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ABSTRACT: Large-scale integrated cancer genome characterization efforts including the cancer genome atlas and the cancer cell line encyclopedia have created unprecedented opportunities to study cancer biology in the context of knowing the entire catalog of genetic alterations. A clinically important challenge is to discover cancer subtypes and their molecular drivers in a comprehensive genetic context. Curtis et al. [Nature (2012) 486(7403):346-352] has recently shown that integrative clustering of copy number and gene expression in 2,000 breast tumors reveals novel subgroups beyond the classic expression subtypes that show distinct clinical outcomes. To extend the scope of integrative analysis for the inclusion of somatic mutation data by massively parallel sequencing, we propose a framework for joint modeling of discrete and continuous variables that arise from integrated genomic, epigenomic, and transcriptomic profiling. The core idea is motivated by the hypothesis that diverse molecular phenotypes can be predicted by a set of orthogonal latent variables that represent distinct molecular drivers, and thus can reveal tumor subgroups of biological and clinical importance. Using the cancer cell line encyclopedia dataset, we demonstrate our method can accurately group cell lines by their cell-of-origin for several cancer types, and precisely pinpoint their known and potential cancer driver genes. Our integrative analysis also demonstrates the power for revealing subgroups that are not lineage-dependent, but consist of different cancer types driven by a common genetic alteration. Application of the cancer genome atlas colorectal cancer data reveals distinct integrated tumor subtypes, suggesting different genetic pathways in colon cancer progression.
Proceedings of the National Academy of Sciences 02/2013; · 9.68 Impact Factor
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ABSTRACT: In constructing predictive models, investigators frequently assess the incremental value of a predictive marker by comparing the ROC curve generated from the predictive model including the new marker with the ROC curve from the model excluding the new marker. Many commentators have noticed empirically that a test of the two ROC areas often produces a non-significant result when a corresponding Wald test from the underlying regression model is significant. A recent article showed using simulations that the widely used ROC area test produces exceptionally conservative test size and extremely low power. In this article, we demonstrate that both the test statistic and its estimated variance are seriously biased when predictions from nested regression models are used as data inputs for the test, and we examine in detail the reasons for these problems. Although it is possible to create a test reference distribution by resampling that removes these biases, Wald or likelihood ratio tests remain the preferred approach for testing the incremental contribution of a new marker. Copyright © 2012 John Wiley & Sons, Ltd.
Statistics in Medicine 10/2012; · 1.88 Impact Factor
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ABSTRACT: Large-scale cancer genome projects, such as the Cancer Genome Atlas (TCGA) project, are comprehensive molecular characterization efforts to accelerate our understanding of cancer biology and the discovery of new therapeutic targets. The accumulating wealth of multidimensional data provides a new paradigm for important research problems including cancer subtype discovery. The current standard approach relies on separate clustering analyses followed by manual integration. Results can be highly data type dependent, restricting the ability to discover new insights from multidimensional data. In this study, we present an integrative subtype analysis of the TCGA glioblastoma (GBM) data set. Our analysis revealed new insights through integrated subtype characterization. We found three distinct integrated tumor subtypes. Subtype 1 lacks the classical GBM events of chr 7 gain and chr 10 loss. This subclass is enriched for the G-CIMP phenotype and shows hypermethylation of genes involved in brain development and neuronal differentiation. The tumors in this subclass display a Proneural expression profile. Subtype 2 is characterized by a near complete association with EGFR amplification, overrepresentation of promoter methylation of homeobox and G-protein signaling genes, and a Classical expression profile. Subtype 3 is characterized by NF1 and PTEN alterations and exhibits a Mesenchymal-like expression profile. The data analysis workflow we propose provides a unified and computationally scalable framework to harness the full potential of large-scale integrated cancer genomic data for integrative subtype discovery.
PLoS ONE 01/2012; 7(4):e35236. · 4.09 Impact Factor
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Matko Kalac,
Luigi Scotto,
Enrica Marchi,
Jennifer Amengual, Venkatraman E Seshan,
Govind Bhagat,
Netha Ulahannan,
Violetta V Leshchenko,
Alexis M Temkin,
Samir Parekh,
Benjamin Tycko,
Owen A O'Connor
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ABSTRACT: Interactions between histone deacetylase inhibitors (HDACIs) and decitabine were investigated in models of diffuse large B-cell lymphoma (DLBCL). A number of cell lines representing both germinal center B-like and activated B-cell like DLBCL, patient-derived tumor cells and a murine xenograft model were used to study the effects of HDACIs and decitabine in this system. All explored HDACIs in combination with decitabine produced a synergistic effect in growth inhibition and induction of apoptosis in DLBCL cells. This effect was time dependent, mediated via caspase-3 activation, and resulted in increased levels of acetylated histones. Synergy in inducing apoptosis was confirmed in patient-derived primary tumor cells treated with panobinostat and decitabine. Xenografting experiments confirmed the in vitro activity and tolerability of the combination. We analyzed the molecular basis for this synergistic effect by evaluating gene-expression and methylation patterns using microarrays, with validation by bisulfite sequencing. These analyses revealed differentially expressed genes and networks identified by each of the single treatment conditions and by the combination therapy to be unique with few overlapping genes. Among the genes uniquely altered by the combination of panobinostat and decitabine were VHL, TCEB1, WT1, and DIRAS3.
Blood 07/2011; 118(20):5506-16. · 9.90 Impact Factor
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ABSTRACT: If a cancer patient develops multiple tumors, it is sometimes impossible to determine whether these tumors are independent or clonal based solely on pathological characteristics. Investigators have studied how to improve this diagnostic challenge by comparing the presence of loss of heterozygosity (LOH) at selected genetic locations of tumor samples, or by comparing genomewide copy number array profiles. We have previously developed statistical methodology to compare such genomic profiles for an evidence of clonality. We assembled the software for these tests in a new R package called 'Clonality'. For LOH profiles, the package contains significance tests. The analysis of copy number profiles includes a likelihood ratio statistic and reference distribution, as well as an option to produce various plots that summarize the results. AVAILABILITY: Bioconductor (http://bioconductor.org/packages/release/bioc/html/Clonality.html) and http://www.mskcc.org/mskcc/html/13287.cfm.
Bioinformatics 06/2011; 27(12):1698-9. · 5.47 Impact Factor
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ABSTRACT: High-throughput techniques facilitate the simultaneous measurement of DNA copy number at hundreds of thousands of sites on a genome. Older techniques allow measurement only of total copy number, the sum of the copy number contributions from the two parental chromosomes. Newer single nucleotide polymorphism (SNP) techniques can in addition enable quantifying parent-specific copy number (PSCN). The raw data from such experiments are two-dimensional, but are unphased. Consequently, inference based on them necessitates development of new analytic methods.
We have adapted and enhanced the circular binary segmentation (CBS) algorithm for this purpose with focus on paired test and reference samples. The essence of paired parent-specific CBS (Paired PSCBS) is to utilize the original CBS algorithm to identify regions of equal total copy number and then to further segment these regions where there have been changes in PSCN. For the final set of regions, calls are made of equal parental copy number and loss of heterozygosity (LOH). PSCN estimates are computed both before and after calling.
The methodology is evaluated by simulation and on glioblastoma data. In the simulation, PSCBS compares favorably to established methods. On the glioblastoma data, PSCBS identifies interesting genomic regions, such as copy-neutral LOH.
The Paired PSCBS method is implemented in an open-source R package named PSCBS, available on CRAN (http://cran.r-project.org/).
Bioinformatics 06/2011; 27(15):2038-46. · 5.47 Impact Factor
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Bioinformatics. 01/2011; 27:1698-1699.
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ABSTRACT: Pralatrexate (10-propargyl-10-deazaaminopterin) is an antifolate with improved cellular uptake and retention due to greater affinity for the reduced folate carrier (RFC-1) and folyl-polyglutamyl synthase. Based on the PROPEL data, pralatrexate was the first drug approved for patients with relapsed and refractory peripheral T-cell lymphoma. Bortezomib is a proteasome inhibitor that has shown some activity in patients with T-cell lymphoma.
Assays for cytotoxicity including mathematical analysis for synergism, flow cytometry, immunoblotting, and a xenograft severe combined immunodeficient-beige mouse model were used to explore the in vitro and in vivo activities of pralatrexate alone and in combination with bortezomib in T-cell lymphoid malignancies.
In vitro, pralatrexate and bortezomib exhibited concentration- and time-dependent cytotoxicity against a broad panel of T-lymphoma cell lines. Pralatrexate showed synergism when combined with bortezomib in all cell lines studied. Pralatrexate also induced potent apoptosis and caspase activation when combined with bortezomib across the panel. Cytotoxicity studies on normal peripheral blood mononuclear cells showed that the combination was not more toxic than the single agents. Western blot assays for proteins involved in broad growth and survival pathways showed that p27, NOXA, HH3, and RFC-1 were all significantly modulated by the combination. In a severe combined immunodeficient-beige mouse model of transformed cutaneous T-cell lymphoma, the addition of pralatrexate to bortezomib enhanced efficacy compared with either drug alone.
Collectively, these data suggest that pralatrexate in combination with bortezomib represents a novel and potentially important platform for the treatment of T-cell malignancies.
Clinical Cancer Research 07/2010; 16(14):3648-58. · 7.74 Impact Factor
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Adrienne A Phillips,
Iuliana Shapira,
Robert D Willim,
Jasotha Sanmugarajah,
William B Solomon,
Steven M Horwitz,
David G Savage,
Govind Bhagat,
Gerald Soff,
Jasmine M Zain,
Bachir Alobeid, Venkatraman E Seshan,
Owen A O'Connor
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ABSTRACT: To define the clinicopathologic and prognostic features of patients with human T-cell lymphotropic virus type-1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATLL) in North America, standard criteria were used to identify patients with ATLL.
Statistical analyses used included descriptive statistics, Kaplan-Meir survival analysis, and recursive partitioning.
Eighty-nine patients were identified between August 1992 and May 2007, including 37 (41.6%) males and 52 (58.4%) females with a median age of 50 years (range, 22-82 years). All but 6 patients had immigrated to the United States from the Caribbean, Latin America, or Africa. The acute subtype predominated (68.5%). The majority of patients received a combination-alkylator-based chemotherapy regimen in the front-line setting (72.6%). The most common regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone at standard doses or attenuated and/or with methotrexate (CHOP-like), which produced an overall response rate of 64.1%. Despite initial responses to therapy, the median overall survival for all subtypes was 24 weeks (range, 0.9-315 weeks). Although the International Prognostic Index and Prognostic Index for peripheral T-cell lymphoma unspecified identified subsets of patients, these models were not completely predictive. A recursive partitioning analysis was performed on the data, which successfully identified 3 prognostic categories based on Eastern Cooperative Oncology Group performance status, stage, age, and calcium level at diagnosis.
This series proposed a new prognostic model for patients with HTLV-1-associated ATLL and confirmed a poor outcome for these patients in North America.
Cancer 07/2010; 116(14):3438-46. · 4.77 Impact Factor
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ABSTRACT: When a cancer patient develops a new tumor it is necessary to determine if it is a recurrence (metastasis) of the original cancer, or an entirely new occurrence of the disease. This is accomplished by assessing the histo-pathology of the lesions. However, there are many clinical scenarios in which this pathological diagnosis is difficult. Since each tumor is characterized by a distinct pattern of somatic mutations, a more definitive diagnosis is possible in principle in these difficult clinical scenarios by comparing the two patterns. In this article we develop and evaluate a statistical strategy for this comparison when the data are derived from array copy number data, designed to identify all of the somatic allelic gains and losses across the genome. First a segmentation algorithm is used to estimate the regions of allelic gain and loss. The correlation in these patterns between the two tumors is assessed, and this is complemented with more precise quantitative comparisons of each plausibly clonal mutation within individual chromosome arms. The results are combined to determine a likelihood ratio to distinguish clonal tumor pairs (metastases) from independent second primaries. Our data analyses show that in many cases a strong clonal signal emerges. Sensitivity analyses show that most of the diagnoses are robust when the data are of high quality.
Statistics in Medicine 03/2010; 29(15):1608-21. · 1.88 Impact Factor
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ABSTRACT: Distinguishing synchronous primary lung cancers (SPLCs) from advanced disease is important because prognosis and treatments are very different and a surgical approach to SPLC may result in survival similar to solitary cancers. Determining this distinction with certainty, however, is challenging. We reviewed our experience with surgical resection of presumed SPLC to analyze outcomes and identify factors associated with prolonged survival.
A retrospective review identified patients treated for presumptive SPLC. Cases were defined using modified criteria set forth by Martini and Melamed and histologic subtyping. Survival was estimated using the Kaplan-Meier method, and factors associated with survival were evaluated using a log-rank test or Cox proportional hazards model for categorical and continuous variables, respectively.
From January 1995 to July 2006, 175 patients met study criteria and underwent complete resection. Tumors were more often in different lobes of an ipsilateral chest (55 of 175, 31%) or contralateral lesions (45 of 175, 26%). More than half (104 of 175, 59%) of the patients underwent a single operation. Median follow-up was 50.3 months (4.8-164.7); median overall survival (OS) for the group was 67.4 months (46.4-80.0) with a 3-year OS of 64%. On multivariable analysis controlling for stage, only female gender was a significant predictor of better OS (p = 0.001).
An aggressive surgical approach to patients with apparent SPLC can result in survival that is comparable with patients with single lung cancers of similar stage. The Martini and Melamed criteria and histologic subtyping can identify appropriate patients for resection. Female gender was associated with superior OS.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2010; 5(2):197-205. · 4.55 Impact Factor
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ABSTRACT: Romidepsin and belinostat are inhibitors of histone deacetylases (HDACI). HDACIs are known to induce cell death in malignant cells through multiple mechanisms, including upregulation of death receptors and induction of cell cycle arrest. They are also known to be prodifferentiating. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1.
Assays for cytotoxicty including mathematical analysis for synergism, flow-cytometry, immunoblottings, and a xenograft severe combined immunodeficient beige mouse model were used to explore the in vitro and in vivo activity of romidepsin and/or belinostat alone or in combination with the proteasome inhibitor bortezomib in MCL.
In vitro, romidepsin and belinostat exhibited concentration-dependent cytotoxicity against a panel of MCL cell lines. Both HDACI showed strong synergism when combined with the proteasome inhibitor bortezomib in MCL. An HDACI plus bortezomib also induced potent mitochondrial membrane depolarization and apoptosis, whereas no significant apoptosis was observed in peripheral blood mononuclear cells from healthy donors with the combination. These events were associated with a decrease in cyclin D1 and Bcl-X(L), and an increase in accumulation of acetylated histone H3, acetylated alpha-tubulin, and Noxa in cell lines. In a severe combined immunodeficient beige mouse model of MCL, the addition of belinostat to bortezomib enhanced efficacy compared with either drug alone.
Collectively, these data strongly suggest that HDACI such as romidepsin or belinostat in combination with a proteasome inhibitor could represent a novel and rationale platform for the treatment of MCL.
Clinical Cancer Research 01/2010; 16(2):554-65. · 7.74 Impact Factor
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Owen A O'Connor,
Steven Horwitz,
Paul Hamlin,
Carol Portlock,
Craig H Moskowitz,
Debra Sarasohn,
Ellen Neylon,
Jill Mastrella,
Rachel Hamelers,
Barbara Macgregor-Cortelli,
Molly Patterson, Venkatraman E Seshan,
Frank Sirotnak,
Martin Fleisher,
Diane R Mould,
Mike Saunders,
Andrew D Zelenetz
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ABSTRACT: To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma.
Pralatrexate, initially given at a dose of 135 mg/m(2) on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m(2) weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/microL, and a platelet count greater than 50,000/microL for the first dose of any cycle.
The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m(2) weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months.
Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma.
Journal of Clinical Oncology 09/2009; 27(26):4357-64. · 18.37 Impact Factor
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ABSTRACT: Pulmonary nodules are common incidental findings on thoracic imaging examinations. This study sought to determine whether antibiotic use is associated with any improvement in nodule appearance and to identify clinical findings and nodule characteristics potentially influencing the decision to prescribe antibiotics.
Electronic medical records were reviewed of outpatients referred to a metropolitan cancer center for pulmonary nodules seen on chest CT scans who did not undergo biopsy. The primary end point was the appearance of each nodule on the first follow-up scan. A subset analysis was performed for patients manifesting symptoms or radiographic findings suggesting infection. An analysis was performed to determine what clinical and radiographic findings were associated with the decision to prescribe antibiotics.
Between January 2003 and December 2004, 143 evaluations were performed for 293 nodules. Antibiotics were prescribed to 34 (24%) evaluations. A trend toward improvement was seen with antibiotic use, which was not significant. The percentage of nodules that improved was 33% among those receiving antibiotics and 27% among those who did not (odds ratio 1.33; 95% CI, 0.55-3.27). Among 63 patients with pulmonary symptoms, 41% of nodules improved among those receiving antibiotics and 28% among those who did not (odds ratio 1.78; 95% CI, 0.42-7.78). The decision to prescribe antibiotics was associated only with larger nodule size and bronchiectasis.
These data do not support antibiotic use for pulmonary nodules. However, the trend toward improved nodule appearance suggests that larger prospective trials are warranted to clarify the role of antibiotics in managing lung nodules.
Chest 09/2009; 137(2):369-75. · 5.25 Impact Factor
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ABSTRACT: Cyproheptadine, an inhibitor of the H1 histamine receptors, has recently shown activity in models of leukaemia and myeloma, presumably through inhibition of cyclin-D expression. Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma characterized by overexpression of cyclin-D1. We investigated the effect of cyproheptadine alone and in combination with the proteasome inhibitor bortezomib in models of MCL. The combination of these drugs was mathematically synergistic, producing significant reductions in the mitochondrial membrane potential leading to apoptosis. In a severe combined immunodeficient beige mouse model, cyproheptadine plus bortezomib demonstrated a statistically significant advantage compared to either agent alone.
British Journal of Haematology 08/2009; 146(6):656-9. · 4.94 Impact Factor
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ABSTRACT: To report the influence of posttreatment prostate-specific antigen (PSA) nadir response at 2 years after external beam radiotherapy (RT) on distant metastases (DM) and cause-specific mortality (CSM).
Eight hundred forty-four patients with localized prostate cancer were treated with conformal RT. The median duration of follow-up was 9.1 years. A fixed landmark time point at 2 years was used to assess the influence of nadir PSA value as a time-dependent variable on long-term outcomes.
Multivariate analysis demonstrated that nadir PSA <or=1.5 ng/mL at the landmark was an independent predictor of progression-free survival after adjusting for T stage, Gleason score, pre-RT PSA value, and RT dose (p = 0.03). The 5- and 10-year cumulative incidences of DM were 2.4% and 7.9%, respectively, in those with nadir PSA levels <or=1.5 ng/mL at the 2-year landmark, and were 10.3% and 17.5%, respectively, in patients with higher nadir values. Multivariate analysis showed that the higher nadir PSA value at the 2-year landmark (p = 0.002), higher Gleason scores (p < 0.001), and increasing T stage (p = 0.03) were predictors of DM after adjusting for pre-RT PSA values and RT dose. Multivariate analysis also showed that higher Gleason scores (p = 0.002), and higher nadir PSA values at the 2-year landmark (p = 0.03) were risk factors associated with CSM after adjusting for T stage and pre-RT PSA value.
Nadir PSA values of <or=1.5 ng/mL at 2 years after RT for prostate cancer predict for long-term DM and CSM outcomes. Patients with higher absolute nadir levels at 2 years after treatment should be evaluated for the presence of nonresponding disease, and earlier salvage treatment interventions should be considered.
International journal of radiation oncology, biology, physics 06/2009; 75(5):1350-6. · 4.59 Impact Factor
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ABSTRACT: RNA triphosphatases are attractive and mostly unexplored therapeutic targets for the development of broad spectrum antiprotozoal, antiviral and antifungal agents. The use of malachite green as a readout for phosphatases is well characterized and widely employed. However, the reaction depends on high quantities of inorganic phosphate to be generated, which makes this assay not easily amenable to screening in 1536-well format. The overly long reading times required also prohibit its use to screen large chemical libraries. To overcome these limitations, we sought to develop a fluorescence polarization (FP) -based assay for triphosphatases, compatible with miniaturization and fast readouts. For this purpose, we took advantage of the nucleoside triphosphatase activity of this class of enzyme to successfully adapt the Transcreener ADP assay based on the detection of generated ADP by immunocompetition fluorescence polarization to the RNA triphosphatase TbCet1 in 1536-well format. We also tested the performance of this newly developed assay in a pilot screen of 3,000 compounds and we confirmed the activity of the obtained hits. We present and discuss our findings and their importance for the discovery of novel drugs by high throughput screening.
Combinatorial chemistry & high throughput screening 04/2009; 12(3):258-68. · 2.46 Impact Factor
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Gregory J Riely,
Naiyer A Rizvi,
Mark G Kris,
Daniel T Milton,
David B Solit,
Neal Rosen,
Emir Senturk,
Christopher G Azzoli,
Julie R Brahmer,
Francis M Sirotnak, Venkatraman E Seshan,
Margaret Fogle,
Michelle Ginsberg,
Vincent A Miller,
Charles M Rudin
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ABSTRACT: A prior study demonstrated that addition of continuous daily erlotinib fails to improve response rate or survival in non-small-cell lung cancer (NSCLC) patients treated with carboplatin and paclitaxel. However, preclinical data support the hypothesis that intermittent administration of erlotinib before or after chemotherapy may improve efficacy. We tested this hypothesis in patients with advanced NSCLC.
Eligible patients were former or current smokers with chemotherapy-naive stage IIIB or IV NSCLC. All patients received up to six cycles of carboplatin (area under the curve = 6) and paclitaxel (200 mg/m(2)), with random assignment to one of the following three erlotinib treatments: erlotinib 150 mg on days 1 and 2 with chemotherapy on day 3 (150 PRE); erlotinib 1,500 mg on days 1 and 2 with chemotherapy on day 3 (1,500 PRE); or chemotherapy on day 1 with erlotinib 1,500 mg on days 2 and 3 (1,500 POST). The primary end point was response rate.
Eighty-six patients received treatment. The response rates for the 150 PRE, 1,500 PRE, and 1,500 POST arms were 18% (five of 28 patients), 34% (10 of 29 patients), and 28% (eight of 29 patients), respectively. The median overall survival times were 10, 15, and 10 months for the 150 PRE, 1,500 PRE, and 1,500 POST arms, respectively. The most common grade 3 and 4 toxicities were neutropenia (39%), fatigue (15%), and anemia (12%). Grade 3 and 4 rash and diarrhea were uncommon.
Patients treated on the 1,500 PRE arm had the highest response rate and longest survival, with ranges similar to those reported for carboplatin, paclitaxel, and bevacizumab in a more restricted population. Further evaluation of this strategy in a phase III trial is proposed.
Journal of Clinical Oncology 01/2009; 27(2):264-70. · 18.37 Impact Factor
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ABSTRACT: The passage of a vascular-injected paramagnetic contrast reagent (CR) bolus through a region-of-interest affects tissue (1)H(2)O relaxation and thus MR image intensity. For longitudinal relaxation [R(1) identical with (T(1))(-1)], the CR must have transient molecular interactions with water. Because the CR and water molecules are never uniformly distributed in the histological-scale tissue compartments, the kinetics of equilibrium water compartmental interchange are competitive. In particular, the condition of the equilibrium trans cytolemmal water exchange NMR system sorties through different domains as the interstitial CR concentration, [CR(o)], waxes and wanes. Before CR, the system is in the fast-exchange-limit (FXL). Very soon after CR(o) arrival, it enters the fast-exchange-regime (FXR). Near maximal [CR(o)], the system could enter even the slow-exchange-regime (SXR). These conditions are defined herein, and a comprehensive description of how they affect quantitative pharmacokinetic analyses is presented. Data are analyzed from a population of 22 patients initially screened suspicious for breast cancer. After participating in our study, the subjects underwent biopsy/pathology procedures and only 7 (32%) were found to have malignancies. The transient departure from FXL to FXR (and apparently not SXR) is significant in only the malignant tumors, presumably because of angiogenic capillary leakiness. Thus, if accepted, this analysis would have prevented the 68% of the biopsies that proved benign.
Proceedings of the National Academy of Sciences 12/2008; 105(46):17937-42. · 9.68 Impact Factor
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ABSTRACT: Fallopian tube cancers are rare neoplasms. These malignancies are thought to behave biologically and clinically like ovarian cancer. The purpose of this study was to compare the clinical behavior and outcome of fallopian tube and ovarian cancer.
The Surveillance, Epidemiology, and End Results database was reviewed to identify women with tumors of the fallopian tube (FT) and ovary (OV) diagnosed between 1988 and 2004. Demographic and clinical data were compared, and the impact of tumor site on survival was analyzed using Cox models and the Kaplan-Meier method.
A total of 55,825 patients were identified, 1576 (3%) with FT and 54,249 (97%) with OV cancer. FT patients were more likely to present with early stage tumors (P < .001). Among FT patients, 47% had stage I/II tumors compared with 29% of OV cancers. In an adjusted Cox model of all patients, cancer-specific mortality was 48% lower in FT patients (hazard ratio, 0.52; 95% confidence interval [CI], 0.48-0.56) compared with OV cancer. Among patients with FT tumors, advanced age and stage were independent predictors of decreased survival. When stratified by stage, survival was similar for stage I and II tumors, but stage III and IV FT patients had an improved survival. The 5-year survival for stage III FT cancer was 54% (95% CI, 48%-60%), compared with 30% (95% CI, 29%-31%) for OV.
Fallopian tube cancers present earlier and at advanced stage have a better overall survival than primary ovarian malignancies. Future clinical trials should recognize the possible distinct clinical behavior of fallopian tube cancers.
Cancer 12/2008; 113(12):3298-306. · 4.77 Impact Factor
