154 results on '"Michael V. Seiden"'
Search Results
2. Supplementary Figures 1 - 2, Table 1 from Multidrug Resistance–Linked Gene Signature Predicts Overall Survival of Patients with Primary Ovarian Serous Carcinoma
- Author
-
Michael M. Gottesman, Bo R. Rueda, Michael V. Seiden, Suresh V. Ambudkar, Anil K. Sood, Aparna A. Kamat, Ram Ganapathi, Mari Bunkholt Elstrand, Ben Davidson, Sudhir Varma, Anna Maria Calcagno, and Jean-Pierre Gillet
- Abstract
PDF file, 1202KB, Supplementary Figure 1. Kaplan-Meier Survival Curves. Supplementary Figure 2. Kaplan-Meier Survival Curves. Supplementary Table 1. Univariate analysis of clinical covariates.
- Published
- 2023
3. Data from Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
- Author
-
Minetta C. Liu, Eric T. Fung, Eric A. Klein, Michael V. Seiden, Gerry Meixiong, Ting Ma, Rita Shaknovich, Christina A. Clarke, Collin Melton, Oliver Venn, Geoffrey R. Oxnard, Kathryn N. Kurtzman, Earl Hubbell, Zhao Dong, and Xiaoji Chen
- Abstract
Purpose:We recently reported the development of a cell-free DNA (cfDNA) targeted methylation (TM)-based sequencing approach for a multi-cancer early detection (MCED) test that includes cancer signal origin prediction. Here, we evaluated the prognostic significance of cancer detection by the MCED test using longitudinal follow-up data.Experimental Design:As part of a Circulating Cell-free Genome Atlas (CCGA) substudy, plasma cfDNA samples were sequenced using a TM approach, and machine learning classifiers predicted cancer status and cancer signal origin. Overall survival (OS) of cancer participants in the first 3 years of follow-up was evaluated in relation to cancer detection by the MCED test and clinical characteristics.Results:Cancers not detected by the MCED test had significantly better OS (P < 0.0001) than cancers detected, even after accounting for other covariates, including clinical stage and method of clinical diagnosis (i.e., standard-of-care screening or clinical presentation with signs/symptoms). Additionally, cancers not detected by the MCED test had better OS than was expected when data were adjusted for age, stage, and cancer type from the Surveillance, Epidemiology, and End Results (SEER) program. In cancers with current screening options, the MCED test also differentiated more aggressive cancers from less aggressive cancers (P < 0.0001).Conclusions:Cancer detection by the MCED test was prognostic beyond clinical stage and method of diagnosis. Cancers not detected by the MCED test had better prognosis than cancers detected and SEER-based expected survival. Cancer detection and prognosis may be linked by the underlying biological factor of tumor fraction in cfDNA.
- Published
- 2023
4. Data from Multidrug Resistance–Linked Gene Signature Predicts Overall Survival of Patients with Primary Ovarian Serous Carcinoma
- Author
-
Michael M. Gottesman, Bo R. Rueda, Michael V. Seiden, Suresh V. Ambudkar, Anil K. Sood, Aparna A. Kamat, Ram Ganapathi, Mari Bunkholt Elstrand, Ben Davidson, Sudhir Varma, Anna Maria Calcagno, and Jean-Pierre Gillet
- Abstract
Purpose: This study assesses the ability of multidrug resistance (MDR)–associated gene expression patterns to predict survival in patients with newly diagnosed carcinoma of the ovary. The scope of this research differs substantially from that of previous reports, as a very large set of genes was evaluated whose expression has been shown to affect response to chemotherapy.Experimental Design: We applied a customized TaqMan low density array, a highly sensitive and specific assay, to study the expression profiles of 380 MDR-linked genes in 80 tumor specimens collected at initial surgery to debulk primary serous carcinoma. The RNA expression profiles of these drug resistance genes were correlated with clinical outcomes.Results: Leave-one-out cross-validation was used to estimate the ability of MDR gene expression to predict survival. Although gene expression alone does not predict overall survival (OS; P = 0.06), four covariates (age, stage, CA125 level, and surgical debulking) do (P = 0.03). When gene expression was added to the covariates, we found an 11-gene signature that provides a major improvement in OS prediction (log-rank statistic P < 0.003). The predictive power of this 11-gene signature was confirmed by dividing high- and low-risk patient groups, as defined by their clinical covariates, into four specific risk groups on the basis of expression levels.Conclusion: This study reveals an 11-gene signature that allows a more precise prognosis for patients with serous cancer of the ovary treated with carboplatin- and paclitaxel-based therapy. These 11 new targets offer opportunities for new therapies to improve clinical outcome in ovarian cancer. Clin Cancer Res; 18(11); 3197–206. ©2012 AACR.
- Published
- 2023
5. Supplementary Table 1 from Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
- Author
-
Minetta C. Liu, Eric T. Fung, Eric A. Klein, Michael V. Seiden, Gerry Meixiong, Ting Ma, Rita Shaknovich, Christina A. Clarke, Collin Melton, Oliver Venn, Geoffrey R. Oxnard, Kathryn N. Kurtzman, Earl Hubbell, Zhao Dong, and Xiaoji Chen
- Abstract
Supplementary Table 1 from Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
- Published
- 2023
6. Supplementary Table 3 from Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
- Author
-
Minetta C. Liu, Eric T. Fung, Eric A. Klein, Michael V. Seiden, Gerry Meixiong, Ting Ma, Rita Shaknovich, Christina A. Clarke, Collin Melton, Oliver Venn, Geoffrey R. Oxnard, Kathryn N. Kurtzman, Earl Hubbell, Zhao Dong, and Xiaoji Chen
- Abstract
Supplementary Table 3 from Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
- Published
- 2023
7. Supplementary Table 2 from Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
- Author
-
Minetta C. Liu, Eric T. Fung, Eric A. Klein, Michael V. Seiden, Gerry Meixiong, Ting Ma, Rita Shaknovich, Christina A. Clarke, Collin Melton, Oliver Venn, Geoffrey R. Oxnard, Kathryn N. Kurtzman, Earl Hubbell, Zhao Dong, and Xiaoji Chen
- Abstract
Supplementary Table 2 from Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
- Published
- 2023
8. Supplementary Figures from Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
- Author
-
Minetta C. Liu, Eric T. Fung, Eric A. Klein, Michael V. Seiden, Gerry Meixiong, Ting Ma, Rita Shaknovich, Christina A. Clarke, Collin Melton, Oliver Venn, Geoffrey R. Oxnard, Kathryn N. Kurtzman, Earl Hubbell, Zhao Dong, and Xiaoji Chen
- Abstract
Supplementary Figures from Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
- Published
- 2023
9. Patient Preferences for Multi-Cancer Early Detection (MCED) Screening Tests
- Author
-
Heather, Gelhorn, Melissa M, Ross, Anuraag R, Kansal, Eric T, Fung, Michael V, Seiden, Nicolas, Krucien, and Karen C, Chung
- Abstract
Emerging blood-based multi-cancer early detection (MCED) tests can detect a variety of cancer types across stages with a range of sensitivity, specificity, and ability to predict the origin of the cancer signal. However, little is known about the general US population's preferences for MCED tests.To quantify preferences for MCED tests among US adults aged 50-80 years using a discrete choice experiment (DCE).To quantify preferences for attributes of blood-based MCED tests, an online DCE was conducted with five attributes (true positives, false negatives, false positives, likelihood of the cancer type unknown, number of cancer types detected), among the US population aged 50-80 years recruited via online panels and social media. Data were analyzed using latent class multinomial logit models and relative attribute importance was obtained.Participants (N = 1700) were 54% female, mean age 63.3 years. Latent class modeling identified three classes with distinct preferences for MCED tests. The rank order of attribute importance based on relative attribute importance varied by latent class, but across all latent classes, participants preferred higher accuracy (fewer false negatives and false positives, more true positives) and screenings that detected more cancer types and had a lower likelihood of cancer type unknown. Overall, 72% of participants preferred to receive an MCED test in addition to currently recommended cancer screenings.While there is significant heterogeneity in cancer screening preferences, the majority of participants preferred MCED screening and the accuracy of these tests is important. While the majority of participants preferred adding an MCED test to complement current cancer screenings, the latent class analyses identified a small (16%) and specific subset of individuals who value attributes differently, with particular concern regarding false-negative and false-positive test results, who are significantly less likely to opt-in.
- Published
- 2022
10. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA
- Author
-
M.C. Liu, G.R. Oxnard, E.A. Klein, C. Swanton, M.V. Seiden, Minetta C. Liu, Geoffrey R. Oxnard, Eric A. Klein, David Smith, Donald Richards, Timothy J. Yeatman, Allen L. Cohn, Rosanna Lapham, Jessica Clement, Alexander S. Parker, Mohan K. Tummala, Kristi McIntyre, Mikkael A. Sekeres, Alan H. Bryce, Robert Siegel, Xuezhong Wang, David P. Cosgrove, Nadeem R. Abu-Rustum, Jonathan Trent, David D. Thiel, Carlos Becerra, Manish Agrawal, Lawrence E. Garbo, Jeffrey K. Giguere, Ross M. Michels, Ronald P. Harris, Stephen L. Richey, Timothy A. McCarthy, David M. Waterhouse, Fergus J. Couch, Sharon T. Wilks, Amy K. Krie, Rama Balaraman, Alvaro Restrepo, Michael W. Meshad, Kimberly Rieger-Christ, Travis Sullivan, Christine M. Lee, Daniel R. Greenwald, William Oh, Che-Kai Tsao, Neil Fleshner, Hagen F. Kennecke, Maged F. Khalil, David R. Spigel, Atisha P. Manhas, Brian K. Ulrich, Philip A. Kovoor, Christopher Stokoe, Jay G. Courtright, Habte A. Yimer, Timothy G. Larson, Charles Swanton, Michael V. Seiden, Steven R. Cummings, Farnaz Absalan, Gregory Alexander, Brian Allen, Hamed Amini, Alexander M. Aravanis, Siddhartha Bagaria, Leila Bazargan, John F. Beausang, Jennifer Berman, Craig Betts, Alexander Blocker, Joerg Bredno, Robert Calef, Gordon Cann, Jeremy Carter, Christopher Chang, Hemanshi Chawla, Xiaoji Chen, Tom C. Chien, Daniel Civello, Konstantin Davydov, Vasiliki Demas, Mohini Desai, Zhao Dong, Saniya Fayzullina, Alexander P. Fields, Darya Filippova, Peter Freese, Eric T. Fung, Sante Gnerre, Samuel Gross, Meredith Halks-Miller, Megan P. Hall, Anne-Renee Hartman, Chenlu Hou, Earl Hubbell, Nathan Hunkapiller, Karthik Jagadeesh, Arash Jamshidi, Roger Jiang, Byoungsok Jung, TaeHyung Kim, Richard D. Klausner, Kathryn N. Kurtzman, Mark Lee, Wendy Lin, Jafi Lipson, Hai Liu, Qinwen Liu, Margarita Lopatin, Tara Maddala, M. Cyrus Maher, Collin Melton, Andrea Mich, Shivani Nautiyal, Jonathan Newman, Joshua Newman, Virgil Nicula, Cosmos Nicolaou, Ongjen Nikolic, Wenying Pan, Shilpen Patel, Sarah A. Prins, Richard Rava, Neda Ronaghi, Onur Sakarya, Ravi Vijaya Satya, Jan Schellenberger, Eric Scott, Amy J. Sehnert, Rita Shaknovich, Avinash Shanmugam, K.C. Shashidhar, Ling Shen, Archana Shenoy, Seyedmehdi Shojaee, Pranav Singh, Kristan K. Steffen, Susan Tang, Jonathan M. Toung, Anton Valouev, Oliver Venn, Richard T. Williams, Tony Wu, Hui H. Xu, Christopher Yakym, Xiao Yang, Jessica Yecies, Alexander S. Yip, Jack Youngren, Jeanne Yue, Jingyang Zhang, Lily Zhang, Lori (Quan) Zhang, Nan Zhang, Christina Curtis, and Donald A. Berry
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Bisulfite sequencing ,Rectum ,Gastroenterology ,Article ,cell-free DNA ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Positron Emission Tomography Computed Tomography ,Internal medicine ,Biomarkers, Tumor ,medicine ,cancer ,Humans ,Mass Screening ,Prospective Studies ,Esophagus ,Early Detection of Cancer ,business.industry ,Stomach ,DNA, Neoplasm ,Hematology ,DNA Methylation ,Plasma cell neoplasm ,16. Peace & justice ,Anus ,Confidence interval ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Cell-free fetal DNA ,030220 oncology & carcinogenesis ,Feasibility Studies ,Female ,next-generation sequencing ,methylation ,business ,Cell-Free Nucleic Acids - Abstract
Background Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. Participants and methods The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. Results Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I–III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. Conclusions cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.
- Published
- 2020
11. Evaluation of cell-free DNA approaches for multi-cancer early detection
- Author
-
Arash Jamshidi, Minetta C. Liu, Eric A. Klein, Oliver Venn, Earl Hubbell, John F. Beausang, Samuel Gross, Collin Melton, Alexander P. Fields, Qinwen Liu, Nan Zhang, Eric T. Fung, Kathryn N. Kurtzman, Hamed Amini, Craig Betts, Daniel Civello, Peter Freese, Robert Calef, Konstantin Davydov, Saniya Fayzullina, Chenlu Hou, Roger Jiang, Byoungsok Jung, Susan Tang, Vasiliki Demas, Joshua Newman, Onur Sakarya, Eric Scott, Archana Shenoy, Seyedmehdi Shojaee, Kristan K. Steffen, Virgil Nicula, Tom C. Chien, Siddhartha Bagaria, Nathan Hunkapiller, Mohini Desai, Zhao Dong, Donald A. Richards, Timothy J. Yeatman, Allen L. Cohn, David D. Thiel, Donald A. Berry, Mohan K. Tummala, Kristi McIntyre, Mikkael A. Sekeres, Alan Bryce, Alexander M. Aravanis, Michael V. Seiden, and Charles Swanton
- Subjects
Chemical Biology & High Throughput ,Signalling & Oncogenes ,Human Biology & Physiology ,Cancer Research ,Ecology,Evolution & Ethology ,Oncology ,Genome Integrity & Repair ,Tumour Biology ,Genetics & Genomics ,Computational & Systems Biology - Abstract
In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection (LOD) based on circulating tumor allele fraction (cTAF), enabling performance comparisons. Among 10 machine-learning classifiers trained on the same samples and independently validated, when evaluated at 98% specificity, those using whole-genome (WG) methylation, single nucleotide variants with paired white blood cell background removal, and combined scores from classifiers evaluated in this study show the highest cancer signal detection sensitivities. Compared with clinical stage and tumor type, cTAF is a more significant predictor of classifier performance and may more closely reflect tumor biology. Clinical LODs mirror relative sensitivities for all approaches. The WG methylation feature best predicts cancer signal origin. WG methylation is the most promising technology for MCED and informs development of a targeted methylation MCED test.
- Published
- 2022
12. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set
- Author
-
Rosanna Lapham, Charles Swanton, Jianjun Gao, David Cosgrove, Eric A. Klein, Allen Lee Cohn, G. Chung, Nathan Hunkapiller, Donald A. Richards, Kathryn N. Kurtzman, Jessica M. Clement, Minetta C. Liu, Arash Jamshidi, Michael V. Seiden, and M.K. Tummala
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Stage ii ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Neoplasms ,Biomarkers, Tumor ,Medicine ,Humans ,Prospective Studies ,Liquid biopsy ,Stage (cooking) ,Early Detection of Cancer ,business.industry ,Cancer ,Hematology ,Oncogenes ,DNA Methylation ,medicine.disease ,Cancer Early Detection ,Confidence interval ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,Stage iv - Abstract
Background A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. Patients and methods This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. Results Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). Conclusion In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. Clinical trial number NCT02889978.
- Published
- 2021
13. Performance of a Multi-Cancer Detection Test as a Tool for Diagnostic Resolution of Symptomatic Gynecological Cancers
- Author
-
Minetta C. Liu, David D. Thiel, Jianjun Gao, Eric A. Klein, C. Becerra, Donald A. Richards, E.T. Fung, Earl Hubbell, Kathryn N. Kurtzman, T. Wu, Q. Zhang, X. Chen, Arash Jamshidi, Alan H. Bryce, N. Zhang, and Michael V. Seiden
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Endometriosis ,Obstetrics and Gynecology ,Cancer ,Test sensitivity ,Subgroup analysis ,Disease ,Cancer detection ,medicine.disease ,Confidence interval ,Internal medicine ,medicine ,Stage (cooking) ,business - Abstract
Study Objective Assess performance of a multi-cancer detection (MCD) test. Design Circulating Cell-free Genome Atlas (CCGA; NCT02889978) is a prospective, longitudinal, case-control study. Samples from the second CCGA substudy were used to validate performance of an MCD test, which uses targeted methylation-based cell-free DNA sequencing and machine learning classifiers to detect cancer signal, including from clinically presenting gynecologic cancers, and predict cancer signal origin (CSO). Setting N/A. Patients or Participants MCD test sensitivity and CSO prediction accuracy were evaluated in a subgroup of participants with clinically presenting cancers (CPCs). Specificity was assessed in noncancer participants and a subgroup with significant nonmalignant conditions, including endometriosis. Interventions N/A. Measurements and Main Results Specificity was 99.5% (95% confidence interval [CI]: 98.2-99.9%; 396/398) for the noncancer group and 93.8% (71.7-99.7%; 15/16) for the significant nonmalignant conditions noncancer subgroup. Overall sensitivity was 66.4% (62.2-70.3%; 344/518) for CPC participants, 50.0% (15.0-85.0%; 2/4) for cervical, 70.6% (46.9-86.7%; 12/17) for ovarian, and 25.0% (13.8-41.1%; 9/36) for uterine cancers and varied by stage (Table). CSO prediction accuracy was broadly consistent with CSOs for CPC participants with cancers detected (excluding those with multiple, unknown primaries, or “other” cancer; 91.7% [88.3-94.3%; 300/327]). Conclusion Consistent with the overall CCGA study, this MCD test performed with high specificity and accuracy of CSO prediction in this subgroup analysis of CPCs, including gynecological cancers. Findings support potential use of this test for diagnostic workup of symptomatic disease.
- Published
- 2021
14. Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA
- Author
-
Earl Hubbell, Christina A. Clarke, Collin Melton, Eric T. Fung, Eric A. Klein, Xiaoji Chen, Geoffrey R. Oxnard, Kathryn N. Kurtzman, Minetta C. Liu, Gerry Meixiong, Ting Ma, Rita Shaknovich, Venn Oliver Claude, Michael V. Seiden, and Zhao Dong
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Early detection ,Cancer detection ,Plasma cell ,Free dna ,Circulating Tumor DNA ,Internal medicine ,Neoplasms ,medicine ,Overall survival ,Humans ,Longitudinal Studies ,Stage (cooking) ,Early Detection of Cancer ,Aged ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Prognosis ,Plasma.cfDNA ,Survival Rate ,medicine.anatomical_structure ,Female ,business ,Follow-Up Studies - Abstract
Purpose: We recently reported the development of a cell-free DNA (cfDNA) targeted methylation (TM)-based sequencing approach for a multi-cancer early detection (MCED) test that includes cancer signal origin prediction. Here, we evaluated the prognostic significance of cancer detection by the MCED test using longitudinal follow-up data. Experimental Design: As part of a Circulating Cell-free Genome Atlas (CCGA) substudy, plasma cfDNA samples were sequenced using a TM approach, and machine learning classifiers predicted cancer status and cancer signal origin. Overall survival (OS) of cancer participants in the first 3 years of follow-up was evaluated in relation to cancer detection by the MCED test and clinical characteristics. Results: Cancers not detected by the MCED test had significantly better OS (P < 0.0001) than cancers detected, even after accounting for other covariates, including clinical stage and method of clinical diagnosis (i.e., standard-of-care screening or clinical presentation with signs/symptoms). Additionally, cancers not detected by the MCED test had better OS than was expected when data were adjusted for age, stage, and cancer type from the Surveillance, Epidemiology, and End Results (SEER) program. In cancers with current screening options, the MCED test also differentiated more aggressive cancers from less aggressive cancers (P < 0.0001). Conclusions: Cancer detection by the MCED test was prognostic beyond clinical stage and method of diagnosis. Cancers not detected by the MCED test had better prognosis than cancers detected and SEER-based expected survival. Cancer detection and prognosis may be linked by the underlying biological factor of tumor fraction in cfDNA.
- Published
- 2021
15. Response to W.C. Taylor, and C. Fiala and E.P. Diamandis
- Author
-
Eric A. Klein, Charles Swanton, Geoffrey R. Oxnard, Minetta C. Liu, and Michael V. Seiden
- Subjects
Combinatorics ,Oncology ,business.industry ,Neoplasms ,Medicine ,Humans ,Hematology ,business ,Cell-Free Nucleic Acids ,Methylation ,Models, Biological - Published
- 2020
16. Contributors
- Author
-
James L. Abbruzzese, Omar Abdel-Wahab, Ghassan K. Abou-Alfa, Janet L. Abrahm, Jeffrey S. Abrams, Jeremy S. Abramson, Dara L. Aisner, Michelle Alonso-Basanta, Jesus Anampa, Megan E. Anderson, Emmanuel S. Antonarakis, Richard Aplenc, Frederick R. Appelbaum, Luiz H. Araujo, Ammar Asban, Edward Ashwood, Farrukh T. Awan, Juliet L. Aylward, Arjun V. Balar, Courtney J. Balentine, Stefan K. Barta, Nancy Bartlett, Karen Basen-Engquist, Lynda Kwon Beaupin, Ross S. Berkowitz, Donald A. Berry, Therese Bevers, John F. Boggess, Julie R. Brahmer, Janet Brown, Karen Brown, Powel Brown, Ilene Browner, Paul A. Bunn, William R. Burns, John C. Byrd, Karen Cadoo, David P. Carbone, H. Ballentine Carter, Jorge J. Castillo, Alfred E. Chang, Eric Chang, Stephen J. Chanock, Claudia I. Chapuy, Vikash P. Chauhan, Herbert Chen, Ronald C. Chen, Nai-Kong V. Cheung, Jennifer H. Choe, Michaele C. Christian, Paul M. Cinciripini, Michael F. Clarke, Robert E. Coleman, Robert L. Coleman, Adriana M. Coletta, Jerry M. Collins, Jean M. Connors, Michael Cools, Kevin R. Coombes, Jorge Cortes, Mauro W. Costa, Anne Covey, Kenneth H. Cowan, Christopher H. Crane, Jeffrey Crawford, Kristy Crooks, Daniel J. Culkin, Brian G. Czito, Piero Dalerba, Josep Dalmau, Mai Dang, Michael D'Angelica, Kurtis D. Davies, Myrtle Davis, Nicolas Dea, Ana De Jesus-Acosta, Angelo M. DeMarzo, Theodore L. DeWeese, Maximilian Diehn, Subba R. Digumarthy, Angela Dispenzieri, Khanh T. Do, Konstantin Dobrenkov, Jeffrey S. Dome, James H. Doroshow, Jay F. Dorsey, Marianne Dubard-Gault, Steven G. DuBois, Dan G. Duda, Malcolm Dunlop, Linda R. Duska, Madeleine Duvic, Imane El Dika, Hashem El-Serag, Jeffrey M. Engelmann, David S. Ettinger, Lola A. Fashoyin-Aje, Eric R. Fearon, James M. Ford, Wilbur A. Franklin, Phoebe E. Freer, Boris Freidlin, Alison G. Freifeld, Terence W. Friedlander, Debra L. Friedman, Arian F. Fuller, Lorenzo Galluzzi, Mark C. Gebhardt, Daniel J. George, Mark B. Geyer, Amato J. Giaccia, Mark R. Gilbert, Whitney Goldner, Donald P. Goldstein, Annekathryn Goodman, Karyn A. Goodman, Kathleen Gordon, Laura Graeff-Armas, Alexander J. Greenstein, Stuart A. Grossman, Stephan Grupp, Arjun Gupta, Irfanullah Haider, Missak Haigentz, John D. Hainsworth, Benjamin E. Haithcock, Christopher L. Hallemeier, Samir Hanash, Aphrothiti J. Hanrahan, James Harding, Michael R. Harrison, Muneer G. Hasham, Ernest Hawk, Jonathan Hayman, Jonathan E. Heinlen, N. Lynn Henry, Joseph Herman, Brian P. Hobbs, Ingunn Holen, Leora Horn, Neil S. Horowitz, Steven M. Horwitz, Odette Houghton, Scott C. Howard, Clifford A. Hudis, Stephen P. Hunger, Arti Hurria, David H. Ilson, Annie Im, Gopa Iyer, Elizabeth M. Jaffee, Reshma Jagsi, Rakesh K. Jain, William Jarnagin, Aminah Jatoi, Anuja Jhingran, David H. Johnson, Brian Johnston, Patrick G. Johnston, Kevin D. Judy, Lisa A. Kachnic, Orit Kaidar-Person, Sanjeeva Kalva, Deborah Y. Kamin, Hagop Kantarjian, Giorgos Karakousis, Maher Karam-Hage, Nadine M. Kaskas, Michael B. Kastan, Nora Katabi, Daniel R. Kaul, Scott R. Kelley, Nancy Kemeny, Erin E. Kent, Oliver Kepp, Simon Khagi, Joshua E. Kilgore, D. Nathan Kim, Bette K. Kleinschmidt-DeMasters, Edward L. Korn, Guido Kroemer, Geoffrey Y. Ku, Shivaani Kummar, Bonnie Ky, Daniel A. Laheru, Paul F. Lambert, Mark Lawler, Jennifer G. Le-Rademacher, John Y.K. Lee, Nancy Y. Lee, Susanna L. Lee, Jonathan E. Leeman, Andreas Linkermann, Jinsong Liu, Simon Lo, Jason W. Locasale, Charles L. Loprinzi, Maeve Lowery, Emmy Ludwig, Matthew A. Lunning, Robert A. Lustig, Mitchell Machtay, Crystal Mackall, David A. Mahvi, David M. Mahvi, Amit Maity, Neil Majithia, Marcos Malumbres, Karen Colbert Maresso, John D. Martin, Koji Matsuo, Natalie H. Matthews, Lauren Mauro, R. Samuel Mayer, Worta McCaskill-Stevens, Megan A. McNamara, Neha Mehta-Shah, Robert E. Merritt, Matthew I. Milowsky, Lori M. Minasian, Tara C. Mitchell, Demytra Mitsis, Michelle Mollica, Margaret Mooney, Farah Moustafa, Lida Nabati, Jarushka Naidoo, Amol Narang, Heidi Nelson, William G. Nelson, Suzanne Nesbit, Mark Niglas, Tracey O'Connor, Kenneth Offit, Mihaela Onciu, Eileen M. O’Reilly, Elaine A. Ostrander, Lisa Pappas-Taffer, Drew Pardoll, Jae H. Park, Anery Patel, Anish J. Patel, Steven R. Patierno, Steven Z. Pavletic, Peter C. Phillips, Miriam D. Post, Amy A. Pruitt, Christiane Querfeld, Vance A. Rabius, S. Vincent Rajkumar, Mohammad O. Ramadan, Erinn B. Rankin, Sushanth Reddy, Michael A. Reid, Scott Reznik, Tina Rizack, Jason D. Robinson, Leslie Robinson-Bostom, Carlos Rodriguez-Galindo, Paul B. Romesser, Steven T. Rosen, Myrna R. Rosenfeld, Nadia Rosenthal, Meredith Ross, Julia H. Rowland, Anthony H. Russell, Michael S. Sabel, Arjun Sahgal, Ryan D. Salinas, Erin E. Salo-Mullen, Manuel Salto-Tellez, Sydney M. Sanderson, John T. Sandlund, Victor M. Santana, Michelle Savage, Eric C. Schreiber, Lynn Schuchter, Liora Schultz, Michael V. Seiden, Morgan M. Sellers, Payal D. Shah, Jinru Shia, Konstantin Shilo, Eric Small, Angela B. Smith, Stephen N. Snow, David B. Solit, Anil K. Sood, Enrique Soto-Perez-de-Celis, Joseph A. Sparano, Vladimir S. Spiegelman, Sheri L. Spunt, Zsofia K. Stadler, David P. Steensma, Richard M. Stone, Steven Kent Stranne, Kelly Stratton, Bill Sugden, Andrew M. Swanson, Martin S. Tallman, James E. Talmadge, David T. Teachey, Catalina V. Teba, Ayalew Tefferi, Bin Tean Teh, Joyce M.C. Teng, Joel E. Tepper, Premal H. Thaker, Aaron P. Thrift, Arthur-Quan Tran, Grace Triska, Donald Trump, Kenneth Tsai, Chia-Lin Tseng, Diane Tseng, Sandra Van Schaeybroeck, Brian A. Van Tine, Erin R. Vanness, Gauri Varadhachary, Marileila Varella-Garcia, Richard L. Wahl, Michael F. Walsh, Thomas Wang, Jared Weiss, Irving L. Weissman, Shannon N. Westin, Jeffrey D. White, Richard Wilson, Richard J. Wong, Gary S. Wood, Yaohui G. Xu, Meng Xu-Welliver, Shlomit Yust-Katz, Timothy Zagar, Elaine M. Zeman, Tian Zhang, and James A. Zwiebel
- Published
- 2020
17. 1123O Evaluation of cell-free DNA approaches for multi-cancer early detection
- Author
-
Arash Jamshidi, John F. Beausang, Alan H. Bryce, Michael V. Seiden, M.K. Tummala, Charles Swanton, Kathryn N. Kurtzman, Kristi McIntyre, Donald A. Richards, Earl Hubbell, T.J. Yeatman, Minetta C. Liu, Oliver Venn, David D. Thiel, Mikkael A. Sekeres, Eric A. Klein, N. Zhang, Allen Lee Cohn, and Chenlu Hou
- Subjects
Oncology ,Cell-free fetal DNA ,business.industry ,Cancer research ,Medicine ,Hematology ,business ,Cancer Early Detection - Published
- 2021
18. PR01.08 Simultaneous Multi-Cancer Detection and Tissue of Origin Prediction Via Targeted Bisulfite Sequencing of Plasma Cell-Free DNA
- Author
-
Alexander P. Fields, Geoffrey R. Oxnard, Gross Samuel S, Eric A. Klein, Donald A. Richards, R. Shaknovich, P.P. Yu, E.T. Fung, J. Yecies, John F. Beausang, Anne-Renee Hartman, Mikkael A. Sekeres, A. Jamshidi, N. Zhang, Oliver Venn, Earl Hubbell, Alex Aravanis, Minetta C. Liu, Michael V. Seiden, and Kathryn N. Kurtzman
- Subjects
Pulmonary and Respiratory Medicine ,medicine.anatomical_structure ,Oncology ,business.industry ,Bisulfite sequencing ,medicine ,Cancer detection ,Plasma cell ,business ,Free dna ,Molecular biology - Published
- 2021
19. Abstract LB058: Performance of a cell-free DNA-based multi-cancer detection test as a tool for diagnostic resolution of symptomatic cancers
- Author
-
Carlos Becerra, Donald A. Richards, Michael V. Seiden, Jingjing Gao, Earl Hubbell, Quan Zhang, Xiaoji Chen, Minetta C. Liu, Eric T. Fung, Kathryn N. Kurtzman, Nan Zhang, Eric A. Klein, Arash Jamshidi, Alan H. Bryce, Tony J. Wu, and David D. Thiel
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Hematology ,business.industry ,Confounding ,Cancer ,Cancer detection ,medicine.disease ,Confidence interval ,Test (assessment) ,Cell-free fetal DNA ,Internal medicine ,medicine ,Stage (cooking) ,business - Abstract
Introduction: A test that detects cancer signal across multiple cancer types and predicts signal (tissue) origin (SO) could aid in more efficient diagnostic workup and shorten time to cancer diagnosis in individuals with signs and symptoms.Methods: The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study is a prospective, longitudinal, multicenter, case-control study to develop and validate a multi-cancer detection test. The 2nd CCGA substudy utilized a targeted methylation-based cell-free DNA assay and machine learning algorithm and included assessment of test performance (sensitivity and SO prediction accuracy) in a subgroup of participants with clinically presenting cancers (CPCs) that were undiagnosed prior to blood draw. Specificity was assessed in the noncancer group and subgroups with confounding (nonmalignant) conditions (CCs; eg, cirrhosis) and noncancer participants enrolled in hematology clinics (HCs).Results: Specificity was 99.5% (95% confidence interval: 98.2-99.9%; 396/398), 93.8% (71.7-99.7%; 15/16), and 99.3% (96.0-100.0%; 136/137) for the noncancer group, CCs subgroup, and HCs subgroup, respectively. Overall sensitivity among those with CPCs was 66.4% (62.2-70.3%; 344/518). Sensitivity of cancer signal detection increased with increasing clinical stage (Table). SO prediction accuracy was 91.7% (88.3-94.3%; 300/327) among CPC participants with cancers detected, excluding those with multiple or unknown primaries. The test demonstrated prognostic value as detected cancer participants had worse survival probability than those not detected. Conclusions: This multi-cancer detection test detected cancer signals and predicted SO in individuals with CPCs with high specificity. These findings support further clinical development of this multi-cancer detection test that could accelerate the diagnostic resolution of symptomatic cancers. Table. Sensitivity by Clinical Stage Across Cancer Type in Clinically Presenting CancersClinical StagePositive Test/Total Cancer; Sensitivity (95% CI)All*344/518; 66.4% (62.2-70.3%)I33/122; 27.0% (20.0-35.5%)II60/102; 58.8% (49.1-67.9%)III103/121; 85.1% (77.7-90.4%)IV136/147; 92.5% (87.1-95.8%)Not expected to be staged9/21; 42.9% (24.5-63.5%)Non-informative2/4; 50.0% (15.0-85.0%)CI, confidence interval.*One participant who had a positive test result had multiple primaries with clinical stage I and not-expected-to-be-staged. Citation Format: Alan H. Bryce, Minetta C. Liu, Michael V. Seiden, David D. Thiel, Donald Richards, Carlos Becerra, Kathryn N. Kurtzman, Xiaoji Chen, Tony Wu, Quan Zhang, Jingjing Gao, Nan Zhang, Earl Hubbell, Arash Jamshidi, Eric T. Fung, Eric A. Klein. Performance of a cell-free DNA-based multi-cancer detection test as a tool for diagnostic resolution of symptomatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB058.
- Published
- 2021
20. Final report on serial phase II trials of all-intraperitoneal chemotherapy with or without bevacizumab for women with newly diagnosed, optimally cytoreduced carcinoma of Müllerian origin
- Author
-
Ursula A. Matulonis, D. K. Armstrong, Michael J. Birrer, Cesar M. Castro, Michael V. Seiden, Don S. Dizon, Carolyn N. Krasner, Mark A. Morgan, Maria Roche, Richard T. Penson, J.K. Wolfe, Hang Lee, Jeffrey G. Supko, and Charles W. Drescher
- Subjects
0301 basic medicine ,Adult ,medicine.medical_specialty ,Bevacizumab ,Paclitaxel ,medicine.medical_treatment ,Ovariectomy ,Carcinoma, Ovarian Epithelial ,Gastroenterology ,Drug Administration Schedule ,Carboplatin ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,Medicine ,Humans ,Infusions, Parenteral ,Infusions, Intravenous ,Mullerian Ducts ,Aged ,Ovarian Neoplasms ,Chemotherapy ,business.industry ,Obstetrics and Gynecology ,Cytoreduction Surgical Procedures ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Regimen ,030104 developmental biology ,Oncology ,chemistry ,Tolerability ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Female ,business ,Ovarian cancer ,medicine.drug - Abstract
Background Intraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). Methods Both trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m2 on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. Results 81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36–76) and 55 (range, 19–69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3–4 diarrhea (22 versus 8%). Median PFS was 23.5 (95%CI 16.2–35.3) and 25 (95%CI 16.4–42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95%CI 59.0–79.7) months, respectively for Trial A and B. Conclusions Weekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials.
- Published
- 2018
21. Abstract CT021: Prediction of cancer and tissue of origin in individuals with suspicion of cancer using a cell-free DNA multi-cancer early detection test
- Author
-
Quan Zhang, Eric T. Fung, Earl Hubbell, Xiaoji Chen, Jessica L. Yecies, Geoffrey R. Oxnard, Anne-Renee Hartman, Hai Liu, Tony J. Wu, Alex Aravanis, Kathryn N. Kurtzman, Michael V. Seiden, David D. Thiel, Minetta C. Liu, Nan Zhang, and Eric A. Klein
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Training set ,business.industry ,Cancer ,Renal cancers ,medicine.disease ,Cancer Early Detection ,Confidence interval ,Cell-free fetal DNA ,Clinical diagnosis ,Internal medicine ,medicine ,False positive rate ,business - Abstract
Background: The Circulating Cell-free Genome Atlas study (NCT02889978) is a multi-center, case-control, observational study with longitudinal follow-up (n=15,254; 56% cancer, 44% non-cancer) to support development of a cell-free DNA (cfDNA) multi-cancer early detection test. Previously, we reported that a targeted methylation assay detected and localized >20 cancer types at >99% specificity in individuals with cancer.1,2 Here, we report prediction of cancer (presence/absence) and tissue of origin (TOO) in individuals enrolled with clinical suspicion of cancer but without pathologic diagnosis or treatment at time of enrollment. Methods: Plasma cfDNA from blood samples collected prior to clinical diagnosis was subjected to targeted methylation sequencing. Samples were divided into a training set and an independent validation set to train and validate a machine learning classifier to assess cancer and predict TOO. Performance was assessed in a subset of participants enrolled with suspicion of cancer; subsequently, cancer was confirmed by evaluating a pathologic specimen. Results: Participants being evaluated for suspicion of cancer were classified as confirmed cancer (>20 cancer types; n=164 in training, n=75 in validation) or confirmed non-cancer (n=49 training, n=15 validation). In the confirmed non-cancer group, all training and validation samples were correctly predicted as non-cancer (100% specificity). In the confirmed cancer group, cancer detection across all stages was 40.2% (66/164; 95% confidence interval [CI], 32.7-48.2%) in training and 46.7% (35/75; 95% CI, 35.1-58.6%) in validation. Excluding stage I renal cancers (where detection/tumor fraction is low in plasma and which comprised 20% of participants in this subset) detection across stages was 50.4% (66/131; 95% CI, 41.5-59.2%) and 59.3% (35/59; 95% CI, 45.7-71.9%), respectively. In stages II and above, detection was 70.7% (58/82; 95% CI, 59.6-80.3%) and 78.9% (30/38; 95% CI, 62.7-90.4%), respectively. For detected cancers, TOO was predicted in 93.9% (62/66) samples in training and 100% (35/35) in validation. Of those with a TOO call, accuracy was 85.5% (53/62; 95% CI, 74.2-93.1%) and 97.1% (34/35; 95% CI, 85.1-99.9%), respectively. Conclusion: A cfDNA multi-cancer detection test has shown the potential to predict cancer and TOO in individuals with suspicion of cancer ahead of histologic diagnosis with performance comparable to those with confirmed cancer at the time of blood collection. This was achieved with high specificity and TOO accuracy. The high specificity suggests that the false positive rate could be comparable in populations with average versus higher risk (suspicion) of cancer. These findings suggest that a cfDNA multi-cancer detection test could accelerate the diagnostic resolution of suspicion of cancer. References: 1. Oxnard GR, et al. ASCO Breakthrough Meeting 2019; Abstract 44. 2. Oxnard GR, et al. ESMO Annual Meeting 2019; Abstract 5639. Citation Format: David D. Thiel, Xiaoji Chen, Kathryn N. Kurtzman, Jessica Yecies, Tony Wu, Quan Zhang, Hai Liu, Nan Zhang, Eric T. Fung, Michael V. Seiden, Minetta C. Liu, Geoffrey R. Oxnard, Earl Hubbell, Alexander M. Aravanis, Anne-Renee Hartman, Eric A. Klein. Prediction of cancer and tissue of origin in individuals with suspicion of cancer using a cell-free DNA multi-cancer early detection test [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT021.
- Published
- 2020
22. Su1772 MULTI-CANCER DETECTION OF EARLY-STAGE CANCERS WITH SIMULTANEOUS TISSUE LOCALIZATION USING A PLASMA CIRCULATING TUMOR CELL-FREE DNA-BASED TARGETED METHYLATION ASSAY
- Author
-
Oliver Venn, Samuel Gross, Eric T. Fung, Peter T. Yu, Hai Liu, Minetta C. Liu, Anne-Renee Hartman, Nan Zhang, Earl Hubbell, Geoffrey R. Oxnard, Michael V. Seiden, Eric A. Klein, Alex Aravanis, Mikkael A. Sekeres, Kathryn N. Kurtzman, Donalds Richards, John F. Beausang, Brian C. Allen, Alexander P. Fields, and Arash Jamshidi
- Subjects
Circulating tumor cell ,Hepatology ,Chemistry ,Gastroenterology ,Cancer research ,Cancer detection ,Methylation ,Stage (cooking) ,Free dna - Published
- 2020
23. Reevaluation of matrix-isolation infrared spectra of the isotopologues of trans-diazene and attempts to prepare cis-diazene by photoisomerization
- Author
-
Kwabena J. Appiah, Joseph E. Varley, Charles E. Miller, Michael V. Seiden, and Norman C. Craig
- Subjects
Photoisomerization ,Infrared ,Matrix isolation ,Infrared spectroscopy ,Atomic and Molecular Physics, and Optics ,chemistry.chemical_compound ,Crystallography ,chemistry ,Deuterium ,Diimide ,Isotopologue ,Physical and Theoretical Chemistry ,Spectroscopy ,Cis–trans isomerism - Abstract
IR spectra of trans -diazene (diimide, HN NH) have been recorded in nitrogen and argon matrices at 20 K. An IR spectrum of a mixture of trans -diazene- d 1 and - d 2 in a nitrogen matrix has also been recorded. The method for preparing pure trans-diazene has been clarified. Revised assignments are reported for these spectra. A definitive experimental assignment of the wavenumbers of normal modes the three hydrogen/deuterium isotopologues is given. Attempts were made to photoisomierize matrix-isolated trans -diazene into the elusive cis isomer. No bands for the cis isomer were found.
- Published
- 2015
24. Advanced APMs and the emerging role of immuno-oncology agents: balancing innovation and value
- Author
-
Michael V, Seiden, Marcus, Neubauer, and Diana, Verrilli
- Subjects
Reimbursement Mechanisms ,Neoplasms ,Humans ,Immunotherapy ,Medical Oncology - Published
- 2017
25. Simultaneous multi-cancer detection and tissue of origin (TOO) localization using targeted bisulfite sequencing of plasma cell-free DNA (cfDNA)
- Author
-
Earl Hubbell, Oliver Venn, Donald A. Richards, Arash Jamshidi, John F. Beausang, P.P. Yu, Gross Samuel S, Eric A. Klein, Geoffrey R. Oxnard, Mikkael A. Sekeres, N. Zhang, E.T. Fung, Anne-Renee Hartman, H. Liu, Michael V. Seiden, Alex Aravanis, Kathryn N. Kurtzman, Minetta C. Liu, Alexander P. Fields, and Brian C. Allen
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Cancer Research ,Bisulfite sequencing ,Stock options ,Cancer detection ,Stage ii ,Plasma cell ,Free dna ,Single test ,03 medical and health sciences ,Breast cancer ,0302 clinical medicine ,Shareholder ,Internal medicine ,medicine ,Blood test ,030212 general & internal medicine ,Head and neck ,Cancer mortality ,medicine.diagnostic_test ,business.industry ,Hematology ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,business - Abstract
Background Our previous discovery work identified whole-genome bisulfite sequencing as outperforming whole-genome and targeted sequencing approaches for multi-cancer detection. We developed a targeted methylation assay for multi-cancer detection and tissue of origin (TOO) localization. Methods Participants were from Circulating Cell-free Genome Atlas (CCGA; NCT02889978) and STRIVE (NCT03085888), both prospective, multi-center, observational studies with longitudinal follow-up. cfDNA from 3,583 evaluable samples (1,530 cancer, 2,053 non-cancer) spanned >20 tumor types of all stages; a prespecified subset of these comprised the "multi-cancer" group: anorectal, hormone-receptor (HR)-negative breast, colorectal, esophageal, gallbladder, gastric, head and neck, hepatobiliary, lung, lymphoid leukemia, lymphoma, multiple myeloma, ovarian, and pancreatic (937 cancer [all stages]). A cross-validated targeted methylation test evaluated cfDNA for predictability of cancer presence and TOO; precision defined as the fraction of correct calls. Breast and lung cancer subtypes were also assessed. All analyses targeted 99.4% specificity (0.6% false-positive rate). Results Participants with and without cancer were similar in age. Specificity was set to 99.4%. For the prespecified multi-cancer group, overall sensitivity was 76% (73-78): stage I 32% (25-40), stage II 76% (69-82), stage III 85% (80-89), and stage IV 93% (89-95). Among all samples, overall sensitivity was 55% (52-57%): stage I 19% (15-23%), stage II 43% (38-48%), stage III 78% (73-82%), and stage IV 90% (86-93%). Overall TOO precision for the multi-cancer group and all samples was 89%, and was similar across stages. Squamous-cell and small-cell lung cancer had higher sensitivity than adenocarcinoma: 84% (75-91) vs 83% (69-92) vs 58% (49-67); HR-negative had higher sensitivity than HR-positive breast cancer: 66% (53-77) vs 20% (15-27). Conclusions This targeted methylation assay detected cancer signal across >20 cancer types with a single, fixed, low false positive rate and highly accurate TOO localization. These data support the feasibility of a single test that can screen for multiple cancers. Clinical trial identification NCT02889978, NCT03085888. Editorial acknowledgement Sarah Prins, PhD (GRAIL, Inc.), and Megan P. Hall, PhD (GRAIL, Inc.). Legal entity responsible for the study GRAIL, Inc. Funding GRAIL, Inc. Disclosure G.R. Oxnard: Advisory / Consultancy, Officer / Board of Directors: Inivata; Honoraria (self): Guardant Health; Honoraria (self): Sysmex; Honoraria (self): Bio-Rad; Advisory / Consultancy: DropWorks; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: GRAIL, Inc.. E.A. Klein: Advisory / Consultancy: GRAIL, Inc.; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: GenomeDx Biosciences. M.V. Seiden: Shareholder / Stockholder / Stock options, Full / Part-time employment: McKesson. E. Hubbell: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. O. Venn: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. A. Jamshidi: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc.; Shareholder / Stockholder / Stock options: Illumina. N. Zhang: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. J.F. Beausang: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. S. Gross: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. K.N. Kurtzman: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc.; Shareholder / Stockholder / Stock options: Illumina. E.T. Fung: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. B. Allen: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. A.P. Fields: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. H. Liu: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. A.M. Aravanis: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. A. Hartman: Shareholder / Stockholder / Stock options, Full / Part-time employment: GRAIL, Inc. M.C. Liu: Honoraria (institution): GRAIL, Inc. All other authors have declared no conflicts of interest.
- Published
- 2019
26. The Circulating Cell-free Genome Atlas (CCGA) Study: Follow-up (F/U) on non-cancer participants with cancer-like cell-free DNA signals
- Author
-
Kathryn N. Kurtzman, David M. Waterhouse, Michael V. Seiden, Anne-Renee Hartman, Oliver Venn, Allen Lee Cohn, Eric A. Klein, Minetta C. Liu, Geoffrey R. Oxnard, Samuel Gross, Eric T. Fung, and Earl Hubbell
- Subjects
Cancer Research ,medicine.diagnostic_test ,business.industry ,Non cancer ,Cancer detection ,Cell free ,Genome ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,Cell-free fetal DNA ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,Blood test ,business ,DNA ,030215 immunology - Abstract
5574 Background: A noninvasive cell-free DNA (cfDNA)-based cancer detection assay offers the hope of a blood test that might reduce morbidity and mortality of cancers, particularly those without recommended screening tests (eg, some gynecologic cancers). CCGA (NCT02889978) is a prospective, multi-center, longitudinal, case-control study evaluating models for discriminating cancer versus non-cancer. Here, we report F/U of control participants (pts) who demonstrated a cancer-signal in CCGA. Methods: Clinically evaluable samples (N = 2508) from pts enrolled without a cancer diagnosis (dx; NC) and treatment-naive pts with newly diagnosed cancer (C) were divided into training (n = 1564; 580 NC, 984 C) and test (n = 944; 368 NC, 576 C) sets. Classification performance (cancer/non-cancer) was assessed via 3 prototype assays: whole-genome bisulfite (WGBS), whole-genome (WGS), and targeted (507 gene) sequencing. Notable outlier NC pts were identified with cancer-like scores in either ≥2 assay classification results or by the presence of known cancer drivers with ≥1 assay classification result suggesting cancer. All pts are currently in F/U in accordance with study protocol (to date: 80% with > 10 mo and 15% with > 22 mo F/U). Results: Among training and test sets, 8 ( < 1%) NC pts were identified with a cancer-like signal. To-date, 2 have been diagnosed with a gynecologic malignancy: 1 stage IIIc clear cell endometrial carcinoma and 1 stage IIIc ovarian cancer, 3 and 2 months (mo) post-enrollment [PE], respectively. Among C pts in the study, sensitivity (at 98% specificity; WGBS) in these cancer types was: uterine/endometrial: 11% (n = 27 train) and 22% (n = 9 test); ovarian: 82% (n = 17) and 71% (n = 7). In addition, a third NC pt was diagnosed with a stage IV lung cancer 15 mo PE. Conclusions: This cfDNA-based assay detected a cancer-like signal that anticipated a clinical presentation of cancer in undiagnosed pts as early as 15 months prior to the actual dx. High specificity ( > 99%) requires accounting for undiagnosed cancers in study design and analysis. Together, these data suggest that this prototype assay may have high performance detecting a variety of gynecological and other cancers. Clinical trial information: NCT02889978.
- Published
- 2019
27. Prognostic significance of blood-based cancer detection in plasma cell-free DNA (cfDNA): Evaluating risk of overdiagnosis
- Author
-
Eric A. Klein, Ting Ma, Earl Hubbell, Alex Aravanis, Zhao Dong, Xiaoji Chen, Geoffrey R. Oxnard, Shilpen Patel, Eric T. Fung, David R. Spigel, Michael V. Seiden, Jacqueline D. Brooks, Anne-Renee Hartman, Jafi A. Lipson, Kathryn N. Kurtzman, Minetta C. Liu, Rita Shaknovich, and Hai Liu
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Screening test ,business.industry ,Cancer detection ,Plasma cell ,Free dna ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Good prognosis ,Overdiagnosis ,Early Cancer Detection ,business ,030215 immunology - Abstract
1545 Background: Screening tests for early cancer detection are often criticized due to risk of overdiagnosis—detection of good prognosis cancers which may not require immediate treatment. We recently reported development of cfDNA sequencing approaches for cancer detection; longitudinal follow-up (F/U) data were utilized here to evaluate prognostic significance of cancer detection using cfDNA. Methods: Plasma cfDNA samples were subjected to whole-genome bisulfite sequencing (WGBS, 30X) as part of a previously-reported Circulating Cell-free Genome Atlas (CCGA; NCT02889978) substudy. This exploratory analysis evaluated the overall survival (OS) of training and test set participants (pts) with cancer (20 cancer types, any stage I-IV). Combining train and test set pts, univariate and multivariate analyses (Cox proportional hazards) assessed OS association with WGBS result (cancer detected vs not detected, set at 98% specificity), clinical stage (IV vs I-III), diagnostic method (symptom- vs screen-detected), sex, age, and histologic grade. Results: Of 827 pts from the training set with F/U (median 12.2 mo), 334 (40.4%) had WGBS-detected cancer. Among 127 (15.4%) pts with cancer that died during F/U, cancer was detected in 104 (81.9%). Results were similar in the test set. In univariate analyses all variables were associated with prognosis, including WGBS result (HR 7.7 p
- Published
- 2019
28. Rare Epithelial Tumors Arising in or near the Ovary: A Review of the Risk Factors, Presentation, and Future Treatment Direction for Ovarian Clear Cell and Mucinous Carcinoma
- Author
-
Angela, Jain and Michael V, Seiden
- Subjects
Ovarian Neoplasms ,Treatment Outcome ,Predictive Value of Tests ,Risk Factors ,Biomarkers, Tumor ,Humans ,Female ,Genetic Predisposition to Disease ,Neoplasms, Glandular and Epithelial ,General Medicine ,Carcinoma, Ovarian Epithelial ,Adenocarcinoma, Mucinous ,Neoplasm Staging - Abstract
Currently all advanced-stage epithelial ovarian cancers are treated with a total abdominal hysterectomy, bilateral oophorectomy, and complete tumor debulking surgery, followed by carboplatin and paclitaxel. This treatment recommendation is based on clinical trials that are mostly populated with women with high-grade serous carcinomas. Patients with mucinous or clear cell carcinomas of the ovary tend to present with earlier-stage disease, and may not require adjuvant chemotherapy; those with advanced-stage disease tend to have carboplatin-resistant disease. Patients with mucinous ovarian carcinoma have presentations and tumor biology that are similar to colorectal carcinomas and may benefit from colorectal regimens containing fluorouracil (FU) and oxaliplatin. Their tumors may also be KRAS wild-type or have HER2 amplification, and could benefit from drugs like cetuximab or trastuzumab. Patients with clear cell carcinoma of the ovary often harbor AIRD1a mutations, an early event in oncogenesis that is not a currently drugable target. Anecdotal cases and our biologic understanding of these malignancies suggest they might be preferentially sensitive to antiangiogenesis inhibitors. Focused international trials will be needed in both of these rare epithelial ovarian cancers to better define optimal treatment regimens.
- Published
- 2013
29. The FACIT-AI, a new tool for assessing symptoms associated with malignant ascites
- Author
-
Jay Thomas, David Cella, Jean S. Kutner, Michael V. Seiden, and Nikki L. Neubauer
- Subjects
Adult ,medicine.medical_specialty ,Constipation ,Genital Neoplasms, Female ,MEDLINE ,Quality of life ,Surveys and Questionnaires ,Internal medicine ,Ascites ,medicine ,Content validity ,Humans ,Clinical significance ,Aged ,Aged, 80 and over ,business.industry ,Reproducibility of Results ,Obstetrics and Gynecology ,Middle Aged ,humanities ,Clinical trial ,Clinical research ,Oncology ,Physical therapy ,Female ,Symptom Assessment ,medicine.symptom ,business - Abstract
Objective The objectives of this study are to assess the clinical relevance and validity of the Functional Assessment of Chronic Illness Therapy-Ascites Index (FACIT-AI) in women with ovarian cancer and malignant ascites, and to modify the instrument guided by qualitative feedback from patients with recurrent malignant ascites. Methods Fourteen adult female patients with recurrent symptomatic malignant ascites were enrolled from three centers. All completed an open-ended symptom list to identify their primary concerns regarding their condition. They then completed a draft 10-item FACIT-AI questionnaire created from expert input. Eleven patients provided comments regarding the FACIT-AI questionnaire using a written feedback format. Three patients participated in a "think-aloud" cognitive debriefing interview to ensure patient comprehension of questionnaire items. Results Of the first 11 patients surveyed, 7 believed that the draft FACIT-AI contained all important symptoms associated with malignant ascites. Responses from the remaining 4 patients revealed three symptoms that 2 or more patients nominated for inclusion: urinary frequency, constipation and emotional distress. These items were added to the original FACIT-AI to produce a 13-item index of symptoms associated with malignant ascites. Conclusions The 13-item FACIT-AI has content validity among women with malignant ascites associated with ovarian cancer. It is available for use in clinical research or practice, with the expectation that more will be learned about its performance and interpretation over time.
- Published
- 2013
30. Metastatic Mucinous Ovarian Cancer and Treatment Decisions Based on Histology and Molecular Markers Rather Than the Primary Location
- Author
-
Paula D. Ryan, Angela Jain, and Michael V. Seiden
- Subjects
Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Bevacizumab ,Receptor, ErbB-2 ,medicine.medical_treatment ,Ovary ,Antibodies, Monoclonal, Humanized ,Cystadenocarcinoma, Mucinous ,Lapatinib ,Young Adult ,Trastuzumab ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Mucinous carcinoma ,Cystadenocarcinoma ,Ovarian Neoplasms ,Chemotherapy ,Brain Neoplasms ,Vascular Endothelial Growth Factors ,business.industry ,medicine.disease ,ErbB Receptors ,medicine.anatomical_structure ,Quinazolines ,Female ,Ovarian cancer ,business ,medicine.drug - Abstract
Approximately 22,000 cases of ovarian cancer occur each year in the United States, and likely fewer than 2000 cases of mucinous ovarian cancers. Although 90% of patients with mucinous ovarian cancer present with stage I disease and have curative surgeries, advanced-stage disease is known to have a poor response to standard platinum- and taxane-based chemotherapy. Despite limited enthusiasm, standard chemotherapy is still recommended for most patients with advanced-stage mucinous malignancies of the ovary. This report presents an unusual case of a woman with HER2-positive metastatic mucinous carcinoma of the ovary treated with chemotherapy regimens typically used for colorectal malignancies, followed by epidermal growth factor receptor-targeted therapies.
- Published
- 2012
31. Plasma cell-free DNA (cfDNA) assays for early multi-cancer detection: The circulating cell-free genome atlas (CCGA) study
- Author
-
Anne-Renee Hartman, Geoffrey R. Oxnard, J. Yecies, Kathryn N. Kurtzman, Arash Jamshidi, John F. Beausang, Timothy J. Yeatman, Tara Maddala, N. Zhang, Eric A. Klein, David Smith, Minetta C. Liu, Alex Aravanis, Gross Samuel S, S. Patel, L. Shen, Michael V. Seiden, Darya Filippova, Earl Hubbell, and Oliver Venn
- Subjects
0301 basic medicine ,business.industry ,Hematology ,Cell free ,Cancer detection ,Plasma cell ,Genome ,Free dna ,Molecular biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,Atlas (anatomy) ,030220 oncology & carcinogenesis ,Medicine ,business - Published
- 2018
32. Abstract LB-343: Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas Study (CCGA)
- Author
-
Arash Jamshidi, Timothy J. Yeatman, Tara Maddala, Daniel Civello, Chenlu Hou, Anne-Renee Hartman, Roger Jiang, Rosanna Lapham, Kristan Steffen, Samuel Gross, Craig Betts, Ling Shen, Donald A. Richards, Byoungsok Jung, Seyedmehdi Shojaee, Collin Melton, Onur Sakarya, Hui Xu, Ravi Vijaya Satya, Konstantin Davydov, Jeanne Yue, Geoffrey R. Oxnard, Jonathan Newman, Robert Tibshirani, Cosmos Nicolaou, Earl Hubbell, José Baselga, Shivani Nautiyal, John A. Beausang, David J. Smith, Christina Curtis, Charles Swanton, Hamed Amini, Sante Gnerre, Michael V. Seiden, Darya Filippova, Oliver Venn, Kathryn N. Kurtzman, Saniya Fazullina, Richard P. Rava, Richard J. Williams, Nan Zhang, Eric A. Klein, Alex Aravanis, Joshua Newman, Minetta C. Liu, Daron G. Davis, Anton Valouev, and Sylvia K. Plevritis
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Concordance ,Bisulfite sequencing ,Newly diagnosed ,Cell free ,Plasma cell ,Biology ,Free dna ,Genome ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Internal medicine ,medicine ,Early Cancer Detection - Abstract
CCGA [NCT02889978] is the largest study of cfDNA-based early cancer detection; the first CCGA learnings from multiple cfDNA assays are reported here. This prospective, multi-center, observational study has enrolled 10,012 of 15,000 demographically-balanced participants at 141 sites. Blood was collected from participants with newly diagnosed therapy-naive cancer (C, case) and participants without a diagnosis of cancer (noncancer [NC], control) as defined at enrollment. This preplanned substudy included 878 cases, 580 controls, and 169 assay controls (n=1627) across 20 tumor types and all clinical stages. All samples were analyzed by: 1) Paired cfDNA and white blood cell (WBC)-targeted sequencing (60,000X, 507 gene panel); a joint caller removed WBC-derived somatic variants and residual technical noise; 2) Paired cfDNA and WBC whole-genome sequencing (WGS; 35X); a novel machine learning algorithm generated cancer-related signal scores; joint analysis identified shared events; and 3) cfDNA whole-genome bisulfite sequencing (WGBS; 34X); normalized scores were generated using abnormally methylated fragments. In the targeted assay, non-tumor WBC-matched cfDNA somatic variants (SNVs/indels) accounted for 76% of all variants in NC and 65% in C. Consistent with somatic mosaicism (i.e., clonal hematopoiesis), WBC-matched variants increased with age; several were non-canonical loss-of-function mutations not previously reported. After WBC variant removal, canonical driver somatic variants were highly specific to C (e.g., in EGFR and PIK3CA, 0 NC had variants vs 11 and 30, respectively, of C). Similarly, of 8 NC with somatic copy number alterations (SCNAs) detected with WGS, 4 were derived from WBCs. WGBS data revealed informative hyper- and hypo-fragment level CpGs (1:2 ratio); a subset was used to calculate methylation scores. A consistent “cancer-like” signal was observed in 99% specificity for invasive cancer, and support the promise of cfDNA assay for early cancer detection. Additional data will be presented on detected plasma:tissue variant concordance and on multi-assay modeling. Citation Format: Alexander A. Aravanis, Geoffrey R. Oxnard, Tara Maddala, Earl Hubbell, Oliver Venn, Arash Jamshidi, Ling Shen, Hamed Amini, John A. Beausang, Craig Betts, Daniel Civello, Konstantin Davydov, Saniya Fazullina, Darya Filippova, Sante Gnerre, Samuel Gross, Chenlu Hou, Roger Jiang, Byoungsok Jung, Kathryn Kurtzman, Collin Melton, Shivani Nautiyal, Jonathan Newman, Joshua Newman, Cosmos Nicolaou, Richard Rava, Onur Sakarya, Ravi Vijaya Satya, Seyedmehdi Shojaee, Kristan Steffen, Anton Valouev, Hui Xu, Jeanne Yue, Nan Zhang, Jose Baselga, Rosanna Lapham, Daron G. Davis, David Smith, Donald Richards, Michael V. Seiden, Charles Swanton, Timothy J. Yeatman, Robert Tibshirani, Christina Curtis, Sylvia K. Plevritis, Richard Williams, Eric Klein, Anne-Renee Hartman, Minetta C. Liu. Development of plasma cell-free DNA (cfDNA) assays for early cancer detection: first insights from the Circulating Cell-Free Genome Atlas Study (CCGA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-343.
- Published
- 2018
33. Prevalence of clonal hematopoiesis of indeterminate potential (CHIP) measured by an ultra-sensitive sequencing assay: Exploratory analysis of the Circulating Cancer Genome Atlas (CCGA) study
- Author
-
José Baselga, Minetta C. Liu, John F. Beausang, Samuel Gross, Ling Shen, Nan Zhang, Richard Thomas Williams, Oliver Venn, Arash Jamshidi, Geoffrey R. Oxnard, Charles Swanton, Timothy J. Yeatman, Alex Aravanis, Tara Maddala, Anne-Renee Hartman, Michael V. Seiden, Darya Filippova, Kelly L. Bolton, Anton Valouev, and Earl Hubbell
- Subjects
0301 basic medicine ,Cancer Research ,business.industry ,Clonal hematopoiesis ,Exploratory analysis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer genome ,Cancer research ,Hematopoietic progenitor cells ,Medicine ,Indeterminate ,business ,Ultra sensitive - Abstract
12003Background: CHIP is defined by the presence of age-dependent acquired mutations in hematopoietic progenitor cells and has been reported to occur in up to 30% of individuals 60-70 years of age....
- Published
- 2018
34. CD133 Expression Defines a Tumor Initiating Cell Population in Primary Human Ovarian Cancer
- Author
-
Michael V. Seiden, Bo R. Rueda, Drucilla J. Roberts, Michael D. Curley, Anne M. Friel, David T. Scadden, Rosemary Foster, Petra A. Sergent, Vanessa A. Therrien, Carolyn R. Koulouris, and Christine L. Cummings
- Subjects
Population ,Cell ,Cell Count ,Mice, SCID ,Nod ,Biology ,Metastasis ,Mice ,Ovarian tumor ,Antigens, CD ,Mice, Inbred NOD ,Cancer stem cell ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,AC133 Antigen ,education ,Glycoproteins ,Ovarian Neoplasms ,education.field_of_study ,Cell Biology ,Cell sorting ,medicine.disease ,Xenograft Model Antitumor Assays ,medicine.anatomical_structure ,Immunology ,Neoplastic Stem Cells ,Cancer research ,Molecular Medicine ,Female ,Peptides ,Ovarian cancer ,Developmental Biology - Abstract
Evidence is accumulating that solid tumors contain a rare phenotypically distinct population of cells, termed cancer stem cells (CSC), which give rise to and maintain the bulk of the tumor. These CSC are thought to be resistant to current chemotherapeutic strategies due to their intrinsic stem-like properties and thus may provide the principal driving force behind recurrent tumor growth. Given the high frequency of recurrent metastasis associated with human ovarian cancer, we sought to determine whether primary human ovarian tumors contain populations of cells with enhanced tumor-initiating capacity, a characteristic of CSC. Using an in vivo serial transplantation model, we show that primary uncultured human ovarian tumors can be reliably propagated in NOD/SCID mice, generating heterogeneous tumors that maintain the histological integrity of the parental tumor. The observed frequency of tumor engraftment suggests only certain subpopulations of ovarian tumor cells have the capacity to recapitulate tumor growth. Further profiling of human ovarian tumors for expression of candidate CSC surface markers indicated consistent expression of CD133. To determine whether CD133 expression could define a tumor-initiating cell population in primary human ovarian tumors, fluorescence-activated cell sorting (FACS) methods were employed. Injection of sorted CD133+ and CD133− cell populations into NOD/SCID mice established that tumor-derived CD133+ cells have an increased tumorigenic capacity and are capable of recapitulating the original heterogeneous tumor. Our data indicate that CD133 expression defines a NOD/SCID tumor initiating subpopulation of cells in human ovarian cancer that may be an important target for new chemotherapeutic strategies aimed at eliminating ovarian cancer. Disclosure of potential conflicts of interest is found at the end of this article.
- Published
- 2009
35. CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells
- Author
-
Francis J. Hornicek, Michael V. Seiden, Rachel Y. Ames, Zhenfeng Duan, Henry J. Mankin, and Meagan B. Ryan
- Subjects
STAT3 Transcription Factor ,Cancer Research ,Blotting, Western ,Apoptosis ,Biology ,Toxicology ,Article ,chemistry.chemical_compound ,Survivin ,Tumor Cells, Cultured ,medicine ,Humans ,Pharmacology (medical) ,RNA, Messenger ,Oleanolic Acid ,Phosphorylation ,Cell Proliferation ,Ovarian Neoplasms ,Pharmacology ,Interleukin-6 ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Kinase ,medicine.disease ,Drug Resistance, Multiple ,Protein Transport ,Oncology ,Paclitaxel ,chemistry ,Drug Resistance, Neoplasm ,Cancer research ,Female ,Signal transduction ,Ovarian cancer ,Signal Transduction - Abstract
Previous studies have identified interleukin 6 (IL-6) as an important cytokine with prognostic significance in ovarian cancer. Activation of the IL-6-Stat3 pathway contributes to tumor cell growth, survival and drug resistance in several cancers, including ovarian cancer. To explore potential therapeutic strategies for interrupting signaling through this pathway, we assessed the ability of CDDO-Me, a synthetic triterpenoid, to inhibit IL-6 secretion, Stat3 phosphorylation, Stat3 nuclear translocation and paclitaxel sensitivity in several cell line model systems. These studies demonstrated that CDDO-Me significantly inhibits IL-6 secretion in paclitaxel-resistant ovarian cancer cells and specifically suppresses IL-6- or oncostatin M-induced Stat3 nuclear translocation. Treatment with CDDO-Me significantly decreases the levels of Stat3, Jak2, and Src phosphorylation in ovarian and breast cancer cell lines with constitutively activated Stat3. This inhibition of the IL-6-Stat3 pathway correlated with suppression of the anti-apoptotic Stat3 target genes Bcl-X(L), survivin, and Mcl-1, and with apoptosis induction as measured by monitoring PARP and its cleavage product, as well as by quantitative measurement of the apoptosis-associated CK18Asp396. Furthermore, CDDO-Me increases the cytotoxic effects of paclitaxel in the paclitaxel-resistant ovarian cancer cell line OVCAR8(TR) (2 to 5-fold) and of cisplatin in the cisplatin-resistant ovarian cancer cell line A2780cp70 (2 to 4-fold). Our data confirm that CDDO-Me interrupts the signaling of multiple kinases involved in the IL-6-Stat3 and Src signaling pathways. Inhibition is likely achieved through multiple points within these pathways. In a model system of established acquired drug resistance, CCDO-Me is effective at partially reversing the drug-resistance phenotype.
- Published
- 2008
36. Modulation of Drug Resistance in Ovarian Adenocarcinoma by Enhancing Intracellular Ceramide Using Tamoxifen-Loaded Biodegradable Polymeric Nanoparticles
- Author
-
Mansoor M. Amiji, Michael V. Seiden, Zhenfeng Duan, and Harikrishna Devalapally
- Subjects
Selective Estrogen Receptor Modulators ,Cytoplasm ,Cancer Research ,Ceramide ,Paclitaxel ,endocrine system diseases ,Polyesters ,Mice, Nude ,Adenocarcinoma ,Pharmacology ,Ceramides ,Polyethylene Glycols ,Mice ,chemistry.chemical_compound ,Drug Delivery Systems ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,In Situ Nick-End Labeling ,medicine ,Animals ,Humans ,Ovarian Neoplasms ,Chemistry ,medicine.disease ,Drug Resistance, Multiple ,Acute toxicity ,Multiple drug resistance ,Tamoxifen ,Oncology ,Drug Resistance, Neoplasm ,Cell culture ,Apoptosis ,Nanoparticles ,Female ,Ovarian cancer ,medicine.drug - Abstract
Purpose: To modulate intracellular ceramide levels and lower the apoptotic threshold in multidrug-resistant ovarian adenocarcinoma, we have examined the efficacy and preliminary safety of tamoxifen coadministration with paclitaxel in biodegradable poly(ethylene oxide)–modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles.Experimental Design: In vitro cytotoxicity and proapoptotic activity of paclitaxel and tamoxifen, either as single agent or in combination, was examined in wild-type (SKOV3) and MDR-1–positive (SKOV3TR) human ovarian adenocarcinoma cells. Subcutaneous SKOV3 and SKOV3TR xenografts were established in female nu/nu mice, and this model was used to evaluate the antitumor efficacy and preliminary safety. Paclitaxel (20 mg/kg) and tamoxifen (70 mg/kg) were administered i.v. either as a single agent or in combination in aqueous solution and in PEO-PCL nanoparticles.Results: In vitro cytotoxicity results showed that administration of paclitaxel and tamoxifen in combination lowered the IC50 of paclitaxel by 10-fold in SKOV3 cells and by >3-fold in SKOV3TR cells. The combination paclitaxel/tamoxifen co-therapy showed even more pronounced effect when administered in nanoparticle formulations. Upon i.v. administration of paclitaxel/tamoxifen combination in PEO-PCL nanoparticle formulations, significant enhancement in antitumor efficacy was observed. Furthermore, the combination paclitaxel/tamoxifen therapy did not induce any acute toxicity as measured by body weight changes, blood cell counts, and hepatotoxicity.Conclusions: The results of this study show that combination of paclitaxel and tamoxifen in biodegradable PEO-PCL nanoparticles can serve as an effective clinically translatable strategy to overcome multidrug resistance in ovarian cancer.
- Published
- 2008
37. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients
- Author
-
Michael T. Jaklitsch, Frank G. Haluska, Marybeth Nelson, Sara Russell, James P. Allison, Darryl A. Oble, Alan J. Korman, Glenn Dranoff, Nikhil H. Ramaiya, F. Stephen Hodi, Suzanne MacRae, Christine Canning, Israel Lowy, Donna Neuberg, Teresa C. Chen, David B. Lautz, Martin C. Mihm, Marcus O. Butler, Michael V. Seiden, and Andrea Kruse
- Subjects
medicine.medical_treatment ,Enzyme-Linked Immunosorbent Assay ,chemical and pharmacologic phenomena ,Ipilimumab ,T-Lymphocytes, Regulatory ,Cohort Studies ,Antigen ,Antigens, CD ,medicine ,Humans ,Cytotoxic T cell ,CTLA-4 Antigen ,Melanoma ,Ovarian Neoplasms ,Multidisciplinary ,business.industry ,Carcinoma ,Immunization, Passive ,Antibodies, Monoclonal ,Granulocyte-Macrophage Colony-Stimulating Factor ,FOXP3 ,Immunotherapy ,Biological Sciences ,Antigens, Differentiation ,GVAX ,CTLA-4 ,Immunology ,Female ,business ,CD8 ,medicine.drug - Abstract
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8 + effector T cells to FoxP3 + regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.
- Published
- 2008
38. Extent of extracranial disease is a powerful predictor of survival in patients with brain metastases from gynecological cancer
- Author
-
Ramey D. Littell, Whitfield B. Growdon, Carolyn N. Krasner, E. Lopez-Varela, Esther Oliva, Arlan F. Fuller, Hang Lee, and Michael V. Seiden
- Subjects
Oncology ,medicine.medical_specialty ,Genital Neoplasms, Female ,medicine.medical_treatment ,Metastasis ,Internal medicine ,medicine ,Humans ,Survival analysis ,Retrospective Studies ,Chemotherapy ,Brain Neoplasms ,Proportional hazards model ,business.industry ,Hazard ratio ,Obstetrics and Gynecology ,Multimodal therapy ,Retrospective cohort study ,Middle Aged ,Prognosis ,medicine.disease ,Combined Modality Therapy ,Survival Analysis ,Female ,business ,Brain metastasis - Abstract
Central nervous system metastasis from gynecological malignancy is a rare phenomenon that has been described in the past 30 years. The objective of this study is to analyze the treatment modalities and prognostic factors for brain metastases from gynecological tumors that predict prolonged survival. A retrospective chart and pathology review of 47 patients diagnosed with a gynecological tumor with brain metastasis in 1994–2004 was performed. Thirty patients had undergone initial diagnosis and treatment at our institution, and 17 patients were referred following primary treatment at an outside institution. Adjusted Chi-square, Kaplan–Meier survival estimates, log-rank tests, and Cox regression analysis were utilized for statistical analysis of the total cohort. Of the 3146 patients with newly diagnosed gynecological cancer in this 10-year period, 30 developed brain metastasis demonstrating an incidence of 0.95%. Overall median survival from the time of diagnosis of brain metastasis was 7.5 months (95% CI 4–15, range 9 days–64 months) and 40% survival at 1 year. Multivariate analysis revealed evidence of extracranial disease at time of metastasis diagnosis predicted decreased survival (hazard ratio 6.207), while papillary serous histology (hazard ratio 0.42), and use of any chemotherapy (hazard ratio 0.24) predicted longer survival. No other patient or tumor characteristics were found to be independent prognostic indicators affecting survival. Despite the ominous prognosis associated with the development of brain metastasis, these retrospective data suggest that multimodal therapy with whole brain radiation therapy, chemotherapy, and surgical resection of metastases in selected patients without evidence of extracranial and with solitary or multiple lesions can prolong survival.
- Published
- 2008
39. 8-Benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic Acid (SD-1008), a Novel Janus Kinase 2 Inhibitor, Increases Chemotherapy Sensitivity in Human Ovarian Cancer Cells
- Author
-
Edward Greenberg, James E. Bradner, Jennifer Mahoney, Michael V. Seiden, Rosemary Foster, Ralph Mazitschek, and Zhenfeng Duan
- Subjects
STAT3 Transcription Factor ,Paclitaxel ,Active Transport, Cell Nucleus ,Antineoplastic Agents ,Apoptosis ,Breast Neoplasms ,Biology ,Cell Line, Tumor ,Humans ,Phosphorylation ,STAT3 ,Protein Kinase Inhibitors ,Transcription factor ,Ovarian Neoplasms ,Pharmacology ,Janus kinase 2 ,Autophosphorylation ,JAK-STAT signaling pathway ,Janus Kinase 2 ,Drug Resistance, Neoplasm ,Cancer cell ,STAT protein ,biology.protein ,Cancer research ,Molecular Medicine ,Female ,Signal transduction ,Apoptosis Regulatory Proteins ,Tropanes - Abstract
Interleukin 6 and the signal transducer and activator of transcription (STAT) 3 proteins have important roles in cancer cell survival and proliferation. Recent studies demonstrate that abnormal STAT3 activation promotes tumor growth and supports survival of many human cancers, and thus, this protein or the pathway responsible for its activation is a potential target for the new anticancer therapy. STAT3 is a DNA binding transcription factor, and therefore, its function depends on nuclear translocation. To discover inhibitors of the STAT3 pathway, we designed a cell-based screening assay capable of identifying small molecules that inhibit nuclear translocation. Among the 2000-compound National Cancer Institute Diversity set, we identified 8-benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic acid (SD-1008) as a micromolar inhibitor of interleukin-6 or oncostatin-induced STAT3 nuclear translocation. In addition, SD-1008 inhibits tyrosyl phosphorylation of STAT3, Janus kinase 2 (JAK2), and Src. SD-1008 also reduces STAT3-dependent luciferase activity. Biochemical studies with recombinant JAK2 proteins demonstrate that high concentrations of SD-1008 directly inhibit JAK2 kinase autophosphorylation. Exposure of various cell lines to SD-1008 decreases levels of the STAT3-dependent proteins, Bcl-X(L) and survivin, inducing apoptosis. SD-1008 also enhances apoptosis induced by paclitaxel in ovarian cancer cells. These results demonstrate that SD-1008 directly blocks the JAK-STAT3 signaling pathway in human cancer cells that express constitutively active Stat and add to the growing literature that identifies this pathway as a viable target for drug development. Finally, SD-1008 may be a suitable prototype for further chemical modification and exploration as a therapeutic agent.
- Published
- 2007
40. Modulation of Intracellular Ceramide Using Polymeric Nanoparticles to Overcome Multidrug Resistance in Cancer
- Author
-
Mansoor M. Amiji, Michael V. Seiden, Lilian E. van Vlerken, and Zhenfeng Duan
- Subjects
Ethylene Oxide ,Cancer Research ,Ceramide ,Paclitaxel ,Population ,Pharmacology ,Biology ,Ceramides ,Lactones ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,education ,Ovarian Neoplasms ,education.field_of_study ,Antineoplastic Agents, Phytogenic ,Sphingolipid ,Drug Resistance, Multiple ,Multiple drug resistance ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Apoptosis ,Drug delivery ,Cancer cell ,Nanoparticles ,Female - Abstract
Although multidrug resistance (MDR) is known to develop through a variety of molecular mechanisms within the tumor cell, many tend to converge toward the alteration of apoptotic signaling. The enzyme glucosylceramide synthase (GCS), responsible for bioactivation of the proapoptotic mediator ceramide to a nonfunctional moiety glucosylceramide, is overexpressed in many MDR tumor types and has been implicated in cell survival in the presence of chemotherapy. The purpose of this study was to investigate the therapeutic strategy of coadministering ceramide with paclitaxel, a commonly used chemotherapeutic agent, in an attempt to restore apoptotic signaling and overcome MDR in the human ovarian cancer cell line SKOV3. Poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were used to encapsulate and deliver the therapeutic agents for enhanced efficacy. Results show that indeed the cotherapy eradicates the complete population of MDR cancer cells when they are treated at their IC50 dose of paclitaxel. More interestingly, when the cotherapy was combined with the properties of nanoparticle drug delivery, the MDR cells can be resensitized to a dose of paclitaxel near the IC50 of non-MDR (drug sensitive) cells, indicating a 100-fold increase in chemosensitization via this approach. Molecular analysis of activity verified the hypothesis that the efficacy of this therapeutic approach is indeed due to a restoration in apoptotic signaling, although the beneficial properties of PEO-PCL nanoparticle delivery seemed to enhance the therapeutic success even further, showing the promising potential for the clinical use of this therapeutic strategy to overcome MDR. [Cancer Res 2007;67(10):4843–50]
- Published
- 2007
41. A phase II trial of EMD72000 (matuzumab), a humanized anti-EGFR monoclonal antibody, in patients with platinum-resistant ovarian and primary peritoneal malignancies
- Author
-
James B. Hall, H. A. Burris, J. Speyer, J.D.A. Weber, Ursula A. Matulonis, Michael V. Seiden, Deborah K. Armstrong, and Franco M. Muggia
- Subjects
Adult ,medicine.medical_specialty ,Organoplatinum Compounds ,medicine.medical_treatment ,Population ,Cetuximab ,Phases of clinical research ,Antineoplastic Agents ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Internal medicine ,medicine ,Humans ,education ,Adverse effect ,Peritoneal Neoplasms ,Aged ,Aged, 80 and over ,Ovarian Neoplasms ,Chemotherapy ,education.field_of_study ,business.industry ,Matuzumab ,Antibodies, Monoclonal ,Obstetrics and Gynecology ,Middle Aged ,medicine.disease ,Rash ,Surgery ,ErbB Receptors ,Oncology ,Tolerability ,Drug Resistance, Neoplasm ,Female ,medicine.symptom ,business ,Ovarian cancer ,medicine.drug - Abstract
Objective. The primary objective of this study was to determine the rate of response to matuzumab in patients with recurrent, EGFR-positive ovarian, or primary peritoneal cancer. Secondary end points included safety and tolerability, time to tumor progression, duration of response, and overall survival. Methods. A multi-institutional single arm phase II trial. Results. Of 75 women screened for the study, 37 were enrolled and treated. Median age of the treated patient population was 58 years, and most patients had more than four prior lines of chemotherapy. Therapy was well tolerated, the most common toxicities being a constellation of skin toxicities, including rash, acne, dry skin, and paronychia, as well as headache, fatigue, and diarrhea. Serious adverse events were very rare but included a single episode of pancreatitis that may have been drug related. All patients completed therapy, receiving 1 to 30 infusions of matuzumab. There were no formal responses (RR=0%, 95% CI: 0–9.5%), although 7 patients (21%) were on therapy for more than 3 months with stable disease. Conclusions. Matuzumab at the dose and schedule selected is well tolerated. In this population of very heavily pretreated patients with epithelial ovarian and primary peritoneal malignancies, there was no evidence of significant clinical activity when matuzumab was administered as monotherapy.
- Published
- 2007
42. Phase I Clinical Trial of STA-4783 in Combination with Paclitaxel in Patients with Refractory Solid Tumors
- Author
-
Michael V. Seiden, David P. Ryan, Noriaki Tatsuta, Joseph Paul Eder, Anna Berkenblit, Matthew L. Sherman, Bruce J. Dezube, Thomas A. Dahl, and Jeffrey G. Supko
- Subjects
Adult ,Male ,Cancer Research ,Time Factors ,Maximum Tolerated Dose ,Paclitaxel ,Phases of clinical research ,Pharmacology ,digestive system ,chemistry.chemical_compound ,Therapeutic index ,Pharmacokinetics ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Mucositis ,medicine ,Humans ,Aged ,Volume of distribution ,Taxane ,Dose-Response Relationship, Drug ,business.industry ,Drug Synergism ,Middle Aged ,medicine.disease ,Hydrazines ,Treatment Outcome ,Models, Chemical ,Oncology ,chemistry ,Toxicity ,Female ,business - Abstract
Purpose: STA-4783 is a new compound that markedly enhances the therapeutic index of paclitaxel against human tumor xenograft models. A phase I clinical trial was undertaken to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of STA-4783 in combination with paclitaxel. Experimental Design: Adults with refractory solid tumors concurrently received STA-4783 and paclitaxel as a 3-h i.v. infusion at starting doses of 44 and 135 mg/m2, respectively. After increasing paclitaxel to 175 mg/m2, the STA-4783 dose was escalated as permitted by dose-limiting toxicity during the first 21-day cycle. Results: Thirty-five patients were treated with eight dose levels of STA-4783/paclitaxel. In patients receiving 175 mg/m2 paclitaxel, the incidence of severe toxicity increased with escalation of the STA-4783 dose above 263 mg/m2, and 438 mg/m2 was the maximum tolerated dose. All toxicities were typical of paclitaxel, with neutropenia, mucositis, and myalgia/arthralgia being dose limiting. Partial responses were achieved in one patient with Kaposi's sarcoma and another with ovarian cancer that progressed during prior treatment with paclitaxel. STA-4783 exhibited linear pharmacokinetics characterized by rapid elimination from plasma (biological half-life, 1.06 ± 0.24 h) and a low steady-state apparent volume of distribution (25.1 ± 8.1 L/m2). The total body clearance of paclitaxel decreased significantly with escalation of the STA-4783 dose. Conclusions: The STA-4783/paclitaxel combination was well tolerated with a toxicity profile similar to single-agent paclitaxel. Enhanced systemic exposure to paclitaxel resulting from a dose-dependent interaction with STA-4783 was associated with increased toxicity. Objective responses in two heavily pretreated patients, both with taxane exposure, have encouraged further clinical evaluation of this regimen.
- Published
- 2007
43. Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer
- Author
-
Michael V. Seiden, Zhenfeng Duan, Harikrishna Devalapally, and Mansoor M. Amiji
- Subjects
Cancer Research ,Time Factors ,Paclitaxel ,Polyesters ,Transplantation, Heterologous ,Mice, Nude ,Apoptosis ,Biocompatible Materials ,Drug resistance ,Adenocarcinoma ,Pharmacology ,Ceramides ,Mice ,chemistry.chemical_compound ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm ,Ovarian Neoplasms ,Chemistry ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Transplantation ,Multiple drug resistance ,Oncology ,Drug Resistance, Neoplasm ,Immunology ,Systemic administration ,Nanoparticles ,Female ,Ovarian cancer - Abstract
The objective of this study was to overcome drug resistance upon systemic administration of combination paclitaxel (PTX) and the apoptotic signaling molecule C(6)-ceramide (CER) in biodegradable poly(ethylene oxide)-modified poly(epsilon-caprolactone (PEO-PCL) nanoparticles. Subcutaneous sensitive (wild-type) and multidrug resistant (MDR-1 positive) SKOV-3 human ovarian adenocarcinoma xenografts were established in female Nu/Nu mice. PTX and CER were administered intravenously either as a single agent or in combination in aqueous solution and in PEO-PCL nanoparticles to the tumor-bearing mice. There was significant (p< 0.05) tumor growth suppression in both wild-type SKOV-3 and multidrug resistant SKOV-3(TR) models upon single dose co-administration of PTX (20 mg/kg) and CER (100 mg/kg) in nanoparticle formulations as compared to the individual agents and administration in aqueous solutions. For instance, in SKOV-3 wild-type model, more than 4.3-fold increase (p < 0.05) in tumor growth delay and 3.6-fold (p < 0.05) increase in tumor volume doubling time (DT) were observed with the combination treatment in nanoparticles as compared to untreated animals. Similarly, 3-fold increase (p < 0.05) in tumor growth delay and tumor volume DT was observed in SKOV-3(TR) model. Body weight changes and blood cells counts were used as measures of safety and, except for an increase in platelet counts (p < 0.05) in PTX + CER treated animals, there was no difference between various treatment strategies. The results of this study show that combination of PTX and CER in biodegradable polymeric nanoparticles can serve as a very effective therapeutic strategy to overcome drug resistance in ovarian cancer.
- Published
- 2007
44. Negative laparoscopy is highly predictive of negative second-look laparotomy following chemotherapy for ovarian, tubal, and primary peritoneal carcinoma
- Author
-
Ross S. Berkowitz, Michael V. Seiden, Ursula A. Matulonis, Linda R. Duska, Heidi Hallonquist, and Ramey D. Littell
- Subjects
Adult ,medicine.medical_specialty ,medicine.medical_treatment ,Phases of clinical research ,Peritoneal Neoplasm ,Clinical Trials, Phase II as Topic ,Primary peritoneal carcinoma ,Predictive Value of Tests ,Laparotomy ,medicine ,Fallopian Tube Neoplasms ,Humans ,Laparoscopy ,Peritoneal Neoplasms ,Aged ,Ovarian Neoplasms ,medicine.diagnostic_test ,business.industry ,Obstetrics and Gynecology ,Middle Aged ,Prognosis ,medicine.disease ,Surgery ,Clinical trial ,Oncology ,Chemotherapy, Adjuvant ,Second-Look Surgery ,Predictive value of tests ,Female ,Ovarian cancer ,business - Abstract
Objective. To determine the negative predictive value of second-look laparoscopy compared to laparotomy for assessment of pathologic complete response (CR) in patients with epithelial ovarian, tubal, and peritoneal carcinoma who achieved a clinical CR. Methods. Data were analyzed from patients who participated in two sequential phase II clinical trials following primary cytoreductive surgery. Both trials required surgical evaluation for pathologic CR in those patients who achieved clinical CR. Protocol specified that assessment begin with laparoscopy; if negative, conversion to laparotomy was required. Collection of peritoneal washings was performed laparoscopically. Results. One hundred thirty-six patients entered the 2 sequential clinical trials. Ninety-nine patients achieved clinical CR and 95 underwent second-look surgery (SLO). Seventy patients began SLO with laparoscopy and converted to planned laparotomy after biopsies were negative. Eighteen cases were positive based on laparoscopy with frozen section. Five additional patients had peritoneal washings and/or permanent pathology positive based on laparoscopic findings, yielding a positive SLO rate of 32.9%. Four of the 52 patients who underwent laparotomy (7.7%) were found to have persistent disease that was not detected on laparoscopic biopsy or washings and represent false-negative laparoscopy; all four patients had disease at peritoneal-based sites. The sensitivity and negative predictive value for intraoperative diagnosis of persistent disease by laparoscopy were 66.6% and 82.7%, respectively. The sensitivity and negative predictive value of laparoscopic peritoneal biopsies and washings compared to laparotomy, as determined by final pathology, were 85.2% and 91.5%, respectively. Conclusion. A negative second-look laparoscopy with negative peritoneal pathology and cytology is 91.5% predictive of negative laparotomy and is associated with a low complication rate even in the setting of prior extensive cytoreductive surgery. The small increase in sensitivity and negative predictive value afforded by laparotomy does not warrant the increased morbidity.
- Published
- 2006
45. Signal Transducers and Activators of Transcription 3 Pathway Activation in Drug-Resistant Ovarian Cancer
- Author
-
Jennifer Mahoney, Constanze Hampel, Debra A. Bell, Zhenfeng Duan, Hang Lee, Kathryn Wolak, Ami P. Vaidya, Rosemary Foster, and Michael V. Seiden
- Subjects
STAT3 Transcription Factor ,Cancer Research ,ATP Binding Cassette Transporter, Subfamily B ,Paclitaxel ,medicine.medical_treatment ,Apoptosis ,Biology ,Paracrine signalling ,chemistry.chemical_compound ,Cell Line, Tumor ,medicine ,Humans ,Phosphorylation ,RNA, Small Interfering ,STAT3 ,Ovarian Neoplasms ,Chemotherapy ,Tissue microarray ,Interleukin-6 ,medicine.disease ,Immunohistochemistry ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Tissue Array Analysis ,biology.protein ,Cancer research ,Female ,Signal transduction ,Ovarian cancer ,Signal Transduction - Abstract
Purpose: One of the major obstacles in the treatment of ovarian cancer is the development of multidrug resistance. Recent evidence shows that high-grade ovarian cancer often shows activation of the signal transducers and activators of transcription 3 (Stat3) pathway with subsequent transcription of genes that support tumor growth and survival. Less studied is the role of the Stat3 pathway in acquired drug resistance. There is no information on Stat3 expression in chemotherapy naïve ovarian cancer as compared with tumors collected later in the natural history of the disease. To further clarify the significance of Stat3 activation in ovarian cancer, here we investigated the Stat3 expression and activation in ovarian cancer and ovarian cancer multidrug resistance cell lines. Experimental Design: Western blotting, electrophoretic mobility shift assay, luciferase assays, ELISA assay, and real-time reverse transcription-PCR determined interleukin-6 and Stat3 pathway expression and activation in cell lines. Stat3 expression in ovarian cancer tissue microarray was evaluated by immunohistochemistry. Results: Activated (phosphorylated) Stat3 is overexpressed in most paclitaxel-resistant ovarian cancer cells. Inhibition of Stat3 activation results in significant decreases in paclitaxel resistance and enhanced apoptosis. Drug-resistant recurrent tumors have significantly greater phosphorylated Stat3 (pStat3) expression as compared with matched primary tumors. Tumors with associated inflammatory cell infiltrates also have a higher proportion of cells staining intensely for nuclear phosphorylated Stat3 as compared with tumors without inflammatory infiltrates, consistent with paracrine activation of the Stat3 pathway by immune-mediated cytokines. Conclusions: These data support the hypothesis that interruption of Stat3 signaling could reverse resistance to paclitaxel and perhaps other chemotherapy agents in human cancer.
- Published
- 2006
46. Reclassification of a tubal leiomyosarcoma as an eGIST by molecular evaluation of c-KIT
- Author
-
Esther Oliva, Rosemary Foster, Jennifer Mahoney, Arlan F. Fuller, Steven M. Solano, and Michael V. Seiden
- Subjects
Leiomyosarcoma ,Pathology ,medicine.medical_specialty ,Stromal cell ,Gastrointestinal Stromal Tumors ,Molecular Sequence Data ,Cell morphology ,Diagnosis, Differential ,medicine ,Fallopian Tube Neoplasms ,Humans ,Base Sequence ,business.industry ,Obstetrics and Gynecology ,Imatinib ,Middle Aged ,medicine.disease ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Oncology ,Immunohistochemistry ,Female ,Sarcoma ,Differential diagnosis ,business ,Fallopian tube ,medicine.drug - Abstract
Background. Extragastrointestinal stromal tumors (eGISTs) are rare mesenchymal-derived tumors arising outside of the GI tract. eGISTs are often histologically confused with leiomyosarcoma. Distinction between eGIST and leiomyosarcoma is critical because of the unique responsiveness of eGISTs to the molecularly targeted agent imatinib. Case. A woman presented with a history of tubal spindle cell tumor that was initially diagnosed and treated as a leiomyosarcoma. Because of minimal response to sarcoma directed chemotherapy, the possibility that the tumor was in fact an eGIST was investigated and supported by immunohistochemical and mutational analyses of the c-Kit receptor tyrosine kinase. The patient currently has stable disease control on imatinib for the last 18 months. Conclusions. The possibility of eGIST should be considered in the differential diagnosis of tumors with a spindle cell morphology in the gynecologic tract especially when involving the ovary, fallopian tube, or uterine serosa.
- Published
- 2006
47. Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway
- Author
-
Richard D. Kennedy, Michael V. Seiden, Anne Renee Hartman, Ami P. Vaidya, Deborah Chirnomas, Rosemary Foster, Michelle de la Vega, Toshiyasu Taniguchi, Alan D. D'Andrea, Maria Vasserman, and Jennifer Mahoney
- Subjects
Cancer Research ,Curcumin ,Indoles ,Cell Survival ,medicine.medical_treatment ,Cell ,Biology ,Wortmannin ,chemistry.chemical_compound ,Fanconi anemia ,medicine ,Humans ,Protein kinase A ,Cisplatin ,Sulfonamides ,Chemotherapy ,BRCA1 Protein ,Benzazepines ,Isoquinolines ,medicine.disease ,Androstadienes ,Fanconi Anemia ,medicine.anatomical_structure ,Oncology ,chemistry ,Biochemistry ,Cancer cell ,Cancer research ,DNA Damage ,HeLa Cells ,medicine.drug - Abstract
Cisplatin resistance occurs, at least in part, through the function of the Fanconi anemia (FA)/BRCA pathway, a DNA-damage response pathway required for repair of cisplatin cross-links. In the current study, we designed a cell-based screening strategy to identify small-molecule inhibitors of the FA/BRCA pathway with the hypothesis that such molecules could restore sensitivity to platinum agents. We identified four inhibitors, including three protein kinase inhibitors (wortmannin, H-9, and alsterpaullone) and one natural compound (curcumin) that inhibit the FA/BRCA pathway. We show that curcumin, a compound that is generally regarded as safe, inhibits the monoubiquitination of the FANCD2 protein as predicted by the screen and consequently sensitizes ovarian and breast tumor cell lines to cisplatin through apoptotic cell death. We believe that this study shows an efficient, high-throughput method for identifying new compounds that may sensitize cancer cells to DNA-damaging chemotherapy. [Mol Cancer Ther 2006;5(4):952–61]
- Published
- 2006
48. Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission
- Author
-
John T. Soper, Joanna Lambert, Dennis Thurston, Gordon Stamp, Benedict B. Benigno, René H.M. Verheijen, Theo Falke, Alberto Lopes, Janica Markowska, Gregory Spiegel, Michael V. Seiden, Rostislav Vyzula, Agamemnon A. Epenetos, Leon F.A.G. Massuger, and T. Jobling
- Subjects
Adult ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Urology ,Aetiology, screening and detection [ONCOL 5] ,Disease-Free Survival ,law.invention ,Randomized controlled trial ,Translational research [ONCOL 3] ,law ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Clinical endpoint ,Humans ,Infusions, Parenteral ,Yttrium Radioisotopes ,Treatment Failure ,Stage (cooking) ,Laparoscopy ,Aged ,Proportional Hazards Models ,Ovarian Neoplasms ,Chemotherapy ,Hereditary cancer and cancer-related syndromes [ONCOL 1] ,medicine.diagnostic_test ,business.industry ,Standard treatment ,Carcinoma ,Remission Induction ,Antibodies, Monoclonal ,Immunotherapy, gene therapy and transplantation [UMCN 1.4] ,Middle Aged ,Surgery ,Clinical trial ,Oncology ,Chemotherapy, Adjuvant ,Second-Look Surgery ,Female ,business ,Adjuvant - Abstract
Purpose This was a multinational, open-label, randomized phase III trial comparing yttrium-90–labeled murine HMFG1 (90Y-muHMFG1) plus standard treatment versus standard treatment alone in patients with epithelial ovarian cancer (EOC) who had attained a complete clinical remission after cytoreductive surgery and platinum-based chemotherapy. Patients and Methods In total, 844 International Federation of Gynecology and Obstetrics stage Ic to IV patients were initially screened, of whom 447 patients with a negative second-look laparoscopy (SLL) were randomly assigned to receive either a single dose of 90Y-muHMFG1 plus standard treatment (224 patients) or standard treatment alone (223 patients). Patients in the active treatment arm received a single intraperitoneal dose of 25 mg of 90Y-muHMFG1 (target dose 666 MBq/m2). The primary end point was length of survival; secondary end points included time to relapse and safety. The study had an 80% power to detect a 15% change in survival. Results After a median follow-up of 3.5 years (range, 1 to 6 years), 70 patients had died in the active treatment arm compared with 61 patients in the control arm. Cox proportional hazards analysis of survival demonstrated no difference between treatment arms. In the study drug arm, 104 patients experienced relapse compared with 98 patients in the standard treatment arm. No difference in time to relapse was observed between the two study arms. Active therapy was associated with occasional grade 3 or 4 thrombocytopenia and neutropenia and grade 1 or 2 GI symptoms, abdominal discomfort, arthralgia, and myalgia. Conclusion A single IP administration of 90Y-muHMFG1 to patients with EOC who had a negative SLL after primary therapy did not extend survival or time to relapse.
- Published
- 2006
49. Prolonged stabilization of platinum-resistant ovarian cancer in a single patient consuming a fermented soy therapy
- Author
-
Jeffrey G. Supko, Allison Mallett, Xiaoying He, Linda R. Duska, Michael V. Seiden, Amber Klein, and Maria Roche
- Subjects
Complementary Therapies ,Oncology ,medicine.medical_specialty ,Paclitaxel ,endocrine system diseases ,Genistein ,Disease ,Deoxycytidine ,Carboplatin ,chemistry.chemical_compound ,Glucuronides ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,In patient ,Tumor marker ,Platinum resistant ,Ovarian Neoplasms ,business.industry ,Disease progression ,Obstetrics and Gynecology ,Middle Aged ,medicine.disease ,Isoflavones ,Gemcitabine ,female genital diseases and pregnancy complications ,Soy Milk ,Single patient ,Endocrinology ,chemistry ,Doxorubicin ,Drug Resistance, Neoplasm ,Female ,Topotecan ,business ,Ovarian cancer - Abstract
Background. Women with ovarian cancer who experience disease progression during or within 6 months of first-line treatment with platinum-based anticancer drugs are considered to have platinum-resistant tumors. These patients have an unfavorable prognosis, and they frequently seek complementary and alternative therapies (CAM). Historically, this represents an understudied and underreported component of ovarian cancer treatment. Case. This report describes the case of a woman with rapidly progressive, platinum-resistant ovarian cancer. Upon initiating self-directed treatment with Haelan951®, a commercially available fermented soy beverage, she entered into a phase of prolonged disease stabilization including improvement in the serum tumor marker CA-125. Conclusion. Fermented soy products are known to contain high concentrations of the isoflavone, genistein, and other compounds that exhibit anticancer activity in preclinical models. This case report supports the prospective evaluation of alternative therapies such as these in patients with platinum-refractory ovarian cancer.
- Published
- 2006
50. Long-Acting Octreotide for the Treatment and Symptomatic Relief of Bowel Obstruction in Advanced Ovarian Cancer
- Author
-
Michael V. Seiden, Carolyn N. Krasner, Ursula A. Matulonis, Arlan F. Fuller, Maria Roche, Alice B. Kornblith, Richard T. Penson, and T. Atkinson
- Subjects
Adult ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,medicine.medical_treatment ,Pain ,Octreotide ,Pilot Projects ,Severity of Illness Index ,Gastroenterology ,Gastrointestinal Agents ,Internal medicine ,Severity of illness ,Humans ,Medicine ,General Nursing ,Aged ,Ovarian Neoplasms ,Chemotherapy ,business.industry ,Palliative Care ,Middle Aged ,medicine.disease ,Symptomatic relief ,Surgery ,Clinical trial ,Bowel obstruction ,Treatment Outcome ,Anesthesiology and Pain Medicine ,Somatostatin ,Female ,Neurology (clinical) ,business ,Ovarian cancer ,Intestinal Obstruction ,medicine.drug - Abstract
Symptoms of malignant bowel obstruction in patients with recurrent ovarian cancer lead to a poor quality of life. Sandostatin LAR® Depot (LAR) (Novartis Pharmaceuticals Corp., East Hanover, NJ) is an intramuscular, monthly administered, long-acting form of octreotide. LAR's safety and utility were evaluated in a pilot study enrolling 15 advanced ovarian cancer patients with bowel dysfunction. Once safety with subcutaneous (SQ) octreotide was assessed, patients were given 30 mg LAR on Day 1 and octreotide SQ for 2 weeks. Of 13 evaluable patients, three patients had a major response to LAR treatment with reduction in bowel obstruction symptoms, two had a minor response, four had no response, and four had progressive symptoms. Three patients remained on LAR for more than 9 months. No significant toxicities were attributable to octreotide or LAR. Because three patients received nine or more monthly injections of LAR, possible direct antitumor effects of LAR or synergy with chemotherapy needs to be explored.
- Published
- 2005
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.