months; log-rank = .003; HR, 4.92; 95% CI, 1.53-15.84) and OS (median, 3.9 vs. 19.4 months; log-rank < .001; HR, 7.77; 95% CI, 2.17-27.76).

Conclusions: cfDNA concentration is a promising prognostic biomarker for patients with wild-type GBM. Plasma cfDNA can be obtained noninvasively and may enable more accurate estimates of survival and effective clinical trial stratification.
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http://dx.doi.org/10.1093/noajnl/vdab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883768PMC
January 2021

A dual-genotype oligoastrocytoma with histologic, molecular, radiological and time-course features.

Acta Neuropathol Commun 2020 07 20;8(1):115. Epub 2020 Jul 20.

Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.

A case of a true dual-genotype IDH-mutant oligoastrocytoma with two different cell types within a single mass in a young woman is presented. Imaging findings of the left frontal infiltrating glioma predicted the two neoplastic components that were identified upon resection. Tissue examination demonstrated areas of tumor with contrasting histologic and molecular features, including specific IDH1, ATRX, TP53, TERT and CIC mutational profiles, consistent with oligodendroglioma and astrocytoma, respectively. The clinical and radiological course over 17 months from first diagnosis included three surgical resections with slow progression of the astrocytic component, and ultimately chemotherapy and radiation treatments were commenced. Reports of the clinical courses for these rare cases of dual-genotype oligoastrocytomas will inform therapy choices, to optimize benefit while minimizing side effects. The steadily increasing number of cases suggests that the neoplasm might be reconsidered as an official entity by the WHO.
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http://dx.doi.org/10.1186/s40478-020-00998-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372861PMC
July 2020

Immunotherapy and Response Assessment in Malignant Glioma: Neuro-oncology Perspective.

Top Magn Reson Imaging 2020 Apr;29(2):95-102

Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.

Glioblastoma (GBM) is the deadliest form of brain cancer and recurs uniformly. Despite aggressive treatment with maximal safe surgical resection, adjuvant radiation with temozolomide chemotherapy, and alternating electrical field therapy, median survival for newly diagnosed GBM remains <2 years. Novel therapies are desperately needed. Immunotherapy, which has led to significant improvement in patient outcomes across many tumor types, is currently being studied in a large number of GBM clinical trials. One of the biggest challenges in immunotherapy trials in GBM has been accurate response assessment using currently available imaging modalities, including magnetic resonance imaging. In this review, we will discuss the rationale for immunotherapy for GBM, immunotherapeutic modalities currently under clinical evaluation in GBM, and the challenges and recent advances in imaging response assessment in GBM immunotherapy.
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http://dx.doi.org/10.1097/RMR.0000000000000233DOI Listing
April 2020

F-Fluciclovine PET to distinguish treatment-related effects from disease progression in recurrent glioblastoma: PET fusion with MRI guides neurosurgical sampling.

Neurooncol Pract 2020 Mar 8;7(2):152-157. Epub 2019 Dec 8.

Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia.

Differentiation of true tumor progression from treatment-related effects remains a major unmet need in caring for patients with glioblastoma. Here, we report how the intraoperative combination of MRI withF-fluciclovine PET guided surgical sampling in 2 patients with recurrent glioblastoma.F-Fluciclovine PET is FDA approved for use in prostate cancer and carries an orphan drug designation in glioma. To investigate its utility in recurrent glioblastoma, we fused PET and MRI images using 2 different surgical navigation systems and performed targeted stereotactic biopsies from the areas of high ("hot") and low ("cold") radiotracer uptake. Concordant histopathologic and imaging findings suggest that a combinedF-fluciclovine PET-MRI-guided approach can guide neurosurgical resection of viable recurrent glioblastoma in the background of treatment-related effects, which can otherwise look similar on MRI.
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http://dx.doi.org/10.1093/nop/npz068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081387PMC
March 2020

Imaging and histopathologic correlates of plasma cell-free DNA concentration and circulating tumor DNA in adult patients with newly diagnosed glioblastoma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa016. Epub 2020 Feb 27.

Glioblastoma Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Plasma cell-free DNA (cfDNA) concentration is lower in glioblastoma (GBM) compared to other solid tumors, which can lead to low circulating tumor DNA (ctDNA) detection. In this study, we investigated the relationship between multimodality magnetic resonance imaging (MRI) and histopathologic features with plasma cfDNA concentration and ctDNA detection in patients with treatment-naive GBM.

Methods: We analyzed plasma cfDNA concentration, MRI scans, and tumor histopathology from 42 adult patients with newly diagnosed GBM. Linear regression analysis was used to examine the relationship of plasma cfDNA concentration before surgery to imaging and histopathologic characteristics. In a subset of patients, imaging and histopathologic metrics were also compared between patients with and without a detected tumor somatic mutation.

Results: Tumor volume with elevated (>1.5 times contralateral white matter) rate transfer constant (, a surrogate of blood-brain barrier [BBB] permeability) was independently associated with plasma cfDNA concentration ( = .001). Histopathologic characteristics independently associated with plasma cfDNA concentration included CD68+ macrophage density ( = .01) and size of tumor vessels ( = .01). Patients with higher (grade ≥3) perivascular CD68+ macrophage density had lower volume transfer constant (, = .01) compared to those with lower perivascular CD68+ macrophage density. Detection of at least 1 somatic mutation in plasma cfDNA was associated with significantly lower perivascular CD68+ macrophages ( = .01).

Conclusions: Metrics of BBB disruption and quantity and distribution of tumor-associated macrophages are associated with plasma cfDNA concentration and ctDNA detection in GBM patients. These findings represent an important step in understanding the factors that determine plasma cfDNA concentration and ctDNA detection.
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http://dx.doi.org/10.1093/noajnl/vdaa016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045782PMC
February 2020

Histopathology-validated machine learning radiographic biomarker for noninvasive discrimination between true progression and pseudo-progression in glioblastoma.

Cancer 2020 06 4;126(11):2625-2636. Epub 2020 Mar 4.

Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: Imaging of glioblastoma patients after maximal safe resection and chemoradiation commonly demonstrates new enhancements that raise concerns about tumor progression. However, in 30% to 50% of patients, these enhancements primarily represent the effects of treatment, or pseudo-progression (PsP). We hypothesize that quantitative machine learning analysis of clinically acquired multiparametric magnetic resonance imaging (mpMRI) can identify subvisual imaging characteristics to provide robust, noninvasive imaging signatures that can distinguish true progression (TP) from PsP.

Methods: We evaluated independent discovery (n = 40) and replication (n = 23) cohorts of glioblastoma patients who underwent second resection due to progressive radiographic changes suspicious for recurrence. Deep learning and conventional feature extraction methods were used to extract quantitative characteristics from the mpMRI scans. Multivariate analysis of these features revealed radiophenotypic signatures distinguishing among TP, PsP, and mixed response that compared with similar categories blindly defined by board-certified neuropathologists. Additionally, interinstitutional validation was performed on 20 new patients.

Results: Patients who demonstrate TP on neuropathology are significantly different (P < .0001) from those with PsP, showing imaging features reflecting higher angiogenesis, higher cellularity, and lower water concentration. The accuracy of the proposed signature in leave-one-out cross-validation was 87% for predicting PsP (area under the curve [AUC], 0.92) and 84% for predicting TP (AUC, 0.83), whereas in the discovery/replication cohort, the accuracy was 87% for predicting PsP (AUC, 0.84) and 78% for TP (AUC, 0.80). The accuracy in the interinstitutional cohort was 75% (AUC, 0.80).

Conclusion: Quantitative mpMRI analysis via machine learning reveals distinctive noninvasive signatures of TP versus PsP after treatment of glioblastoma. Integration of the proposed method into clinical studies can be performed using the freely available Cancer Imaging Phenomics Toolkit.
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http://dx.doi.org/10.1002/cncr.32790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893811PMC
June 2020

Clinical activity of the tyrosine kinase inhibitor osimertinib in -mutant glioblastoma.

CNS Oncol 2019 11 15;8(3):CNS43. Epub 2019 Nov 15.

Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. The gene is among the most commonly deranged genes in GBM and thus an important therapeutic target. We report the case of a young female with heavily pretreated -mutated GBM, for whom we initiated osimertinib, an oral, third-generation tyrosine kinase inhibitor that irreversibly inhibits EGFR and has significant brain penetration. We then review some of the main challenges in targeting EGFR, including lack of central nervous system penetration with most tyrosine kinase inhibitors, molecular heterogeneity of GBM and the need for enhanced specificity for the mutations relevant in GBM.
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http://dx.doi.org/10.2217/cns-2019-0014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880297PMC
November 2019

Clinical Utility of Plasma Cell-Free DNA in Adult Patients with Newly Diagnosed Glioblastoma: A Pilot Prospective Study.

Clin Cancer Res 2020 01 30;26(2):397-407. Epub 2019 Oct 30.

Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Purpose: The clinical utility of plasma cell-free DNA (cfDNA) has not been assessed prospectively in patients with glioblastoma (GBM). We aimed to determine the prognostic impact of plasma cfDNA in GBM, as well as its role as a surrogate of tumor burden and substrate for next-generation sequencing (NGS).

Experimental Design: We conducted a prospective cohort study of 42 patients with newly diagnosed GBM. Plasma cfDNA was quantified at baseline prior to initial tumor resection and longitudinally during chemoradiotherapy. Plasma cfDNA was assessed for its association with progression-free survival (PFS) and overall survival (OS), correlated with radiographic tumor burden, and subjected to a targeted NGS panel.

Results: Prior to initial surgery, GBM patients had higher plasma cfDNA concentration than age-matched healthy controls (mean 13.4 vs. 6.7 ng/mL, < 0.001). Plasma cfDNA concentration was correlated with radiographic tumor burden on patients' first post-radiation magnetic resonance imaging scan (ρ = 0.77, = 0.003) and tended to rise prior to or concurrently with radiographic tumor progression. Preoperative plasma cfDNA concentration above the mean (>13.4 ng/mL) was associated with inferior PFS (median 4.9 vs. 9.5 months, = 0.038). Detection of ≥1 somatic mutation in plasma cfDNA occurred in 55% of patients and was associated with nonstatistically significant decreases in PFS (median 6.0 vs. 8.7 months, = 0.093) and OS (median 5.5 vs. 9.2 months, = 0.053).

Conclusions: Plasma cfDNA may be an effective prognostic tool and surrogate of tumor burden in newly diagnosed GBM. Detection of somatic alterations in plasma is feasible when samples are obtained prior to initial surgical resection.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980766PMC
January 2020

Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma.

J Neurooncol 2019 Nov 21;145(2):321-328. Epub 2019 Sep 21.

Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania, 10th Floor, South Pavilion, 3400 Civic Center Blvd, Philadelphia, PA, 19104, USA.

Purpose: Young adults with isocitrate-dehydrogenase wild-type (IDH-WT) glioblastoma (GBM) represent a rare, understudied population compared to pediatric high-grade glioma, IDH-mutant GBM, or IDH-WT GBM in older patients. We aimed to explore the prognostic impact of epidermal growth factor receptor copy number gain (EGFR CN gain), one of the most common genetic alterations in IDH-WT glioma, in young adults with IDH-WT GBM.

Methods: We performed a retrospective cohort study of patients 18-45 years old with newly diagnosed, IDH-WT GBM whose tumors underwent next-generation sequencing at our institution between 2014 and 2018. The impact of EGFR CN gain on time to tumor progression (TTP) and overall survival (OS) was assessed. A validation cohort of patients 18-45 years old with IDH-WT GBM was analyzed from The Cancer Genome Atlas (TCGA).

Results: Ten of 28 patients (36%) from our institution had EGFR CN gain, which was associated with shorter TTP (median 6.5 vs. 11.9 months; p = 0.06) and OS (median 16.3 vs. 23.5 months; p = 0.047). The negative prognostic impact of EGFR CN gain on OS persisted in a multivariate model (HR 6.40, 95% CI 1.3-31.0, p = 0.02). In the TCGA cohort (N = 43), EGFR CN gain was associated with shorter TTP and worse OS, although these did not reach statistical significance (TTP, median 11.5 vs. 14.4 months, p = 0.18; OS, median 23.6 vs. 27.8 months; p = 0.18).

Conclusions: EGFR CN gain may be associated with inferior outcomes in young adults with newly diagnosed, IDH-WT GBM, suggesting a potential role for targeting EGFR in this population.
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http://dx.doi.org/10.1007/s11060-019-03298-6DOI Listing
November 2019

Arterial Spin Labeling and Dynamic Susceptibility Contrast-enhanced MR Imaging for evaluation of arteriovenous shunting and tumor hypoxia in glioblastoma.

Sci Rep 2019 06 19;9(1):8747. Epub 2019 Jun 19.

Department of Radiology, Hospital of University of Pennsylvania, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. Significant challenges in the care of patients with GBM include marked vascular heterogeneity and arteriovenous (AV) shunting, which results in tumor hypoxia and inadequate delivery of systemic treatments to reach tumor cells. In this study, we investigated the utility of different MR perfusion techniques to detect and quantify arteriovenous (AV) shunting and tumor hypoxia in patients with GBM. Macrovascular shunting was present in 33% of subjects, with the degree of shunting ranging from (37-60%) using arterial spin labeling perfusion. Among the dynamic susceptibility contrast-enhanced perfusion curve features, there were a strong negative correlation between hypoxia score, DSC perfusion curve recovery slope (r = -0.72, P = 0.018) and angle (r = -0.73, P = 0.015). The results of this study support the possibility of using arterial spin labeling and pattern analysis of dynamic susceptibility contrast-enhanced MR Imaging for evaluation of arteriovenous shunting and tumor hypoxia in glioblastoma.
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http://dx.doi.org/10.1038/s41598-019-45312-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584644PMC
June 2019

Molecular Neuropathology in Practice: Clinical Profiling and Integrative Analysis of Molecular Alterations in Glioblastoma.

Acad Pathol 2019 Jan-Dec;6:2374289519848353. Epub 2019 May 27.

Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Molecular profiling of glioblastoma has revealed complex cytogenetic, epigenetic, and molecular abnormalities that are necessary for diagnosis, prognosis, and treatment. Our neuro-oncology group has developed a data-driven, institutional consensus guideline for efficient and optimal workup of glioblastomas based on our routine performance of molecular testing. We describe our institution's testing algorithm, assay development, and genetic findings in glioblastoma, to illustrate current practices and challenges in neuropathology related to molecular and genetic testing. We have found that coordination of test requisition, tissue handling, and incorporation of results into the final pathologic diagnosis by the neuropathologist improve patient care. Here, we present analysis of promoter methylation and next-generation sequencing results of 189 patients, obtained utilizing our internal processes led by the neuropathology team. Our institutional pathway for neuropathologist-driven molecular testing has streamlined the management of glioblastoma samples for efficient return of results for incorporation of genomic data into the pathological diagnosis and optimal patient care.
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http://dx.doi.org/10.1177/2374289519848353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537274PMC
May 2019

Three-dimensional echo planar spectroscopic imaging for differentiation of true progression from pseudoprogression in patients with glioblastoma.

NMR Biomed 2019 02 17;32(2):e4042. Epub 2018 Dec 17.

Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Accurate differentiation of true progression (TP) from pseudoprogression (PsP) in patients with glioblastomas (GBMs) is essential for planning adequate treatment and for estimating clinical outcome measures and future prognosis. The purpose of this study was to investigate the utility of three-dimensional echo planar spectroscopic imaging (3D-EPSI) in distinguishing TP from PsP in GBM patients. For this institutional review board approved and HIPAA compliant retrospective study, 27 patients with GBM demonstrating enhancing lesions within six months of completion of concurrent chemo-radiation therapy were included. Of these, 18 were subsequently classified as TP and 9 as PsP based on histological features or follow-up MRI studies. Parametric maps of choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) were computed and co-registered with post-contrast T -weighted and FLAIR images. All lesions were segmented into contrast enhancing (CER), immediate peritumoral (IPR), and distal peritumoral (DPR) regions. For each region, Cho/Cr and Cho/NAA ratios were normalized to corresponding metabolite ratios from contralateral normal parenchyma and compared between TP and PsP groups. Logistic regression analyses were performed to obtain the best model to distinguish TP from PsP. Significantly higher Cho/NAA was observed from CER (2.69 ± 1.00 versus 1.56 ± 0.51, p = 0.003), IPR (2.31 ± 0.92 versus 1.53 ± 0.56, p = 0.030), and DPR (1.80 ± 0.68 versus 1.19 ± 0.28, p = 0.035) regions in TP patients compared with those with PsP. Additionally, significantly elevated Cho/Cr (1.74 ± 0.44 versus 1.34 ± 0.26, p = 0.023) from CER was observed in TP compared with PsP. When these parameters were incorporated in multivariate regression analyses, a discriminatory model with a sensitivity of 94% and a specificity of 87% was observed in distinguishing TP from PsP. These results indicate the utility of 3D-EPSI in differentiating TP from PsP with high sensitivity and specificity.
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http://dx.doi.org/10.1002/nbm.4042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519064PMC
February 2019

Multiparametric magnetic resonance imaging in the assessment of anti-EGFRvIII chimeric antigen receptor T cell therapy in patients with recurrent glioblastoma.

Br J Cancer 2019 01 27;120(1):54-56. Epub 2018 Nov 27.

Department of Radiology, Division of Neuroradiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

EGFRvIII targeted chimeric antigen receptor T (CAR-T) cell therapy has recently been reported for treating glioblastomas (GBMs); however, physiology-based MRI parameters have not been evaluated in this setting. Ten patients underwent multiparametric MRI at baseline, 1, 2 and 3 months after CAR-T therapy. Logistic regression model derived progression probabilities (PP) using imaging parameters were used to assess treatment response. Four lesions from "early surgery" group demonstrated high PP at baseline suggestive of progression, which was confirmed histologically. Out of eight lesions from remaining six patients, three lesions with low PP at baseline remained stable. Two lesions with high PP at baseline were associated with large decreases in PP reflecting treatment response, whereas other two lesions with high PP at baseline continued to demonstrate progression. One patient didn't have baseline data but demonstrated progression on follow-up. Our findings indicate that multiparametric MRI may be helpful in monitoring CAR-T related early therapeutic changes in GBM patients.
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http://dx.doi.org/10.1038/s41416-018-0342-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325110PMC
January 2019

Histopathologic quantification of viable tumor versus treatment effect in surgically resected recurrent glioblastoma.

J Neurooncol 2019 Jan 16;141(2):421-429. Epub 2018 Nov 16.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Purpose: The prognostic impact of the histopathologic features of recurrent glioblastoma surgical specimens is unknown. We sought to determine whether key histopathologic characteristics in glioblastoma tumors resected after chemoradiotherapy are associated with overall survival (OS).

Methods: The following characteristics were quantified in recurrent glioblastoma specimens at our institution: extent of viable tumor (accounting for % of specimen comprised of tumor and tumor cellularity), mitoses per 10 high-power fields (0, 1-10, > 10), Ki-67 proliferative index (0-100%), hyalinization (0-6; none to extensive), rarefaction (0-6), hemosiderin (0-6), and % of specimen comprised of geographic necrosis (0-100%; converted to 0-6 scale). Variables associated with OS in univariate analysis, as well as age, eastern cooperative oncology group performance status (ECOG PS), extent of repeat resection, time from initial diagnosis to repeat surgery, and O-methylguanine-DNA methyltransferase promoter methylation, were included in a multivariable Cox proportional hazards model.

Results: 37 specimens were assessed. In a multivariate model, high Ki-67 proliferative index was the only histopathologic characteristic associated with worse OS following repeat surgery for glioblastoma (hazard ratio (HR) 1.3, 95% CI 1.1-1.5, p = 0.003). Shorter time interval from initial diagnosis to repeat surgery (HR 1.11, 95% CI 1.02-1.21, p = 0.016) and ECOG PS ≥ 2 (HR 4.19, 95% CI 1.72-10.21, p = 0.002) were also independently associated with inferior OS.

Conclusion: In patients with glioblastoma undergoing repeat resection following chemoradiotherapy, high Ki-67 index in the recurrent specimen, short time to recurrence, and poor PS are independently associated with worse OS. Histopathologic quantification of viable tumor versus therapy-related changes has limited prognostic influence.
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http://dx.doi.org/10.1007/s11060-018-03050-6DOI Listing
January 2019

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma.

J Neurooncol 2019 Jan 23;141(1):95-102. Epub 2018 Oct 23.

Division of Hematology/Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

Introduction: We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM).

Methods: GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG).

Results: 109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p = 0.003), CD137 (p = 0.042), VEGF-A (p < 0.001), CTLA4 (p = 0.028), CD40 (p = 0.023), GITR (p = 0.020), IL6 (p = 0.02), and OX40 (p < 0.001). In CGCG (n = 52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant.

Conclusions: Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.
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http://dx.doi.org/10.1007/s11060-018-03010-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342649PMC
January 2019

CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges.

Neuro Oncol 2018 10;20(11):1429-1438

Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

In patients with certain hematologic malignancies, the use of autologous T cells genetically modified to express chimeric antigen receptors (CARs) has led to unprecedented clinical responses. Although progress in solid tumors has been elusive, recent clinical studies have demonstrated the feasibility and safety of CAR T-cell therapy for glioblastoma. In addition, despite formidable barriers to T-cell localization and effector function in glioblastoma, signs of efficacy have been observed in select patients. In this review, we begin with a discussion of established obstacles to systemic therapy in glioblastoma and how these may be overcome by CAR T cells. We continue with a summary of previously published CAR T-cell trials in GBM, and end by outlining the key therapeutic challenges associated with the use of CAR T cells in this disease.
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http://dx.doi.org/10.1093/neuonc/noy032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176794PMC
October 2018

A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma.

Sci Transl Med 2017 07;9(399)

Cellular Immunotherapy Program, Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA 02129, USA.

We conducted a first-in-human study of intravenous delivery of a single dose of autologous T cells redirected to the epidermal growth factor receptor variant III (EGFRvIII) mutation by a chimeric antigen receptor (CAR). We report our findings on the first 10 recurrent glioblastoma (GBM) patients treated. We found that manufacturing and infusion of CAR-modified T cell (CART)-EGFRvIII cells are feasible and safe, without evidence of off-tumor toxicity or cytokine release syndrome. One patient has had residual stable disease for over 18 months of follow-up. All patients demonstrated detectable transient expansion of CART-EGFRvIII cells in peripheral blood. Seven patients had post-CART-EGFRvIII surgical intervention, which allowed for tissue-specific analysis of CART-EGFRvIII trafficking to the tumor, phenotyping of tumor-infiltrating T cells and the tumor microenvironment in situ, and analysis of post-therapy EGFRvIII target antigen expression. Imaging findings after CART immunotherapy were complex to interpret, further reinforcing the need for pathologic sampling in infused patients. We found trafficking of CART-EGFRvIII cells to regions of active GBM, with antigen decrease in five of these seven patients. In situ evaluation of the tumor environment demonstrated increased and robust expression of inhibitory molecules and infiltration by regulatory T cells after CART-EGFRvIII infusion, compared to pre-CART-EGFRvIII infusion tumor specimens. Our initial experience with CAR T cells in recurrent GBM suggests that although intravenous infusion results in on-target activity in the brain, overcoming the adaptive changes in the local tumor microenvironment and addressing the antigen heterogeneity may improve the efficacy of EGFRvIII-directed strategies in GBM.
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http://dx.doi.org/10.1126/scitranslmed.aaa0984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762203PMC
July 2017

19-Year-Old Male with Headaches and a Possible Seizure.

Brain Pathol 2017 07;27(4):557-558

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1111/bpa.12529DOI Listing
July 2017

Timed sequential therapy of the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas.

Neuro Oncol 2017 06;19(6):845-852

University of Virginia Medical Center, Charlottesville, Virginia, USA.

Background: Mibefradil (MIB), previously approved for treatment of hypertension, is a selective T-type calcium channel blocker with preclinical activity in high-grade gliomas (HGGs). To exploit its presumed mechanism of impacting cell cycle activity (G1 arrest), we designed a phase I study to determine safety and the maximum tolerated dose (MTD) of MIB when given sequentially with temozolomide (TMZ) in recurrent (r)HGG.

Methods: Adult patients with rHGG ≥3 months from TMZ for initial therapy received MIB in 4 daily doses (q.i.d.) for 7 days followed by standard TMZ at 150-200 mg/m2 for 5 days per 28-day cycle. MIB dose escalation followed a modified 3 + 3 design, with an extension cohort of 10 patients at MTD who underwent 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET imaging, to image proliferation before and after 7 days of MIB.

Results: Twenty-seven patients were enrolled (20 World Health Organization grade IV, 7 grade III; median age 50 y; median KPS 90). The MTD of MIB was 87.5 mg p.o. q.i.d. Dose-limiting toxicities were elevation of alanine aminotransferase/aspartate aminotransferase (grade 3) and sinus bradycardia. The steady-state maximum plasma concentration of MIB at the MTD was 1693 ± 287 ng/mL (mean ± SD). 18F-FLT PET imaging showed a significant decline in standardized uptake value (SUV) signal in 2 of 10 patients after 7 days of treatment with MIB.

Conclusions: MIB followed by TMZ was well tolerated in rHGG patients at the MTD. The lack of toxicity and presence of some responses in this selected patient population suggest that this regimen warrants further investigation.
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http://dx.doi.org/10.1093/neuonc/nox020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464434PMC
June 2017

Repeatability of F-FLT PET in a Multicenter Study of Patients with High-Grade Glioma.

J Nucl Med 2017 Mar 29;58(3):393-398. Epub 2016 Sep 29.

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Quantitative 3'-deoxy-3'-F-fluorothymidine (F-FLT) PET has potential as a noninvasive tumor biomarker for the objective assessment of response to treatment. To guide interpretation of these quantitative data, we evaluated the repeatability of F-FLT PET as part of a multicenter trial involving patients with high-grade glioma. F-FLT PET was performed on 10 patients with recurrent high-grade glioma at 5 different institutions within the Adult Brain Tumor Consortium trial ABTC1101. Data were acquired according to a double baseline protocol in which PET examinations were repeated within 2 d of each other with no intervening treatment. On each of the 2 imaging days, dedicated brain PET was performed at 2 time points, 1 and 3 h after F-FLT administration. Tumor SUVs and related parameters were measured at a central laboratory using various volumes of interest: isocontour at 30% of the maximum pixel (SUV), gradient-based segmentation (SUV), the maximum pixel (SUV), and a 1-mL sphere at the region of highest uptake (SUV). Repeatability coefficients (RCs) were calculated from the relative differences between corresponding SUV measurements obtained on the 2 d. RCs for tumor SUVs were 22.5% (SUV), 23.8% (SUV), 23.2% (SUV), and 18.5% (SUV) at 1 h after injection. Corresponding data at 3 h were 22.4%, 25.0%, 27.3%, and 23.6%. Normalizing the tumor SUV data with reference to a background region improved repeatability, and the most stable parameter was the tumor-to-background ratio derived using SUV (RC, 16.5%). SUV quantification of F-FLT uptake in glioma had an RC in the range of 18%-24% when imaging began 1 h after F-FLT administration. The volume-of-interest methodology had a small but not negligible influence on repeatability, with the best performance obtained using SUV Although changes in F-FLT SUV after treatment cannot be directly interpreted as a change in tumor proliferation, we have established ranges beyond which SUV differences are likely due to legitimate biologic effects.
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http://dx.doi.org/10.2967/jnumed.116.178434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331936PMC
March 2017

Initial evidence that blood-borne microvesicles are biomarkers for recurrence and survival in newly diagnosed glioblastoma patients.

J Neurooncol 2016 Apr 8;127(2):391-400. Epub 2016 Jan 8.

Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

The purpose of this pilot study was to determine whether blood-borne microvesicles from newly diagnosed glioblastoma patients could be used as biomarkers. We collected 2.8 mL blood from 16 post-operative patients at the time that they were being simulated for chemoradiation therapy (radiation with concurrent temozolomide). Two additional samples were collected during chemoradiation therapy and a final sample was collected at the end of chemoradiation therapy. Patients continued with the therapy suggested by their physicians, based on tumor conference consensus and were followed for recurrence and overall survival. Microvesicles were isolated using serial centrifugation and stained for surface markers (Annexin V for phosphotidyl serine, CD41 for platelets, anti-EGFR for tumor cells, and CD235 for red blood cells). Flow cytometry analysis was performed. Our findings provide initial evidence that increases in Annexin V positive microvesicle levels during chemoradiation therapy are associated with earlier recurrence and shorter overall survival in newly diagnosed glioblastoma patients. The effect is dramatic, with over a four-fold increase in the hazard ratio for an individual at the 75th versus the 25th percentile. Moreover the pattern of Annexin V positive microvesicles remain significant after adjustment for confounding clinical variables that have previously been shown to be prognostic for recurrence and survival. Inclusion of neutrophil levels at the start of chemoradiation therapy in the model yielded the largest attenuation of the observed association. Further studies will be needed to verify and further investigate the association between these two entities.
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http://dx.doi.org/10.1007/s11060-015-2051-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783260PMC
April 2016

Head and neck cancer with metastatic spread to the breast.

Am J Med 2015 May 30;128(5):e3. Epub 2014 Dec 30.

Department of Medical Oncology, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1016/j.amjmed.2014.12.003DOI Listing
May 2015

Microvesicles as a Biomarker for Tumor Progression versus Treatment Effect in Radiation/Temozolomide-Treated Glioblastoma Patients.

Transl Oncol 2014 Dec;7(6):752-8

Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Unlabelled: The standard of care for glioblastoma (GB) is surgery followed by concurrent radiation therapy (RT) and temozolomide (TMZ) and then adjuvant TMZ. This regime is associated with increased survival but also increased occurrence of equivocal imaging findings, e.g., tumor progression (TP) versus treatment effect (TE), which is also referred to as pseudoprogression (PsP). Equivocal findings make decisions regarding further treatment difficult and often delayed. Because none of the current imaging assays have proven sensitive and specific for differentiation of TP versus TE/PsP, we investigated whether blood-derived microvesicles (MVs) would be a relevant assay.

Methods: 2.8 ml of citrated blood was collected from patients with GB at the time of their RT simulation, at the end of chemoradiation therapy (CRT), and multiple times following treatment. MVs were collected following multiple centrifugations (300g, 2500g, and 15,000g). The pellet from the final spin was analyzed using flow cytometry. A diameter of approximately 300 nm or greater and Pacific Blue-labeled Annexin V positivity were used to identify the MVs reported herein.

Results: We analyzed 19 blood samples from 11 patients with GB. MV counts in the patients with stable disease or TE/PsP were significantly lower than patients who developed TP (P = .014).

Conclusion: These preliminary data suggest that blood analysis for MVs from GB patients receiving CRT may be useful to distinguish TE/PsP from TP. MVs may add clarity to standard imaging for decision making in patients with equivocal imaging findings.
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http://dx.doi.org/10.1016/j.tranon.2014.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311040PMC
December 2014

A Single-institution Comparison of Cetuximab, Carboplatin, and Paclitaxel Induction Chemotherapy Followed by Chemoradiation (CRT) Versus CRT for Locally Advanced Squamous Cell Carcinoma of the Head and Neck (LA-SCCHN).

Am J Clin Oncol 2016 10;39(5):522-7

Departments of *Radiation Oncology †Biostatistics and Epidemiology ‡Internal Medicine §Otorhinolaryngology, University of Pennsylvania, Philadelphia, PA.

Objectives: Comparisons of induction chemotherapy (IC) against upfront chemoradiation (CRT) for locally advanced head and neck cancer (LA-HNSCC) have demonstrated no differences except greater toxicity with IC. Effective induction regimens that are less toxic are therefore warranted. To inform future efforts with IC, we present our institutional experience comparing a less toxic IC regimen to CRT.

Methods: We included patients with LA-HNSCC treated with organ-preservation CRT (+/-induction) between 2008 and 2011. Patients were of age above 18 years, ECOG performance status 0-1, and had minimum 6 months follow-up. IC consisted of 8 weekly cycles of cetuximab, carboplatin, and paclitaxel followed by CRT. The CRT regimen was platinum based, with cetuximab reserved for patients contraindicated to receive platinum.

Results: Of 118 patients, 24 (20%) received IC and 94 (80%) received CRT. Median follow-up was 17 (IC) and 19 (CRT) months (P=0.05). There were no differences in toxicity between the groups. IC patients were more likely male, with more advanced tumor and nodal stage. Even when controlling for these factors, IC was still associated with worse locoregional control (HR=3.6, P=0.02), distant metastasis-free survival (HR=5.3, P=0.02), and overall survival (HR=5.1, P<0.01).

Conclusions: IC patients had greater disease burden than those receiving CRT. IC was well tolerated, but with significant rates of locoregional and systemic failures. Given the retrospective nature of the study, our findings are not meant to be definitive or conclusive, but rather suggestive in directing future efforts with IC. For now, we favor CRT as the standard option for treatment of inoperable LA-HNSCC.
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http://dx.doi.org/10.1097/COC.0000000000000085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959961PMC
October 2016

Induction chemotherapy with cetuximab, carboplatin and paclitaxel for the treatment of locally advanced squamous cell carcinoma of the head and neck.

Exp Ther Med 2013 Apr 5;5(4):1247-1253. Epub 2013 Feb 5.

Division of Hematology and Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;

Although controversy exists in the management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN), clinicians often use induction chemotherapy for treatment of the most advanced cases. One promising regimen combines weekly cetuximab (400 mg/m loading dose followed by 250 mg/m) with carboplatin (AUC of 2) and paclitaxel (90 mg/m). We retrospectively evaluated patients treated with this regimen prior to definitive chemoradiation or surgery between May 2008 and December 2011. The primary endpoint used for this retrospective analysis was feasibility. Thirty consecutive, unselected patients were included. Median follow-up was 13.7 months (range, 5.0-38.7 months). All but one patient had stage IV SCCHN. Dose intensity was high for carboplatin (92%), paclitaxel (93%) and cetuximab (85%). Grade 3-4 toxicities occurred in <7% of the study population and were limited to rash, neutropenia and infusion reactions. Response rate (RR) to induction chemotherapy was 97% (30% complete response, 67% partial response). All patients completed subsequent chemoradiotherapy or surgery. Nineteen patients (63%) demonstrated a complete response and 11 patients (37%) demonstrated a partial response. Median overall survival and progression-free survival data are not yet mature. The RR to therapy in our off-protocol experience is at least comparable to that observed in the two phase II studies of this regimen and appears superior to that observed with docetaxel, cisplatin and fluorouracil (TPF).
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http://dx.doi.org/10.3892/etm.2013.948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628719PMC
April 2013

Transoral robotic surgery alone for oropharyngeal cancer: an analysis of local control.

Arch Otolaryngol Head Neck Surg 2012 Jul;138(7):628-34

Department of Otorhinolaryngology–Head and Neck Surgery, University of Pennsylvania Medical Center, Philadelphia, USA.

Objective: To evaluate local control following transoral robotic surgery (TORS) with the da Vinci Surgical System (Intuitive Surgical Inc) as a single treatment modality for oropharyngeal squamous cell carcinoma (OSCC).

Design: Prospective, single-center, observational study.

Setting: Academic university health system and tertiary referral center.

Patients: Thirty adults with previously untreated OSCC.

Intervention: Transoral robotic surgery with staged neck dissection as indicated.

Main Outcome Measures: Local control and margin status.

Results: Thirty patients were enrolled with previously untreated OSCC and no prior head and neck radiation therapy. Follow-up duration was at least 18 months. At the time of diagnosis, 9 tumors were T1 (30%); 16 were T2 (53%); 4 were T3 (13%); and 1 was T4a (3%). The anatomic sites of these primary tumors were tonsil in 14 (47%), tongue base in 9 (30%), glossotonsillar sulcus in 3 (10%), soft palate in 3 (10%), and oropharyngeal wall in 1 (3%). There was only 1 patient (3%) who had a positive margin after primary resection; further resection achieved a final negative margin. Perineural invasion was noted in 3 tumors (10%). No patient received postoperative adjuvant therapy. At a mean follow-up of 2.7 years (range, 1.5-5.1 years), there was 1 patient with local failure (3%).

Conclusion: As the only modality used for treatment of pathologically low-risk OSCCs, TORS provides high local control and is associated with low surgical morbidity.
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http://dx.doi.org/10.1001/archoto.2012.1166DOI Listing
July 2012

Tissue concentration of systemically administered antineoplastic agents in human brain tumors.

J Neurooncol 2011 Sep 12;104(3):629-38. Epub 2011 Mar 12.

University of Manitoba, 675 McDermot Avenue, Winnipeg, MB, R3E 0V9, Canada.

The blood-brain-barrier (BBB) limits the penetration of many systemic antineoplastic therapies. Consequently, many agents may be used in clinical studies and clinical practice though they may not achieve therapeutic levels within the tumor. We sought to compile the currently available human data on antineoplastic drug concentrations in brain and tumor tissue according to BBB status. A review of the literature was conducted for human studies providing concentrations of antineoplastic agents in blood and metastatic brain tumors or high-grade gliomas. Studies were considered optimal if they reported simultaneous tissue and blood concentration, multiple sampling times and locations, MRI localization, BBB status at sampling site, tumor histology, and individual subject data. Twenty-Four studies of 19 compounds were included. These examined 18 agents in contrast-enhancing regions of high-grade gliomas, with optimal data for 2. For metastatic brain tumors, adequate data was found for 9 agents. Considerable heterogeneity was found in the measurement value, tumor type, measurement timing, and sampling location within and among studies, limiting the applicability of the results. Tissue to blood ratios ranged from 0.054 for carboplatin to 34 for mitoxantrone in high-grade gliomas, and were lowest for temozolomide (0.118) and etoposide (0.116), and highest for mitoxantrone (32.02) in metastatic tumors. The available data examining the concentration of antineoplastic agents in brain and tumor tissue is sparse and limited by considerable heterogeneity. More studies with careful quantification of antineoplastic agents in brain and tumor tissue is required for the rational development of therapeutic regimens.
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http://dx.doi.org/10.1007/s11060-011-0564-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020433PMC
September 2011

Obesity, mammography use and accuracy, and advanced breast cancer risk.

J Natl Cancer Inst 2008 Dec 25;100(23):1724-33. Epub 2008 Nov 25.

Department of Epidemiology and Biostatistics, General Internal Medicine Section, San Francisco Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA 94121, USA.

Background: Being overweight or obese is associated with increased breast cancer risk and disease severity among postmenopausal women, but whether extent of mammography use and accuracy modify this association and further contribute to increases in disease severity at diagnosis among overweight and obese women is unclear.

Methods: We prospectively collected data during 1996-2005 on 287,115 postmenopausal women not using hormone therapy (HT) who underwent 614,562 mammography examinations; 4,446 women were diagnosed with breast cancer within 12 months of a mammography examination. We calculated rates per 1,000 mammography examinations of large (>15 mm), advanced-stage (IIb, III, or IV), high-grade (3 or 4), estrogen receptor (ER)-positive and -negative, and screen-detected and non-screen-detected breast cancer across body mass index (BMI, kg/m(2)) groups defined as normal (18.5-24.9), overweight (25.0-29.9), obese class I (30.0-34.9), and obese class II/III (> or =35.0), adjusting for age, race/ethnicity, and mammography registry and use. All statistical tests were two-sided.

Results: Adjusted rates per 1000 mammography examinations of overall breast cancer increased across BMI groups (6.6 normal, 7.4 overweight, 7.9 obese I, 8.5 obese II/III; P(trend) < .001), as did rates of advanced disease, including large invasive (2.3 normal, 2.6 overweight, 2.9 obese I, 3.2 obese II/III; P(trend) < .001), advanced-stage (0.8 normal, 0.9 overweight, 1.3 obese I, 1.5 obese II/III; P(trend) < .001), and high nuclear grade (1.5 normal, 1.7 overweight, 1.7 obese I, 1.9 obese II/III; P(trend) = .10) tumors. Rates of ER-positive tumors increased across BMI groups (P(trend) < .001); rates of ER-negative tumors did not. Rates of screen-detected cancers were higher among overweight and obese women than normal and underweight women, but rates of non-screen-detected (false-negative) cancers were similar. Rates of advanced breast cancer increased across BMI groups regardless of extent of mammography use.

Conclusions: Patterns of mammography use and mammography accuracy are not the primary reasons for higher rates of advanced breast cancer among overweight and obese postmenopausal women not using HT; thus, biologic differences in breast tumor development and/or progression may be important.
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http://dx.doi.org/10.1093/jnci/djn388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734114PMC
December 2008

Association between anaemia and N-terminal pro-B-type natriuretic peptide (NT-proBNP): findings from the Heart and Soul Study.

Eur J Heart Fail 2007 Sep 12;9(9):886-91. Epub 2007 Jul 12.

Department of Medicine, Johns Hopkins University, United States.

Background: Anaemia is associated with elevated levels of natriuretic peptides. Whether the association of anaemia with natriuretic peptides is independent of other cardiovascular risk factors is unclear.

Methods: This was a cross-sectional study of 809 ambulatory patients with coronary heart disease (CHD) and no history of heart failure (HF). We evaluated the extent to which the relationship between haemoglobin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) was explained by differences in cardiovascular risk factors, inflammation, and kidney dysfunction.

Results: Of the 809 participants, 189 (23%) had anaemia (haemoglobin <13 g/dL). Haemoglobin (as a continuous variable) was inversely associated with log NT-proBNP (beta coefficient -.28, p<.0001). This association was considerably attenuated after accounting for cardiovascular risk factors, C-reactive protein, and kidney dysfunction. However, haemoglobin remained independently associated with log NT-proBNP even after adjustment for these variables (beta coefficient -.11, p=0.0003). Each 1 g/dL decrease in haemoglobin was associated with a 20% greater odds of having NT-proBNP in the highest quartile.

Conclusions: The relationship between anaemia and NT-proBNP is largely explained by differences in cardiovascular risk factors, ventricular function, myocardial ischaemia, inflammation, and kidney function. Nonetheless, haemoglobin appears to be inversely associated with NT-proBNP even after adjustment for these risk factors.
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http://dx.doi.org/10.1016/j.ejheart.2007.06.005DOI Listing
September 2007