46 results on '"Katherine A. Thornton"'
Search Results
2. Supplementary Figure 1 from Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
- Author
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Neerav Shukla, Marc Ladanyi, Ahmet Zehir, Elli Papaemmanuil, Andrew L. Kung, Paul A. Meyers, Leonard H. Wexler, Michael P. LaQuaglia, Todd E. Heaton, Justin T. Gerstle, Gunes Gundem, Daoqi You, Nancy Bouvier, Katherine A. Thornton, Mrinal M. Gounder, William D. Tap, Shakeel Modak, Nestor Rosales, Glorymar I. Sanchez, Diego F. Coutinho, Filemon Dela Cruz, Max F. Levine, Anita S. Bowman, and Emily K. Slotkin
- Abstract
Supplementary Figure 1 depicts copy number alterations in the described cohort
- Published
- 2023
3. Supplementary Table 1 from Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
- Author
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Neerav Shukla, Marc Ladanyi, Ahmet Zehir, Elli Papaemmanuil, Andrew L. Kung, Paul A. Meyers, Leonard H. Wexler, Michael P. LaQuaglia, Todd E. Heaton, Justin T. Gerstle, Gunes Gundem, Daoqi You, Nancy Bouvier, Katherine A. Thornton, Mrinal M. Gounder, William D. Tap, Shakeel Modak, Nestor Rosales, Glorymar I. Sanchez, Diego F. Coutinho, Filemon Dela Cruz, Max F. Levine, Anita S. Bowman, and Emily K. Slotkin
- Abstract
Supplementary Table 1 shows point mutations found in DSRCT samples
- Published
- 2023
4. Supplementary Figure 3 from Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
- Author
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Neerav Shukla, Marc Ladanyi, Ahmet Zehir, Elli Papaemmanuil, Andrew L. Kung, Paul A. Meyers, Leonard H. Wexler, Michael P. LaQuaglia, Todd E. Heaton, Justin T. Gerstle, Gunes Gundem, Daoqi You, Nancy Bouvier, Katherine A. Thornton, Mrinal M. Gounder, William D. Tap, Shakeel Modak, Nestor Rosales, Glorymar I. Sanchez, Diego F. Coutinho, Filemon Dela Cruz, Max F. Levine, Anita S. Bowman, and Emily K. Slotkin
- Abstract
Supplementary Figure 3 provides a breakdown of the structural variant types found via whole genome sequencing in DSRCT samples
- Published
- 2023
5. Supplementary Figure 2 from Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
- Author
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Neerav Shukla, Marc Ladanyi, Ahmet Zehir, Elli Papaemmanuil, Andrew L. Kung, Paul A. Meyers, Leonard H. Wexler, Michael P. LaQuaglia, Todd E. Heaton, Justin T. Gerstle, Gunes Gundem, Daoqi You, Nancy Bouvier, Katherine A. Thornton, Mrinal M. Gounder, William D. Tap, Shakeel Modak, Nestor Rosales, Glorymar I. Sanchez, Diego F. Coutinho, Filemon Dela Cruz, Max F. Levine, Anita S. Bowman, and Emily K. Slotkin
- Abstract
Supplementary Figure 2 depicts whole genome sequencing findings
- Published
- 2023
6. Data from Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
- Author
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Neerav Shukla, Marc Ladanyi, Ahmet Zehir, Elli Papaemmanuil, Andrew L. Kung, Paul A. Meyers, Leonard H. Wexler, Michael P. LaQuaglia, Todd E. Heaton, Justin T. Gerstle, Gunes Gundem, Daoqi You, Nancy Bouvier, Katherine A. Thornton, Mrinal M. Gounder, William D. Tap, Shakeel Modak, Nestor Rosales, Glorymar I. Sanchez, Diego F. Coutinho, Filemon Dela Cruz, Max F. Levine, Anita S. Bowman, and Emily K. Slotkin
- Abstract
Desmoplastic small round cell tumor (DSRCT) is characterized by the EWSR1–WT1 t(11;22) (p13:q12) translocation. Few additional putative drivers have been identified, and research has suffered from a lack of model systems. Next-generation sequencing (NGS) data from 68 matched tumor-normal samples, whole-genome sequencing data from 10 samples, transcriptomic and affymetrix array data, and a bank of DSRCT patient-derived xenograft (PDX) are presented. EWSR1–WT1 fusions were noted to be simple, balanced events. Recurrent mutations were uncommon, but were noted in TERT (3%), ARID1A (6%), HRAS (5%), and TP53 (3%), and recurrent loss of heterozygosity (LOH) at 11p, 11q, and 16q was identified in 18%, 22%, and 34% of samples, respectively. Comparison of tumor-normal matched versus unmatched analysis suggests overcalling of somatic mutations in prior publications of DSRCT NGS data. Alterations in fibroblast growth factor receptor 4 (FGFR4) were identified in 5 of 68 (7%) of tumor samples, whereas differential overexpression of FGFR4 was confirmed orthogonally using 2 platforms. PDX models harbored the pathognomic EWSR1–WT1 fusion and were highly representative of corresponding tumors. Our analyses confirm DSRCT as a genomically quiet cancer defined by the balanced translocation, t(11;22)(p13:q12), characterized by a paucity of secondary mutations but a significant number of copy number alterations. Against this genomically quiet background, recurrent activating alterations of FGFR4 stood out, and suggest that this receptor tyrosine kinase, also noted to be highly expressed in DSRCT, should be further investigated. Future studies of DSRCT biology and preclinical therapeutic strategies should benefit from the PDX models characterized in this study.Implications:These data describe the general quiescence of the desmoplastic small round cell tumor (DSRCT) genome, present the first available bank of DSRCT model systems, and nominate FGFR4 as a key receptor tyrosine kinase in DSRCT, based on high expression, recurrent amplification, and recurrent activating mutations.
- Published
- 2023
7. Supplementary Figure 4 from Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
- Author
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Neerav Shukla, Marc Ladanyi, Ahmet Zehir, Elli Papaemmanuil, Andrew L. Kung, Paul A. Meyers, Leonard H. Wexler, Michael P. LaQuaglia, Todd E. Heaton, Justin T. Gerstle, Gunes Gundem, Daoqi You, Nancy Bouvier, Katherine A. Thornton, Mrinal M. Gounder, William D. Tap, Shakeel Modak, Nestor Rosales, Glorymar I. Sanchez, Diego F. Coutinho, Filemon Dela Cruz, Max F. Levine, Anita S. Bowman, and Emily K. Slotkin
- Abstract
Supplementary Figure 4 shows data related to FGFR4 inhibition in DSRCT and control models
- Published
- 2023
8. Supplementary Table 2 from Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
- Author
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Neerav Shukla, Marc Ladanyi, Ahmet Zehir, Elli Papaemmanuil, Andrew L. Kung, Paul A. Meyers, Leonard H. Wexler, Michael P. LaQuaglia, Todd E. Heaton, Justin T. Gerstle, Gunes Gundem, Daoqi You, Nancy Bouvier, Katherine A. Thornton, Mrinal M. Gounder, William D. Tap, Shakeel Modak, Nestor Rosales, Glorymar I. Sanchez, Diego F. Coutinho, Filemon Dela Cruz, Max F. Levine, Anita S. Bowman, and Emily K. Slotkin
- Abstract
Supplementary Table 2 shows the raw data further described in Figure 3
- Published
- 2023
9. Supplementary Table from Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma
- Author
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Sandra P. D'Angelo, William D. Tap, Mark T.A. Donoghue, Samuel Singer, Allison L. Richards, Edmund K. Bartlett, Jason E. Chan, Benjamin A. Nacev, Ping Chi, Katherine A. Thornton, Sujana Movva, Mary L. Keohan, Ciara M. Kelly, Mrinal M. Gounder, Mark A. Dickson, Evan Rosenbaum, Martina Bradic, Sinchun Hwang, and Nicholas D. Klemen
- Abstract
Supplementary Table from Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma
- Published
- 2023
10. Supplementary Data from Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors
- Author
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William D. Tap, Cristina R. Antonescu, Yu Chen, Michael F. Berger, Sinchun Hwang, Samuel Singer, Cindy J. Lee, Matthew D. Biniakewitz, Haley T. Phelan, Moriah Martindale, Jasmine H. Francis, Aimee M. Crago, Katherine A. Thornton, Evan Rosenbaum, Benjamin A. Nacev, Sujana Movva, Mary L. Keohan, Mrinal M. Gounder, Mark A. Dickson, Sandra P. D'Angelo, Ciara M. Kelly, Niedzica Camacho, Li-Xuan Qin, and Ping Chi
- Abstract
Supplementary Data from Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors
- Published
- 2023
11. Supplementary Figure from Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors
- Author
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William D. Tap, Cristina R. Antonescu, Yu Chen, Michael F. Berger, Sinchun Hwang, Samuel Singer, Cindy J. Lee, Matthew D. Biniakewitz, Haley T. Phelan, Moriah Martindale, Jasmine H. Francis, Aimee M. Crago, Katherine A. Thornton, Evan Rosenbaum, Benjamin A. Nacev, Sujana Movva, Mary L. Keohan, Mrinal M. Gounder, Mark A. Dickson, Sandra P. D'Angelo, Ciara M. Kelly, Niedzica Camacho, Li-Xuan Qin, and Ping Chi
- Abstract
Supplementary Figure from Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors
- Published
- 2023
12. Data from Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma
- Author
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Sandra P. D'Angelo, William D. Tap, Mark T.A. Donoghue, Samuel Singer, Allison L. Richards, Edmund K. Bartlett, Jason E. Chan, Benjamin A. Nacev, Ping Chi, Katherine A. Thornton, Sujana Movva, Mary L. Keohan, Ciara M. Kelly, Mrinal M. Gounder, Mark A. Dickson, Evan Rosenbaum, Martina Bradic, Sinchun Hwang, and Nicholas D. Klemen
- Abstract
Purpose:Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors.Experimental Design:We pooled patients who were treated prospectively with nivolumab or pembrolizumab as monotherapy or with bempegaldesleukin, epacadostat, ipilimumab, or talimogene laherparepvec. We did a new independent assessment for HPD and analyzed clinical, pathologic, and genomic data from baseline tumor biopsies. Our primary endpoint was the incidence of HPD; secondary endpoints were clinical or genomic correlates of response or HPD.Results:We treated 134 patients with advanced sarcoma from 2015 to 2019. Twenty-one patients (16%) had a complete or partial response (CR/PR), and 30% of responses were durable for over 2 years. Forty-eight (36%) patients had stable disease (SD), 45 (34%) had progressive disease without HPD (PD), and 15 (11%) had HPD. Five patients (4%) were not evaluable for HPD. The sarcoma subtypes, sites of metastasis, clinical course, and genomic alterations in patients with PD and HPD were similar, except HPD tumors were smaller at baseline.Conclusions:In patients with advanced sarcoma, PD-1 blockade can mediate durable responses. HPD occurs in sarcoma at an incidence that is similar to what has been reported in other solid tumors, but patients with HPD were clinically and biologically similar to those who had PD. Further research is required to establish whether HPD is a biologically distinct phenomenon and whether a theoretical risk of HPD should influence patient management.
- Published
- 2023
13. Supplementary Figure from Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma
- Author
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Sandra P. D'Angelo, William D. Tap, Mark T.A. Donoghue, Samuel Singer, Allison L. Richards, Edmund K. Bartlett, Jason E. Chan, Benjamin A. Nacev, Ping Chi, Katherine A. Thornton, Sujana Movva, Mary L. Keohan, Ciara M. Kelly, Mrinal M. Gounder, Mark A. Dickson, Evan Rosenbaum, Martina Bradic, Sinchun Hwang, and Nicholas D. Klemen
- Abstract
Supplementary Figure from Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma
- Published
- 2023
14. Data from Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors
- Author
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William D. Tap, Cristina R. Antonescu, Yu Chen, Michael F. Berger, Sinchun Hwang, Samuel Singer, Cindy J. Lee, Matthew D. Biniakewitz, Haley T. Phelan, Moriah Martindale, Jasmine H. Francis, Aimee M. Crago, Katherine A. Thornton, Evan Rosenbaum, Benjamin A. Nacev, Sujana Movva, Mary L. Keohan, Mrinal M. Gounder, Mark A. Dickson, Sandra P. D'Angelo, Ciara M. Kelly, Niedzica Camacho, Li-Xuan Qin, and Ping Chi
- Abstract
Purpose:This phase Ib trial was designed to evaluate the safety and early efficacy signal of the combination of imatinib and binimetinib in patients with imatinib-resistant advanced gastrointestinal stromal tumors (GISTs).Patients and Methods:This trial used a standard 3 + 3 design to determine the recommended phase II dose (RP2D). Additional patients were enrolled on an expansion cohort at the RP2D enriching for succinate dehydrogenase (SDH)-deficient GISTs to explore potential efficacy.Results:The trial enrolled nine patients in the dose-escalation cohort and 14 in the dose-expansion cohort including six with SDH-deficient GISTs. Imatinib 400 mg daily with binimetinib 45 mg twice daily was established as the RP2D. Dose-limiting toxicity (DLT) was asymptomatic grade 4 creatinine phosphokinase (CPK) elevation. The most common non-DLT grade 3/4 toxicity was asymptomatic CPK elevation (69.6%). Other common ≥grade 2 toxicities included peripheral edema (17.4%), acneiform rash (21.7%), anemia (30.4%), hypophosphatemia (39.1%), and aspartate aminotransferase (AST) increase (17.4%). Two serious adverse events occurred (grade 2 dropped head syndrome and grade 3 central retinal vein occlusion). No unexpected toxicities were observed. Limited clinical activity was observed in KIT-mutant GIST. For SDH-deficient GISTs, one of five had confirmed RECIST1.1 partial response (PR). The median progression-free survival (mPFS) in patients with SDH-deficient GIST was 45.1 months [95% confidence interval (CI), 15.8–not estimable (NE)]; the median overall survival (mOS) was not reached (95% CI, 31.6 months–NE). One patient with a refractory metastatic SDH-deficient GIST had an exceptional pathologic response and durable clinical benefit.Conclusions:The combination of imatinib and binimetinib is safe with manageable toxicity and has encouraging activity in SDH-deficient but not imatinib-refractory KIT/PDGFRA-mutant GISTs. The observed clinical benefits provide a motivation for a larger trial of the combination strategy in SDH-deficient GISTs.
- Published
- 2023
15. Joint Adult and Pediatric Working Group as a Successful Platform to Strengthen Adolescent and Young Adult (AYA) Clinical Trial Collaboration: A Report from the NCTN/SARC AYA Clinical Trials Sarcoma Working Group
- Author
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Susan L. Whiteway, Aaron R. Weiss, Safia K. Ahmed, Wendy A. Allen-Rhoades, Viswatej Avutu, Kenneth Cardona, Lara E. Davis, Elizabeth J. Davis, Daniel J. Indelicato, Michael S. Isakoff, Katherine A. Janeway, J. Andrew Livingston, Shreyaskumar R. Patel, Damon R. Reed, Richard F. Riedel, Katherine A. Thornton, and Lisa M. Kopp
- Subjects
Oncology ,Pediatrics, Perinatology and Child Health - Published
- 2023
16. Functional Somatic Symptoms in Emergency Department Frequent Presenters
- Author
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Vidula Garde, Katherine B. Thornton, Madelyn Pardon, Vinay Gangathimmaiah, Andrew J Mallett, Jaimi Greenslade, and Kerrianne Watt
- Abstract
Background: Patients with Functional Somatic Symptoms (FSS) are frequently encountered within healthcare settings such as Emergency Departments (ED). There is limited research regarding characterisation and frequency of FSS within frequent presenters to ED and no previous Australian evidence. This study aims to fill this gap. Methods: A retrospective, single-centre study of frequent ED presenters over a 6-month period was undertaken. Patients with >3 re-presentations/month were reviewed for the presence of FSS using Stephenson and Price’s 1 categorisation of FSS. Patients were divided into three groups – FSS, possible FSS (pos-FSS) and non-FSS. The characteristics of these groups were compared using descriptive statistics (chi-square tests, ANOVA). Person-time at risk during the 6-month study period was estimated for patients in each group and incidence of ED presentation for each group was then calculated. Psychological distress indicators for ED presenters with FSS, as noted by the treating clinician, were also analysed. Results: 11% (71/638) of frequent ED presenters were categorised as having FSS and 17% (109/638) as having possible FSS (pos-FSS). Mean ED presentations in the FSS group during the study period were significantly higher than in the non-FSS and pos-FSS groups (pConclusion: We found that, amongst frequent ED presenters, patients with FSS presented significantly more frequently to ED than those without FSS. We propose revising the model of care for FSS in ED to promote appropriate referral to therapy services as a possible demand reduction strategy to improve patient care and efficiency in ED.
- Published
- 2023
17. Phase Ib Trial of the Combination of Imatinib and Binimetinib in Patients with Advanced Gastrointestinal Stromal Tumors
- Author
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Ping Chi, Li-Xuan Qin, Niedzica Camacho, Ciara M. Kelly, Sandra P. D'Angelo, Mark A. Dickson, Mrinal M. Gounder, Mary L. Keohan, Sujana Movva, Benjamin A. Nacev, Evan Rosenbaum, Katherine A. Thornton, Aimee M. Crago, Jasmine H. Francis, Moriah Martindale, Haley T. Phelan, Matthew D. Biniakewitz, Cindy J. Lee, Samuel Singer, Sinchun Hwang, Michael F. Berger, Yu Chen, Cristina R. Antonescu, and William D. Tap
- Subjects
Cancer Research ,Oncology ,Gastrointestinal Stromal Tumors ,Antineoplastic Combined Chemotherapy Protocols ,Imatinib Mesylate ,Humans ,Antineoplastic Agents ,Benzimidazoles ,neoplasms ,digestive system diseases ,Article ,Gastrointestinal Neoplasms - Abstract
Purpose: This phase Ib trial was designed to evaluate the safety and early efficacy signal of the combination of imatinib and binimetinib in patients with imatinib-resistant advanced gastrointestinal stromal tumors (GISTs). Patients and Methods: This trial used a standard 3 + 3 design to determine the recommended phase II dose (RP2D). Additional patients were enrolled on an expansion cohort at the RP2D enriching for succinate dehydrogenase (SDH)-deficient GISTs to explore potential efficacy. Results: The trial enrolled nine patients in the dose-escalation cohort and 14 in the dose-expansion cohort including six with SDH-deficient GISTs. Imatinib 400 mg daily with binimetinib 45 mg twice daily was established as the RP2D. Dose-limiting toxicity (DLT) was asymptomatic grade 4 creatinine phosphokinase (CPK) elevation. The most common non-DLT grade 3/4 toxicity was asymptomatic CPK elevation (69.6%). Other common ≥grade 2 toxicities included peripheral edema (17.4%), acneiform rash (21.7%), anemia (30.4%), hypophosphatemia (39.1%), and aspartate aminotransferase (AST) increase (17.4%). Two serious adverse events occurred (grade 2 dropped head syndrome and grade 3 central retinal vein occlusion). No unexpected toxicities were observed. Limited clinical activity was observed in KIT-mutant GIST. For SDH-deficient GISTs, one of five had confirmed RECIST1.1 partial response (PR). The median progression-free survival (mPFS) in patients with SDH-deficient GIST was 45.1 months [95% confidence interval (CI), 15.8–not estimable (NE)]; the median overall survival (mOS) was not reached (95% CI, 31.6 months–NE). One patient with a refractory metastatic SDH-deficient GIST had an exceptional pathologic response and durable clinical benefit. Conclusions: The combination of imatinib and binimetinib is safe with manageable toxicity and has encouraging activity in SDH-deficient but not imatinib-refractory KIT/PDGFRA-mutant GISTs. The observed clinical benefits provide a motivation for a larger trial of the combination strategy in SDH-deficient GISTs.
- Published
- 2022
18. Clinical outcomes following high-dose-rate surface applicator brachytherapy for angiosarcoma of scalp and face
- Author
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Elizabeth H. Baldini, Miranda B. Lam, Ivan Buzurovic, Allen C. Lam, Chandrajit P. Raut, Phillip M. Devlin, Devarati Mitra, and Katherine Anne Thornton
- Subjects
0106 biological sciences ,HDR brachytherapy ,medicine.medical_specialty ,medicine.medical_treatment ,Brachytherapy ,Salvage therapy ,Multimodality Therapy ,01 natural sciences ,medicine ,Radiology, Nuclear Medicine and imaging ,Angiosarcoma ,Original Paper ,angiosarcoma ,business.industry ,Soft tissue sarcoma ,010401 analytical chemistry ,medicine.disease ,0104 chemical sciences ,medicine.anatomical_structure ,Oncology ,Scalp ,Cohort ,Medicine ,Recurrent Angiosarcoma ,Radiology ,business ,010606 plant biology & botany - Abstract
Purpose Angiosarcoma is a sub-type of soft tissue sarcoma, often presenting as a multifocal or diffuse disease process with poor prognosis. This study presents outcomes of a single institution cohort of patients with angiosarcoma of the scalp and face following treatment with multimodality therapy, including high-dose-rate surface applicator (HDR-SA) brachytherapy, and represents the largest cohort utilizing this therapeutic approach. Material and methods Twenty patients with primary or recurrent angiosarcoma of the face or scalp were treated with HDR-SA brachytherapy between 2003-2018, with clinical characteristics and outcomes collected from medical records and used to identify prognostic features. Results Median follow-up was 45 months. Patients treated with HDR-SA brachytherapy had a 4-year local control rate of 63%, a 4-year progression-free survival (PFS) rate of 20%, and a 4-year overall survival rate of 54%. Disease features associated with worse loco-regional control (LRC) included location on the scalp (vs. face, p = 0.04) and tumor size ≥ 5 cm (p = 0.0099). Outcomes after HDR-SA brachytherapy for salvage therapy vs. HDR-SA brachytherapy as a component of an initial treatment approach were also significantly different, with worse LRC (p = 0.0084) and worse overall survival (OS) (p = 0.0019) in a setting of salvage therapy. Conclusions Local control rates following HDR-SA brachytherapy for scalp or face angiosarcoma are moderate and similar to what is described in the literature using a variety of local control treatment modalities. Smaller tumors and those involving the face rather than scalp had better outcomes. PFS rates were poor and there is a pressing need for treatment intensification and novel therapeutic options.
- Published
- 2021
19. Identified Enrollment Challenges of Adolescent and Young Adult Patients on the Nonchemotherapy Arm of Children's Oncology Group Study ARST1321
- Author
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Bree R. Eaton, Wendy Allen-Rhoades, Katherine Anne Thornton, Katherine A. Janeway, Safia K. Ahmed, Shreyaskumar Patel, Damon R. Reed, Yen-Lin Chen, Thomas J. Scharschmidt, Denise K. Reinke, Aaron R. Weiss, Dian Wang, R. Lor Randall, Richard F. Riedel, Douglas S. Hawkins, Lisa M. Kopp, Viswatej Avutu, Lara E. Davis, and Daniel J. Indelicato
- Subjects
Adult ,medicine.medical_specialty ,Pediatric Research Initiative ,Adolescent ,Accrual ,Pediatric Cancer ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,cooperative groups ,Soft Tissue Neoplasms ,Nursing ,NCTN ,Young Adult ,Rare Diseases ,Clinical Research ,Completion rate ,Surveys and Questionnaires ,Medicine ,Cooperative group ,Humans ,survey ,Young adult ,Cancer ,Pediatric ,Clinical Trials as Topic ,clinical trials ,Group study ,business.industry ,Soft tissue sarcoma ,Evaluation of treatments and therapeutic interventions ,Sarcoma ,Hematology ,medicine.disease ,Clinical trial ,Oncology ,Family medicine ,6.1 Pharmaceuticals ,Pediatrics, Perinatology and Child Health ,Public Health and Health Services ,enrollment barriers ,Brief Reports ,Patient Participation ,business - Abstract
ARST1321, a trial of patients with advanced soft tissue sarcoma, was the first National Clinical Trials Network study codeveloped by pediatric and adult consortia with two treatment cohorts. We report on the findings of a survey to identify barriers to enrolling adolescent and young adult patients (15-39 years) onto the nonchemotherapy arm. The survey response rate was 31% with a 70% completion rate. Common identified reasons for low accrual in order of decreasing frequency included insufficient funding, lack of study awareness or interest, competing trials, toxicity concerns, philosophical differences in the therapy backbone, and regulatory and infrastructure barriers. Clinical Trials.gov ID: NCT02180867.
- Published
- 2022
20. Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
- Author
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Marc Ladanyi, Nancy Bouvier, Nestor Rosales, Emily K. Slotkin, Filemon S. Dela Cruz, Todd E. Heaton, Max Levine, Mrinal M. Gounder, Paul A. Meyers, Andrew L. Kung, Anita S. Bowman, Katherine Anne Thornton, Neerav Shukla, Michael P. LaQuaglia, Shakeel Modak, Diego F. Coutinho, Leonard H. Wexler, Elli Papaemmanuil, Justin T. Gerstle, Ahmet Zehir, Glorymar Ibanez Sanchez, Gunes Gundem, William D. Tap, and Daoqi You
- Subjects
Adult ,Male ,0301 basic medicine ,Cancer Research ,Adolescent ,DNA Copy Number Variations ,Oncogene Proteins, Fusion ,Desmoplastic small-round-cell tumor ,ARID1A ,Chromosomal translocation ,Desmoplastic Small Round Cell Tumor ,Article ,Receptor tyrosine kinase ,Loss of heterozygosity ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Humans ,Receptor, Fibroblast Growth Factor, Type 4 ,HRAS ,Child ,WT1 Proteins ,Molecular Biology ,biology ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Cancer ,Fibroblast growth factor receptor 4 ,Middle Aged ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,RNA-Binding Protein EWS ,Multiplex Polymerase Chain Reaction - Abstract
Desmoplastic small round cell tumor (DSRCT) is characterized by the EWSR1–WT1 t(11;22) (p13:q12) translocation. Few additional putative drivers have been identified, and research has suffered from a lack of model systems. Next-generation sequencing (NGS) data from 68 matched tumor-normal samples, whole-genome sequencing data from 10 samples, transcriptomic and affymetrix array data, and a bank of DSRCT patient-derived xenograft (PDX) are presented. EWSR1–WT1 fusions were noted to be simple, balanced events. Recurrent mutations were uncommon, but were noted in TERT (3%), ARID1A (6%), HRAS (5%), and TP53 (3%), and recurrent loss of heterozygosity (LOH) at 11p, 11q, and 16q was identified in 18%, 22%, and 34% of samples, respectively. Comparison of tumor-normal matched versus unmatched analysis suggests overcalling of somatic mutations in prior publications of DSRCT NGS data. Alterations in fibroblast growth factor receptor 4 (FGFR4) were identified in 5 of 68 (7%) of tumor samples, whereas differential overexpression of FGFR4 was confirmed orthogonally using 2 platforms. PDX models harbored the pathognomic EWSR1–WT1 fusion and were highly representative of corresponding tumors. Our analyses confirm DSRCT as a genomically quiet cancer defined by the balanced translocation, t(11;22)(p13:q12), characterized by a paucity of secondary mutations but a significant number of copy number alterations. Against this genomically quiet background, recurrent activating alterations of FGFR4 stood out, and suggest that this receptor tyrosine kinase, also noted to be highly expressed in DSRCT, should be further investigated. Future studies of DSRCT biology and preclinical therapeutic strategies should benefit from the PDX models characterized in this study.Implications:These data describe the general quiescence of the desmoplastic small round cell tumor (DSRCT) genome, present the first available bank of DSRCT model systems, and nominate FGFR4 as a key receptor tyrosine kinase in DSRCT, based on high expression, recurrent amplification, and recurrent activating mutations.
- Published
- 2021
21. FDA Oncology Center of Excellence Project Renewal: Engaging the Oncology Community to Update Product Labeling for Older Oncology Drugs
- Author
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Patricia Keegan, Jennifer J Gao, Martha Donoghue, Stacy Shifflett Shord, Abhilasha Nair, Richard Pazdur, Elleni Alebachew, William F. Pierce, Laurie B. Burke, R. Donald Harvey, George D. Demetri, Joohee Sul, Janice Kim, Harvey Katzen, Katherine Anne Thornton, Paul G. Kluetz, and Sundeep Agrawal
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Product Labeling ,United States Food and Drug Administration ,Fda approval ,Center of excellence ,MEDLINE ,Antineoplastic Agents ,Medical Oncology ,Approved drug ,United States ,Incentive ,Neoplasms ,Internal medicine ,medicine ,Humans ,Product (category theory) ,Business ,Oncology drugs ,Drug Approval ,Drug Labeling - Abstract
The FDA conducts independent reviews of scientific data obtained with investigational drug products to ensure that they are safe and effective. As a result of this process, FDA-approved product labeling is generated that is considered one of the most trusted sources of information for use of an approved drug. But FDA approval is only the beginning of the life cycle of a new drug; the first oncology drugs now have more than 7 decades of clinical experience in the postmarketing setting. Due, in part, to lack of incentives, some companies may not seek inclusion of new data, other than new safety information, in FDA-approved product labeling. Ensuring that product labeling provides adequate directions for use is important for all drugs, including older therapies that may form the backbone of many standard combination regimens for pediatric and adult cancers. Project Renewal is an FDA Oncology Center of Excellence pilot program that leverages expertise from the clinical and scientific oncology communities to review published literature and generate a drug-specific product report summarizing data that may support updates to FDA-approved product labeling. This article provides a broad overview of Project Renewal's collaborative pilot process for identifying and assessing literature supporting potential labeling updates, while engaging the oncology community to increase awareness of FDA's evidentiary standards and deliberative processes used when considering the addition of new indications and dosing regimens to product labeling.
- Published
- 2021
22. State of the science: Uterine sarcomas: From pathology to practice
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Kevin Holcomb, Ramey D. Littell, Alexander Shushkevich, Martee L. Hensley, Michael D. Toboni, Mario M. Leitao, Naishadh A. Shah, Katherine Anne Thornton, Premal H. Thaker, Douglas A. Levine, Sarah Chiang, Brian M. Slomovitz, Jubilee Brown, Matthew A. Powell, Ann H. Klopp, and Sean C. Dowdy
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Leiomyosarcoma ,0301 basic medicine ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,Biopsy ,Sarcoma, Endometrial Stromal ,MEDLINE ,Disease ,Hysterectomy ,Medical Oncology ,Disease-Free Survival ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Carcinosarcoma ,Uterine cancer ,Biomarkers, Tumor ,medicine ,Adjuvant therapy ,Humans ,Uterine carcinosarcoma ,Intensive care medicine ,Endometrial Ablation Techniques ,Adenosarcoma ,business.industry ,Endometrial cancer ,Uterus ,Obstetrics and Gynecology ,Prognosis ,medicine.disease ,Carboplatin ,Clinical trial ,030104 developmental biology ,Oncology ,chemistry ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Uterine Neoplasms ,Female ,Radiotherapy, Adjuvant ,Neoplasm Grading ,Neoplasm Recurrence, Local ,business - Abstract
Objective Uterine carcinosarcoma (UCS) is a rare but aggressive cancer. In early-stage disease data guiding treatment is sparse. The purpose of this review is to summarize the findings from the 2019 NRG oncology group summer symposium meeting as well as a review of the current literature, with a particular focus on molecular targets, ongoing clinical trials, and treatment of early and advanced/recurrent disease. Methods A combination of expert presentations and an extensive literature search was undertaken to summarize the literature in this review. MEDLINE was queried for peer-reviewed publications on UCS. This search was not limited by year or study design, but was limited to English language publications. ClinicalTrials.gov was queried for ongoing trials in UCS. Results UCS is a rare cancer that is biphasic, with the carcinomatous component driving its aggressive nature. Level 3 evidence regarding early stage disease is lacking, but retrospective data suggests adjuvant therapy is warranted. The recent results of GOG 261 have contributed valuable information towards treatment strategy, including use of paclitaxel and carboplatin for UCS. Clinical trials are ongoing to investigate new targeted agents in UCS. Conclusion Ongoing endometrial cancer clinical trials now include UCS patients. In combination with advances in molecular profiling, this will provide patients with UCS improved therapeutic options. Until that time, surgical resection and traditional cytotoxic chemotherapy remains standard of care.
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- 2020
23. Phase II Trial of Imatinib Plus Binimetinib in Patients With Treatment-Naive Advanced Gastrointestinal Stromal Tumor
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Ping Chi, Li-Xuan Qin, Bastien Nguyen, Ciara M. Kelly, Sandra P. D'Angelo, Mark A. Dickson, Mrinal M. Gounder, Mary L. Keohan, Sujana Movva, Benjamin A. Nacev, Evan Rosenbaum, Katherine A. Thornton, Aimee M. Crago, Sam Yoon, Gary Ulaner, Randy Yeh, Moriah Martindale, Haley T. Phelan, Matthew D. Biniakewitz, Sarah Warda, Cindy J. Lee, Michael F. Berger, Nikolaus D. Schultz, Samuel Singer, Sinchun Hwang, Yu Chen, Cristina R. Antonescu, and William D. Tap
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Adult ,Cancer Research ,Treatment Outcome ,Oncology ,Gastrointestinal Stromal Tumors ,Original Reports ,Antineoplastic Combined Chemotherapy Protocols ,Imatinib Mesylate ,Humans ,Benzimidazoles - Abstract
PURPOSE Dual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST. METHODS In this trial ( NCT01991379 ), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in > 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity. RESULTS Between September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response (≥ 90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%). CONCLUSION The study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.
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- 2022
24. Long-term Follow-up and Patterns of Response, Progression, and Hyperprogression in Patients after PD-1 Blockade in Advanced Sarcoma
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Nicholas D. Klemen, Sinchun Hwang, Martina Bradic, Evan Rosenbaum, Mark A. Dickson, Mrinal M. Gounder, Ciara M. Kelly, Mary L. Keohan, Sujana Movva, Katherine A. Thornton, Ping Chi, Benjamin A. Nacev, Jason E. Chan, Edmund K. Bartlett, Allison L. Richards, Samuel Singer, Mark T.A. Donoghue, William D. Tap, and Sandra P. D'Angelo
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Oncolytic Virotherapy ,Cancer Research ,Oncology ,Programmed Cell Death 1 Receptor ,Disease Progression ,Humans ,Sarcoma ,Melanoma ,Article ,Follow-Up Studies - Abstract
Purpose: Programmed cell death protein 1 (PD-1) blockade can mediate objective responses in advanced sarcomas, but their durability has not been established and it is unclear if hyperprogressive disease (HPD) occurs in sarcomas treated with PD-1 inhibitors. Experimental Design: We pooled patients who were treated prospectively with nivolumab or pembrolizumab as monotherapy or with bempegaldesleukin, epacadostat, ipilimumab, or talimogene laherparepvec. We did a new independent assessment for HPD and analyzed clinical, pathologic, and genomic data from baseline tumor biopsies. Our primary endpoint was the incidence of HPD; secondary endpoints were clinical or genomic correlates of response or HPD. Results: We treated 134 patients with advanced sarcoma from 2015 to 2019. Twenty-one patients (16%) had a complete or partial response (CR/PR), and 30% of responses were durable for over 2 years. Forty-eight (36%) patients had stable disease (SD), 45 (34%) had progressive disease without HPD (PD), and 15 (11%) had HPD. Five patients (4%) were not evaluable for HPD. The sarcoma subtypes, sites of metastasis, clinical course, and genomic alterations in patients with PD and HPD were similar, except HPD tumors were smaller at baseline. Conclusions: In patients with advanced sarcoma, PD-1 blockade can mediate durable responses. HPD occurs in sarcoma at an incidence that is similar to what has been reported in other solid tumors, but patients with HPD were clinically and biologically similar to those who had PD. Further research is required to establish whether HPD is a biologically distinct phenomenon and whether a theoretical risk of HPD should influence patient management.
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- 2021
25. A phase I/II trial of the PD-1 inhibitor retifanlimab (R) in combination with gemcitabine and docetaxel (GD) as first-line therapy in patients (Pts) with advanced soft-tissue sarcoma (STS)
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Evan Rosenbaum, Li-Xuan Qin, Katherine Anne Thornton, Sujana Movva, Benjamin Alexander Nacev, Mark Andrew Dickson, Mrinal M. Gounder, Mary Louise Keohan, Viswatej Avutu, Ping Chi, Ciara Marie Kelly, Jason Earl Chan, Moriah Martindale, Travis Adamson, Olivia Robin McKennan, Joseph Patrick Erinjeri, Robert A Lefkowitz, William D. Tap, and Sandra P. D'Angelo
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Cancer Research ,Oncology - Abstract
11516 Background: In a phase III trial, GD had similar response and survival rates to doxorubicin when administered as first-line therapy to advanced STS pts. G and D have each demonstrated synergy with PD-1 blockade in pre-clinical or clinical studies. We hypothesized that GD plus R would be safe, tolerable, and have synergistic activity in STS. Methods: This is an ongoing open-label, single-center, phase I/II trial of R (INCMGA00012) combined with GD in pts with treatment-naïve unresectable or metastatic high-grade STS. Herein, we report the phase I results, which included a safety run-in followed by a 3+3 dose de-escalation design. G (900 mg/m2) was administered on days 1 and 8 and D (75 mg/m2) on day 8, in 21-day cycles. R (210 mg IV flat dose on the run-in portion and 375 mg on the dose de-escalation portion) was administered on day 1 of each cycle starting in cycle 2 and continued as monotherapy after completion of 6 cycles of GD. The primary endpoint of the phase I was to determine the recommended phase 2 dose (RP2D) of R plus GD. Secondary endpoints included describing the safety, assessing best overall response rate (ORR) by RECIST 1.1, disease control rate (DCR), and progression-free survival (PFS). Results: Thirteen pts were treated, 7on the run-in and 6 on the de-escalation portion. One pt progressed prior to starting R and was replaced. Median pt age was 53 (range 28 – 74) and 7 were female. Histologies included leiomyosarcoma (n = 6), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (2), pleomorphic liposarcoma (1), angiosarcoma (1), and myxofibrosarcoma (1). The Table lists treatment-related adverse events (TRAEs) that occurred in ≥ 20% pts in descending order of frequency. Additional Grade (Gr) 3 TRAEs occurring in 1 pt each, included: infusion reaction, leukopenia, anorectal infection, neutropenia, and pyelonephritis. Gr 3 pyelonephritis was the only dose-limiting toxicity. There were no Gr ≥ 4 TRAEs. One pt (Gr 3 elevated AST/ALT) required corticosteroids and cessation of study therapy. The RP2D was determined to be 375 mg of R plus GD. Twelve pts were evaluable for response. ORR was 17% (1 of 6; 95% CI 1 - 64%) and 50% (3 of 6; 95% CI 19% - 81%) in the run-in and de-escalation cohorts, respectively. DCR was 100% (6 of 6; 95% CI 52 - 100%) and 83% (5 of 6; 95% CI: 36 - 99%). PFS rates at 24 weeks were 60% (95% CI: 29 - 100%) and 44% (95% CI: 17 - 100%). Conclusions: R plus GD was generally safe and well tolerated with no unexpected safety signals to date. The phase II portion evaluating efficacy of R plus GD at the RP2D is ongoing. Clinical trial information: NCT04577014. [Table: see text]
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- 2022
26. A pilot study of lenvatinib plus pembrolizumab in patients with advanced sarcoma
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Sujana Movva, Viswatej Avutu, Ping Chi, Mark Andrew Dickson, Mrinal M. Gounder, Ciara Marie Kelly, Mary Louise Keohan, Benjamin Alexander Nacev, Evan Rosenbaum, Katherine Anne Thornton, Seth M. Cohen, Martee Leigh Hensley, Jason A. Konner, Alison M. Schram, Li-Xuan Qin, Robert A Lefkowitz, Joseph Patrick Erinjeri, and Sandra P. D'Angelo
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Cancer Research ,Oncology - Abstract
TPS11588 Background: New treatment options are needed for sarcomas. Pazopanib is the only targeted agent approved for multiple soft tissue sarcoma (STS) subtypes with a response rate of 6% and a PFS of 4.6 months. Immunotherapy has a limited role in STS, as the SARC028 study of pembrolizumab demonstrated an overall response rate of 18%, with the highest response rate seen in the undifferentiated pleomorphic sarcoma (UPS) cohort at 23%. Lenvatinib is an oral, multi-tyrosine kinase inhibitor approved for the treatment of multiple cancer types including progressive, radioiodine-refractory thyroid cancer and unresectable hepatocellular carcinoma with inhibitory activity against the receptor tyrosine kinases VEGFR 1-3, FGFR 1-3, KIT, PDGFR alpha/beta, and RET. Early outcomes with the combination of lenvatinib and pembrolizumab suggest that this regimen could be broadly superior to PD-1 targeting alone for several tumor types as high rates of objective response have been noted. The rationale for this study is based on preclinical work demonstrating the immunosuppressive effects of VEGF in the tumor immune microenvironment including inhibition of dendritic cell maturation, recruitment of immunosuppressive Tregs, MDSCs and TAMs and up-regulation of PD-1 on CD8+ cells. Methods: This is a pilot study evaluating the efficacy of lenvatinib and pembrolizumab in the treatment of select metastatic and/or unresectable sarcomas. Patients will be enrolled in one of five cohorts: Cohort A: leiomyosarcoma; Cohort B: UPS; Cohort C: vascular sarcomas (including angiosarcoma and epithelioid hemangioendothelioma); Cohort D: synovial sarcoma and malignant peripheral nerve sheath tumor; and Cohort E: bone sarcomas (limited to osteosarcoma and chondrosarcoma). Eligible patients should have had at least one prior therapy for unresectable and/or metastatic disease, but no more than three prior lines of therapy. Prior treatment with angiogenesis inhibitors or immunotherapy is excluded. Archival tissue is required for eligibility. Patients enrolled in the study will be treated initially with a 2 week run-in of lenvatinib 20 mg orally daily which will be continued daily thereafter. Subsequently, they will start pembrolizumab 200 mg intravenously every 21 days. The primary endpoint for each cohort is best overall response rate documented by RECIST v1.1 Criteria at 27 weeks. A sample size of 10 patients is planned for each of the five histological cohorts. If 2 or more confirmed responses are observed among the 10 patients in an arm, the drug combination will be considered positive and worthy of further investigation for that arm. Secondary endpoints are PFS, OS, duration of response and safety/tolerability of the combination. On-treatment biopsy and blood samples will be required for correlative assessments. Accrual in all cohorts is ongoing. Clinical trial information: NCT04784247.
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- 2022
27. Presence of immune infiltrates, increased expression of transposable elements, and viral response pathways in sarcoma associate with response to checkpoint inhibition
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Benjamin Alexander Nacev, Martina Bradic, Allison L. Richards, Ciara Marie Kelly, Mark Andrew Dickson, Mrinal M. Gounder, Mary Louise Keohan, Ping Chi, Sujana Movva, Katherine Anne Thornton, Emily K Slotkin, Evan Rosenbaum, Viswatej Avutu, Jason Earl Chan, Lauren Baker Banks, Travis Adamson, Samuel Singer, Mark Donoghue, William D. Tap, and Sandra P. D'Angelo
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Cancer Research ,Oncology - Abstract
11510 Background: Response to checkpoint inhibition (CPI) in sarcoma is overall low and varies between and within subtypes. Understanding tumor intrinsic determinants of this response may improve efficacy and patient selection. The de-repression of transposable elements (TEs), which are epigenetically silenced repetitive DNA elements of viral origin, is linked to anti-tumor immunity through an antiviral inflammatory response. We hypothesize that baseline expression of TEs and epigenetic regulators correlates with overall response rate (ORR) in sarcoma CPI clinical trials. Methods: This is a retrospective analysis of bulk RNA-sequencing data from pre-treatment biopsies of patients on CPI trials in sarcoma (pembrolizumab plus talimogene laherparepvec, nivolumab plus bempegaldesleukin, and pembrolizumab plus epacadostat). Sixty-seven samples from unique patients representing 12 subtypes were analyzed. The MCP counter deconvolution method and unsupervised clustering were used to group samples by immune phenotypes resulting in immune ‘hot’ and ‘cold’ clusters. ORR was defined by RECIST. To determine if baseline expression of TEs and epigenetic regulators significantly predicted immune types, we implemented a lasso penalized logistic regression. Results: Immune ‘hot’ tumors were characterized by increased immune infiltrates including CD8+ T-cells, B-cells, and NK cells vs ‘cold’ tumors. Patients with ‘hot’ vs ‘cold’ tumors had an ORR of 30.5% (11/36) vs. 3.2% (1/31) (p = 0.003; chi-squared). The best predictors of ‘hot vs ‘cold’ was the increased expression of multiple TE families including MER45A, MER57F, and LTR21B (respective lasso coefficients, 0.27, 0.07, and 0.07). Expression of IKZF1, a chromatin-interacting transcription factor, was also predictive (lasso coefficient, 0.35) and increased expression correlated with improved ORR (p = 0.003; unpaired t-test). TE and IKFZ1 expression was significantly correlated with CD8+ T-cell signaling and antiviral response pathways such as cGAS-STING (MER57F, r2= 0.43, padj = 1.75E-4; IKZF1, r2= 0.63, padj = 6.28E-9) and type II interferon (MER57F, r2= 0.67, padj = 2.51E-10; IKZF1, r2= 0.60, padj = 7.19E-8). Increased expression of cGAS-STING (p = 3.9E-4; unpaired t-test) and type II interferon pathways (p = 1.89E-10; unpaired t-test) was significant in ‘hot’ tumors. Conclusions: Immune ‘hot’ baseline immune profiles of sarcoma are associated with improved ORR to CPI and with increased expression of TEs and IKZF1. These differences in gene expression correlate with increased inflammatory signaling, which suggests a response to TE-encoded viral-like sequences that are typically epigenetically silenced. Induction of TE de-repression and IKZF1 expression through epigenetic targeting warrants pre-clinical investigation as a strategy to promote CPI response in sarcomas.
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- 2022
28. A phase 1b lead-in to a randomized phase 2 trial of lurbinectedin plus doxorubicin in leiomyosarcoma (LMS)
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Gregory Michael Cote, Edwin Choy, Katherine Anne Thornton, Emanuele Mazzola, Sara Bouberhan, Priscilla Merriam, Andrew J. Wagner, Jeffrey A. Morgan, Candace L. Haddox, Jay Oza, George D. Demetri, and Suzanne George
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Cancer Research ,Oncology - Abstract
TPS11592 Background: Single agent or combination chemotherapy regimens, typically including doxorubicin or gemcitabine, represent standard of care options for first- and second-line therapy in patients (pts) with metastatic LMS. However, response rates (ORR) and progression-free (PFS)/overall survival (OS) remain poor. Lurbinectedin (PharmaMar S.A. and Jazz Pharmaceuticals) uniquely binds DNA, inducing DNA double strand breaks leading to apoptosis and delaying progression through phase S/G2 of the cell cycle. Lurbinectedin is a novel structural analog of trabectedin with improved toxicity profile, potency, and pharmacokinetics. In a prior pilot study, we showed that the combination of lurbinectedin and doxorubicin (L+D) was safe, with early signs of clinical activity, particularly in LMS. Thus, we designed this investigator-initiated/investigator-sponsored phase 1b lead-in to optimize doses of L+D, to be followed by a randomized (1:1) phase 2 study of L+D versus doxorubicin monotherapy in anthracycline-naïve LMS. Methods: Pts age > 18 years with locally advanced or metastatic, unresectable LMS (non-GIST soft-tissue sarcoma histologies allowed in Phase 1b), without prior anthracycline or lurbinectedin/trabectedin, ECOG PS < 3, measurable disease by RECIST 1.1, and normal organ function, are eligible. Phase 1b dosing will include a fixed dose of lurbinectedin and two dose levels of doxorubicin. The Phase 1b lead-in follows a standard 3+3 design where dose escalation will occur if 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted every two cycles. Once the recommended phase 2 dose (RP2D) is confirmed, Phase 2 will be initiated. Fifty pts will be randomized 1:1 including doxorubicin +/- lurbinectedin. Randomization will be stratified by uterine v. non-uterine origin of LMS. Pts progressing on single agent doxorubicin will be allowed to cross over to lurbinectedin monotherapy. The Phase 2 primary endpoint is PFS. Secondary endpoints include disease control rate, ORR, OS, PFS2 (for doxorubicin monotherapy patients who cross to lurbinectedin monotherapy). Archival tumor, germline DNA, and ctDNA will be collected for correlative studies exploring genomic markers of sensitivity/resistance. We will provide respective point estimate along with 90% confidence interval for each of the arms. Log-rank test will be performed to test the difference in survival (both PFS and OS) between groups. Regression analyses of survival data will be based on the Cox proportional hazards model. The first pt in dose-level 1 of the Phase 1b lead-in was enrolled in February 2022. Clinical trial information: NCT05099666.
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- 2022
29. A phase I/II study of prexasertib in combination with irinotecan in patients with relapsed/refractory desmoplastic small round cell tumor and rhabdomyosarcoma
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Emily K Slotkin, Audrey Mauguen, Michael Vincent Ortiz, Filemon S. Dela Cruz, Tara O'Donohue, Michael David Kinnaman, Paul A. Meyers, Leonard H. Wexler, Scarlett Rodriguez, Viswatej Avutu, Ciara Marie Kelly, Sandra P. D'Angelo, Mary Louise Keohan, Mrinal M. Gounder, Benjamin Alexander Nacev, Evan Rosenbaum, Mark Andrew Dickson, Katherine Anne Thornton, Julia Lynne Glade Bender, and William D. Tap
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Cancer Research ,Oncology - Abstract
11503 Background: Prexasertib (PRX) is an inhibitor of CHK1, prevents DNA repair leading to mitotic catastrophe, and can enhance the activity of DNA-damaging chemotherapy. Translocation driven sarcomas exhibit high levels of replication stress and have demonstrated susceptibility to CHK1 inhibition in preclinical models. Desmoplastic small round cell tumor (DSRCT) and rhabdomyosarcoma (RMS) are aggressive sarcomas of children, adolescents and young adults for which novel therapies are urgently required. Methods: We conducted a phase I/II trial of PRX with irinotecan (irino) in patients ≥ 12 months of age with relapsed or refractory DSRCT or RMS. Eligible patients could have any number of prior therapies, including irino. Dose level 1 was PRX 80 mg/m2 on day 1 + irino 20 mg/m2 for 10 days. Dose levels 2 and 2A were PRX 105 or 150 mg/m2 (>21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 10 (level 2) or 5 (level 2A) days. All cycles were 21 days. The primary objectives were to determine the RP2D of PRX with irino, and to determine the best overall response rate (ORR) in 6 months at the RP2D (RECIST v1.1) in DSRCT, with 3 or more responses out of 16 considered promising. Results: 21 patients were enrolled (DSRCT: 19; 2 RMS:2). The RP2D was dose level 2A. Treatment was well tolerated with the most common adverse events being neutropenia (48%), nausea (48%), and fatigue (52%). Cytopenias were managed with the aid of growth factor support in all patients once the RP2D was established. The DSRCT expansion enrolled 13 of 16 planned patients due to discontinuation of PRX supply prior to study completion. Four patients remain on therapy at the time of this submission. Responses in DSRCT patients at all dose levels are shown in Table. Sixteen of 21 enrolled patients, and 5 of 6 patients achieving PR had previously received irino. The median (range) number of cycles was 7 (2-26). Both RMS patients treated at the RP2D experienced SD as best response. The estimated ORR at the RP2D was 23%, and lower boundary of the one-sided 90% confidence interval was 9%, exceeding the unpromising rate of 5%. The two-sided 90% confidence interval was 7 to 49%. In addition, 3 patients had a PR at doses lower than the RP2D, bringing the ORR for all dose levels (n = 19) to 32% (90%CI: 15 to 53%). Conclusions: The RP2D of PRX in combination with irino is PRX 105 or 150 mg/m2 (>21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 5 days in 21 day cycles with myelosuppression successfully managed with growth factor support. The study met its primary objective to consider PRX + irino promising in DSRCT and should be further investigated. Clinical trial information: NCT04095221. [Table: see text]
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- 2022
30. 1527MO Biomarkers of response and hyperprogression in patients with sarcoma treated with checkpoint blockade
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Mrinal M. Gounder, Sinchun Hwang, Edmund K. Bartlett, William D. Tap, Mark T.A. Donoghue, M. Bradic, Ping Chi, Mark A. Dickson, Sujana Movva, M.L. Keohan, A.L. Richards, Benjamin A. Nacev, Samuel Singer, Nicholas D. Klemen, Jason E. Chan, Sandra P. D'Angelo, Katherine Anne Thornton, Ciara Marie Kelly, and Evan Rosenbaum
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,In patient ,Hematology ,Sarcoma ,medicine.disease ,business ,Blockade - Published
- 2021
31. Demographics, outcomes, and risk factors for patients (Pts) with sarcoma and COVID-19: A multi-institutional cohort analysis
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Vivek Subbiah, Lisa Tachiki, Jonathan C. Trent, Corrie A. Painter, Elizabeth J. Davis, Rana R. McKay, Cathleen Park, Daniel Y. Reuben, Ali Raza Khaki, Katherine Anne Thornton, Rashmi Chugh, Michael J. Wagner, Anup Kasi, Thorvardur R. Halfdanarson, Chris Labaki, Matthew Ingham, Elizabeth A. Griffiths, Clara Hwang, Elizabeth T. Loggers, and James L. Chen
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Cancer Research ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Demographics ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,medicine.disease ,Oncology ,Internal medicine ,medicine ,Sarcoma ,business ,Cohort study - Abstract
11523 Background: Sarcoma pts often receive aggressive, highly immunosuppressive therapy and may be at high risk for severe COVID-19. Demographics, outcomes and risk factors for pts with sarcoma and COVID-19 are unknown. We aimed to describe the course of COVID-19 in sarcoma pts and to identify factors associated with adverse outcomes. Methods: The COVID-19 and Cancer Consortium (NCT04354701) is an international registry of pts with cancer and COVID-19. Adult pts (≥18 years old) with a diagnosis of sarcoma and laboratory confirmed SARS-CoV-2 were included from 50 participating institutions. Data including demographics, sarcoma diagnosis and treatment, and course of COVID-19 infection were analyzed. Primary outcome was the composite rate of hospitalization or death at 30 days from COVID-19 diagnosis. Secondary outcomes were 30 day all-cause mortality, rate of hospitalization, O2 need, and ICU admission. Descriptive statistics and univariate Fisher tests are reported. Results: From March 17, 2020 to February 6, 2021, N=204 pts were included. Median follow up was 42 days. Median age was 58 years (IQR 43-67). 97 (48%) were male. 30 (15%) had ECOG performance status ≥2. 104 (51%) received cancer treatment, including surgery or radiation, within 3 months of COVID-19 diagnosis. 153 (75%) had active cancer, of whom 34 (22%) had lung metastases. 100 (49%) pts met the composite primary endpoint; 96 (47%) were hospitalized and 18 (9%) died within 30 days from COVID-19 diagnosis. 64 (31%) required oxygen, and 16 (8%) required ICU admission. Primary endpoint rates were similar for pts who received cytotoxic chemotherapy (38/58, 66%) or targeted therapy (16/28, 57%). Pts with higher rates of the primary endpoint included patients ≥60 years old (59% vs 40%, OR 2.04, 95% CI 1.12-3.74, p=0.016), pts with ECOG PS ≥2 vs 0-1 (90% vs 41%, OR 12.2, 95% CI 3.44-66.8, p
- Published
- 2021
32. Best practices for the management of local-regional recurrent chordoma: a position paper by the chordoma global consensus group
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Vittoria Colia, Bernd Kasper, R. Imai, Michael Baumann, Stéphanie Bolle, R. Capanna, Riccardo Casadei, Paolo G. Casali, Claire Alapetite, P. A. Gardner, C. L. A. Vleggeert-Lankamp, C. Heery, Elena Tamborini, Anant Desai, Stefano Radaelli, Alessandro Gronchi, Nadia Hindi, Akira Kawai, Daniel Vanel, C. Sen, Francesco Doglietto, Nicolas Penel, Ziya L. Gokaslan, S. Froelich, Katherine Anne Thornton, Carlo Morosi, Hans Gelderblom, Francis J. Hornicek, O. J. Norum, M. Uhl, Palma Dileo, Sandip Pravin Patel, Piero Fossati, J. Martin Broto, Peter Hohenberger, Rick L. Haas, Andreas Leithner, Toru Akiyama, F. Ricchini, Robin L. Jones, Valter Torri, Josh Sommer, Peter Pal Varga, Y. Yamada, Per-Ulf Tunn, J.-Y. Blay, Augusto Caraceni, Piotr Rutkowski, Jürgen Debus, Lee Jeys, Adrienne M. Flanagan, Diego Mazzatenta, I. Logowska, Marco Krengli, Damien C. Weber, Thomas F. DeLaney, Susanne Scheipl, P. Picci, Beate Timmermann, Piero Nicolai, S. Pilotti, P. Bruzzi, Silvia Stacchiotti, Stefano Boriani, S. Dijkstra, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], European Institute of Oncology [Milan] (ESMO), Saitama University, Institut Curie [Paris], University of Dresden Medical School, Centre Léon Bérard [Lyon], Institut Gustave Roussy (IGR), University of Pisa - Università di Pisa, University Medical Center Heidelberg, Massachusetts General Hospital [Boston], Queen Elizabeth Hospital, University College London Hospitals (UCLH), Universiteit Leiden [Leiden], University of Brescia, Cancer Research UK London Research Institute, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Providence University, Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Hospital Universitario Virgen del Rocío [Sevilla], University of Heidelberg, Medical Faculty, Harvard Medical School [Boston] (HMS), Chiba University Hospital, Queens Elizabeth Hospital [Birmingham], Royal Marsden NHS Foundation Trust, National Cancer Center Research Institute [Tokyo], Università del Piemonte Orientale - Dipartimento DISIT Italy, Medical University Graz, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Hospital Graz, New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), University of Duisbourg-Essen, Helios Klinikum [Erfurt], Memorial Sloane Kettering Cancer Center [New York], SwissFEL, Paul Scherrer Institut, Leiden University Medical Center (LUMC), Universiteit Leiden, CHU Lille, Université de Lille, METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, European Institute of Oncology [Milan] [ESMO], Institut Gustave Roussy [IGR], University College London Hospitals [UCLH], Netherlands Cancer Institute [NKI], National Cancer Institute [Bethesda] [NCI-NIH], Harvard Medical School [Boston] [HMS], Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology [MCMCC], Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS], New York University Langone Medical Center [NYU Langone Medical Center], Leiden University Medical Center [LUMC], Stacchiotti, S., Gronchi, A., Fossati, P., Akiyama, T., Alapetite, C., Baumann, M., Blay, J. Y., Bolle, S., Boriani, S., Bruzzi, P., Capanna, R., Caraceni, A., Casadei, R., Colia, V., Debus, J., Delaney, T., Desai, A., Dileo, P., Dijkstra, S., Doglietto, F., Flanagan, A., Froelich, S., Gardner, P. A., Gelderblom, H., Gokaslan, Z. L., Haas, R., Heery, C., Hindi, N., Hohenberger, P., Hornicek, F., Imai, R., Jeys, L., Jones, R. L., Kasper, B., Kawai, A., Krengli, M., Leithner, A., Logowska, I., Martin Broto, J., Mazzatenta, D., Morosi, C., Nicolai, P., Norum, O. J., Patel, S., Penel, N., Picci, P., Pilotti, S., Radaelli, S., Ricchini, F., Rutkowski, P., Scheipl, S., Sen, C., Tamborini, E., Thornton, K. A., B., Timmermann, Torri, V., Tunn, P. U., Uhl, M., Yamada, Y., Weber, D. C., Vanel, D., Varga, P. P., Vleggeert-Lankamp, C. L. A., Casali, P. G., and Sommer, J.
- Subjects
sarcoma ,[SDV]Life Sciences [q-bio] ,Medizin ,chemotherapy ,Patient advocacy ,surgery ,0302 clinical medicine ,Neoplasm Recurrence ,Medicine ,chordoma ,relapse ,radiotherapy ,Relapse ,Sarcoma ,Hematology ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,chordoma, consensus, recurrence ,Sacral Chordoma ,musculoskeletal diseases ,medicine.medical_specialty ,recurrence ,Best practice ,MEDLINE ,Reviews ,610 Medicine & health ,03 medical and health sciences ,Chordoma ,Humans ,Chemotherapy ,Medical physics ,Radiotherapy ,business.industry ,medicine.disease ,Cervical spine ,consensus ,Family medicine ,Position paper ,Surgery ,Neoplasm Recurrence, Local ,business ,030217 neurology & neurosurgery - Abstract
Chordomas are rare, malignant bone tumors of the skull-base and axial skeleton. Until recently, there was no consensus among experts regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation, the global chordoma patient advocacy group, convened a multi-disciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published, covering the management of primary and metastatic chordomas. Additional evidence and further discussion were needed to develop recommendations about the management of local-regional failures. Thus, ESMO and CF convened a second consensus group meeting in November 2015 to address the treatment of locally relapsed chordoma. This meeting involved over 60 specialists from Europe, the United States and Japan with expertise in treatment of patients with chordoma. The consensus achieved during that meeting is the subject of the present publication and complements the recommendations of the first position paper.
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- 2017
33. Cost-Effectiveness of Surveillance for Distant Recurrence in Extremity Soft Tissue Sarcoma
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Rinaa S. Punglia, Elizabeth H. Baldini, Chandrajit P. Raut, Trevor J. Royce, Sagar A. Patel, Katherine Anne Thornton, and Aileen B. Chen
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Adult ,medicine.medical_specialty ,Cost effectiveness ,medicine.medical_treatment ,Cost-Benefit Analysis ,03 medical and health sciences ,0302 clinical medicine ,Positron Emission Tomography Computed Tomography ,medicine ,Humans ,030212 general & internal medicine ,Stage (cooking) ,Survival rate ,health care economics and organizations ,Aged ,Aged, 80 and over ,business.industry ,Soft tissue sarcoma ,Distant recurrence ,Extremities ,Sarcoma ,Middle Aged ,medicine.disease ,Prognosis ,Quality-adjusted life year ,Survival Rate ,Models, Economic ,Oncology ,030220 oncology & carcinogenesis ,Surgery ,Radiology ,Quality-Adjusted Life Years ,Neoplasm Recurrence, Local ,business ,Watchful waiting ,Follow-Up Studies - Abstract
Optimal distant recurrence (DR) surveillance strategies for extremity soft tissue sarcoma (STS) are unknown. We performed a cost-effectiveness analysis of different imaging modalities performed at guideline-specified intervals.We developed a Markov model simulating lifetime outcomes for 54-year-old patients after definitive treatment for American Joint Committee on Cancer stage II-III extremity STS using four surveillance strategies: watchful waiting (WW), chest X-ray (CXR), chest computed tomography (CCT), and positron emission tomography-computed tomography (PET/CT). Probabilities, utilities, and costs were extracted from the literature and Medicare claims to determine incremental cost-effectiveness ratios (ICER).CCT was the most effective and most costly strategy with CXR the most cost-effective strategy at a societal willing-to-pay (WTP) of $100,000/quality-adjusted life year (QALY). The ICER was $12,113/QALY for CXR versus $104,366/QALY for CCT while PET/CT was never cost-effective. Sensitivity analyses demonstrated CCT becomes the preferred imaging modality as the lifetime risk of DR increases beyond 33% or as the WTP increases beyond $120,000/QALY.Optimal DR surveillance imaging for stage II-III extremity STS should be individualized based on patients' risks for DR. These results suggest CXR, or CCT performed at more protracted intervals, may be preferred for lower-risk patients (i.e., DR risk33%), whereas CCT may be preferred for higher-risk patients (i.e., DR risk33%). Further study of optimal strategies is needed. In the interim, these findings may help to refine guidelines to reduce resource overutilization during routine surveillance of lower-risk sarcoma patients.
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- 2017
34. NCCN Guidelines Insights: Bone Cancer, Version 2.2017
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Sujana Movva, Carol D. Morris, Jillian L. Scavone, Damon R. Reed, Herrick J. Siegel, Joseph Kuechle, William T. Curry, Brian E. Brigman, Warren Chow, Robert S. Benjamin, Francis J. Hornicek, Katherine Anne Thornton, Joel L. Mayerson, G. Thomas Budd, Victor M. Santana, Dieter Lindskog, Sean V. McGarry, Herbert S. Schwartz, R. Lor Randall, Mark Agulnik, Nicola Fabbri, J. Sybil Biermann, Lynn Million, Robert L. Satcher, Victor M. Villalobos, Mary Anne Bergman, Peter S. Rose, Aarati Didwania, David R. Lucas, Richard J. O'Donnell, and Douglas Adkins
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musculoskeletal diseases ,Oncology ,medicine.medical_specialty ,Biopsy ,Antineoplastic Agents ,Bone Neoplasms ,Sarcoma, Ewing ,Medical Oncology ,Amputation, Surgical ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Positron Emission Tomography Computed Tomography ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Neoplasm Staging ,Clinical Trials as Topic ,business.industry ,Bone cancer ,Incidence ,Guideline ,Chemoradiotherapy, Adjuvant ,medicine.disease ,Prognosis ,Magnetic Resonance Imaging ,Survival Rate ,Chemotherapy, Adjuvant ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Osteosarcoma ,Neoplasm staging ,Chordoma ,Sarcoma ,Chondrosarcoma ,Neoplasm Recurrence, Local ,business ,030217 neurology & neurosurgery ,Giant-cell tumor of bone - Abstract
The NCCN Guidelines for Bone Cancer provide interdisciplinary recommendations for treating chordoma, chondrosarcoma, giant cell tumor of bone, Ewing sarcoma, and osteosarcoma. These NCCN Guidelines Insights summarize the NCCN Bone Cancer Panel's guideline recommendations for treating Ewing sarcoma. The data underlying these treatment recommendations are also discussed.
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- 2017
35. Molecular characterization and management of secondary resistance to serial TRK inhibitors
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Nora Ku, George D. Demetri, Monica M. Bertagnolli, Otari Chipashvili, Karan Malik, Jia-Ren Lin, Chandrajit P. Raut, Matthew L. Hemming, Ziming Du, Barrett H. Childs, Sandro Santagata, Timothy Hagan, Michael J. Nathenson, Katherine Anne Thornton, Adrián Mariño-Enríquez, and Ewa Sicinska
- Subjects
Cancer Research ,Oncology ,business.industry ,Trk receptor ,Cancer research ,Medicine ,In patient ,business ,Highly selective - Abstract
e22547 Background: TRK inhibitor drugs such as the highly selective larotrectinib (Laro), have proven highly effective in malignancies harboring fusions of NTRK1, 2, or 3. Resistance in patients (pts) with progressive disease (PD) after response to initial TRK inhibitor therapy has been attributed to secondary mutations in the solvent front or gatekeeper domains of the NTRK fusion gene. LOXO-195 (L195) is a 2nd generation TRK inhibitor that overcomes these mutations. Mechanisms of resistance to L195 have not yet been well characterized. Methods: We analyzed molecular mechanisms of resistance in one adult pt with undifferentiated pleomorphic sarcoma (UPS) who had serial responses and PD on Laro and L195. Targeted DNA sequencing, RNA sequencing and multicolor cyclic immunofluorescence (CyCIF) were performed on pre- and post-PD specimens on both drugs. Results: The patient was enrolled on the phase 2 clinical trial of Laro (NCT02576431) with TPM3-NTRK1 fusion UPS. Multifocal PD and resistance to Laro developed after major objective response RECIST -74.9%, of 10 months (mo); the resistant tumor harbored both the initial TPM3-NTRK1 fusion but also evolved a new solvent front mutation in NTRK1 [c.1783G > A (p.G595R)]. A single pt protocol (NCT03206931) was designed to treat with L195. After an initial response to L195, PD limited to 2 sites developed; both sites were resected at 5 and 10 mo. The pt continues on L195 with systemic disease control 20 mo after initiation (in total 30 mo since Laro initiation). Analysis of tumor samples pre- and post-PD on L195 identified the emergence of a KRAS G12V mutation, with associated activation of the KRAS signaling pathway and a significant infiltration by inflammatory cells. A cell line and pt-derived xenografts (PDX), all harboring the initial TPM3-NTRK1 fusion, were generated from this pt. Conclusions: Resection of oligoclonal PD and continuation of L195 post-PD can be an effective treatment strategy. Oncogenic activation of the KRAS pathway is a possible mechanism of resistance to L195. Our studies indicate that the tumor microenvironment of TRK-fusion sarcomas resistant to TRK inhibitors may increase inflammatory cell infiltrates, which may provide clues for future combination therapy.
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- 2019
36. CBT-1 in combination with doxorubicin in patients with metastatic, unresectable sarcomas who previously progressed on doxorubicin
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Melissa Amber Burgess, Susan Matlow, Steven Attia, Katherine Anne Thornton, Gregory M. Cote, Daryl Barnett, Sant P. Chawla, Scott H. Okuno, Robert K. Oldham, and Karla V. Ballman
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Drug ,Cancer Research ,Anthracycline ,business.industry ,media_common.quotation_subject ,Soft tissue ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Doxorubicin ,In patient ,business ,030215 immunology ,medicine.drug ,media_common - Abstract
TPS11077 Background: The response rates of advanced soft tissue sarcomas (STS) to single-agent, first-line anthracycline are typically less than 25%. P-glycoprotein 1 (P-gp), a cell membrane drug efflux pump, is believed to be a resistance mechanism in STS. CBT-1 is a small molecule, orally administered, P-gp antagonist currently under clinical development. This is a multi-institutional open label phase I study of CBT-1 in combination with doxorubicin in patients with anthracycline-refractory sarcoma. The study is designed to determine a maximum tolerable dose (MTD), recommended phase II dose (RP2D), and the safety/tolerability of the combination of CBT-1 and doxorubicin. The study will evaluate anti-cancer activity as a secondary objective as measured by Disease Control Rate (DCR; complete response [CR] + partial response [PR] + stable disease [SD]) at 12 weeks. Objective Response Rate (ORR; CR+PR) and Progression Free Survival (PFS) will be monitored. Correlative studies include assessment of pharmacokinetic and pharmacodynamicendpoints. Methods: Patients 18 years or older with locally advanced metastatic, unresectable STS, prior progression on ≤ 150 mg/m2 of doxorubicin (or another anthracycline equivalent), ECOG PS ≤ 1 and normal organ function, are eligible for this study. Dosing includes fixed doxorubicin (37.5 mg/m2 IV day 5 and day 6) and escalation of oral CBT-1 on days 1-7 of a 21 day cycle. This study follows a standard 3+3 phase I design where dose escalation will occur if < 0/3 or 1/6 patients experience a dose-limiting toxicity (DLT). Tumor assessments are conducted at Week 6 and Week 12. For patients with response or stable disease, treatment is allowed to continue for 4-5 cycles to a maximum of 450 mg/m2 lifetime doxorubicin exposure. Once RP2D is defined, an additional 10 patients will be enrolled into the dose expansion phase. To date, Cohorts 1 (50 mg CBT-1) and 2 (100 mg CBT-1) have been completed with one DLT of grade 4 neutropenia lasting longer than 7 days in Cohort 1. Enrollment to Cohort 3 began December 2018. (References: Oldham, R. K., Reid, W. K., Preisler, H. D., and Barnett, D. (1998) Cancer Biother. Radiopharm. 13, 71-80; Kelly, R. J., Robey, R. W., Chen, C. C., Draper, D., Luchenko, V., Barnett, D., Oldham, R. K., Caluag, Z., Frye, R. A., Steinberg, S. M., Fojo, T., Bates, S. E. (2012) The Oncologist 17 (4) 512-e523; Robey, R. W., Shukla, S., Finely, E. M., Oldham, R. K., Barnett, D., Ambudkar, S. V., Fojo, T., Bates, S. E., (2008) Biochemical Pharmacology 75, 6, 1302-1312). Clinical trial information: NCT03002805.
- Published
- 2019
37. Detection of endoglin-expressing CTCs in patients enrolled in an adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (TAPPAS)
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Katherine Anne Thornton, Keyi Zhu, Robert G. Maki, Wen Liu, Nicolas Penel, Atrayee Basu Mallick, David A. Liebner, Charles P. Theuer, Steven I. Robinson, Steven Attia, Mario Cervantes, Robin L. Jones, Sant P. Chawla, Andrew S. Brohl, Delia Alvarez, Silvia Stacchiotti, Vinod Ravi, Richard F. Riedel, Darren W. Davis, and William D. Tap
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Cancer Research ,biology ,business.industry ,VEGF receptors ,Endoglin ,Hypoxia (medical) ,digestive system diseases ,Pazopanib ,Oncology ,Downregulation and upregulation ,hemic and lymphatic diseases ,otorhinolaryngologic diseases ,medicine ,biology.protein ,Cancer research ,Angiosarcoma ,In patient ,medicine.symptom ,Receptor ,business ,neoplasms ,medicine.drug - Abstract
e23570Background: Endoglin (CD105) is an essential angiogenic receptor expressed on Angiosarcoma (AS) tumor cells and vessels that is upregulated following hypoxia and promotes resistance to VEGF i...
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- 2018
38. TAPPAS: An adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma
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Vinod Ravi, Andrew Scott Brohl, Sant P. Chawla, Steven Attia, Richard F. Riedel, David A. Liebner, Katherine Anne Thornton, Atrayee Basu Mallick, Cyrus R. Mehta, Lingyun Liu, Delia Alvarez, Charles P. Theuer, Steven Ian Robinson, Nicolas Penel, Silvia Stacchiotti, William D. Tap, Robin Lewis Jones, and Robert G. Maki
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Cancer Research ,Oncology - Published
- 2018
39. Targeted tumor profiling and actionable somatic variants in sarcoma
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Andrew J. Wagner, Michael J. Nathenson, Jeffrey A. Morgan, Chandrajit P. Raut, Suzanne George, Katherine Anne Thornton, Priscilla Merriam, George D. Demetri, Eytan Ben Ami, and Matthew L. Hemming
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Oncology ,Cancer Research ,medicine.medical_specialty ,Somatic cell ,business.industry ,medicine.disease ,DNA sequencing ,Internal medicine ,Medicine ,Profiling (information science) ,Sarcoma ,Treatment decision making ,business - Abstract
11551Background: The impact of next generation sequencing data on treatment decision and clinical outcome in sarcoma remains under investigation. Methods: We queried the Dana Farber Cancer Institut...
- Published
- 2018
40. Tappas: An adaptive enrichment phase 3 trial of TRC105 and pazopanib versus pazopanib alone in patients with advanced angiosarcoma (AAS)
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David A. Liebner, Charles P. Theuer, Lingyun Liu, Robert G. Maki, Robin L. Jones, Sant P. Chawla, Silvia Stacchiotti, Katherine Anne Thornton, Vinod Ravi, Steven I. Robinson, Cyrus R. Mehta, William D. Tap, Nicolas Penel, Delia Alvarez, Richard F. Riedel, Atrayee Basu Mallick, Andrew S. Brohl, and Steven Attia
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Soft tissue sarcoma ,medicine.disease ,Pazopanib ,03 medical and health sciences ,030104 developmental biology ,Internal medicine ,medicine ,Overall survival ,In patient ,Angiosarcoma ,business ,medicine.drug - Abstract
TPS11081 Background: AAS is an aggressive soft tissue sarcoma (STS) of endothelial cell origin with an expected median overall survival of 8-12 months. Pazopanib (P) is approved for treatment of advanced STS following progression on chemotherapy. In a retrospective study of 40 AAS patients treated with single agent P the median PFS was 3.1 months and median OS 9.9 months with no complete responses. Endoglin is an essential angiogenic receptor expressed on AAS that is upregulated following VEGF inhibition, and TRC105, an endoglin antibody, given with P produced durable complete responses in AAS patients with median PFS of 5.6 months in refractory patients including those receiving prior P. The TAPPAS trial is the first randomized Phase 3 trial performed in AAS, and was initiated following protocol assistance from the EMA and Special Protocol Assessment from the FDA. Methods: TAPPAS is a randomized multicenter study of TRC105/P vs P alone in the United States and Europe that is actively enrolling cutaneous and non-cutaneous AAS patients and incorporates an adaptive enrichment design. Key inclusion criteria: 0, 1 or 2 prior lines of therapy, ECOG ≤ 1. Primary endpoint is PFS and secondary endpoints include ORR and OS. The initial sample size of 124 patients, followed until 95 PFS events, provides more than 80% power to detect a hazard ratio of 0.55. At the time of interim analysis, projected to occur upon the occurrence of 40 events in approximately 70 patients, the result will be classified as belonging to either the favorable, promising, enrichment or unfavorable zones, based on conditional power. The sample size and PFS events will be unchanged in the favorable and unfavorable zones, and will be increased to a total of 200 patients followed for 170 PFS events in the promising zone. The trial will enroll 100 additional patients, with cutaneous disease only, in the enrichment zone and will follow them until 110 events are observed in the total cutaneous population. An independent DMC will follow the trial for safety and futility. The adaptive design requires the enrollment of fewer patients, preserves type-1 error, and protects power to detect a clinically meaningful survival benefit. (NCT 02979899). Clinical trial information: NCT02979899.
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- 2017
41. Cost effectiveness of surveillance for distant recurrence in extremity soft tissue sarcoma
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Elizabeth H. Baldini, Rinaa S. Punglia, Sagar A. Patel, Katherine Anne Thornton, Trevor J. Royce, and Chandrajit P. Raut
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Cancer Research ,medicine.medical_specialty ,Cost effectiveness ,business.industry ,Soft tissue sarcoma ,Distant recurrence ,medicine.disease ,030218 nuclear medicine & medical imaging ,Imaging modalities ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,medicine ,Radiology ,business - Abstract
11021 Background: Optimal surveillance strategies for extremity soft tissue sarcoma (STS) are unknown. We performed a cost-effectiveness analysis of competing imaging modalities performed at National Cancer Comprehensive Network guideline-specified intervals. Methods: We developed a Markov model simulating lifetime outcomes for 54-year-old patients after definitive treatment for Stage II-III extremity STS using four surveillance strategies: watchful waiting (WW), chest x-ray (CXR), chest computed tomography (CCT) and positron emission tomography-computed tomography (PET/CT) performed every 3-6 months for the first 3 years, every 6 months until year 5, and then annually. We used probabilities, utilities and costs extracted from the literature and Medicare claims to determine incremental cost-effectiveness ratios (ICER). Results: While the model showed that CCT is the most effective strategy, CXR is the most cost-effective strategy at a societal willing-to-pay (WTP) of $100,000/quality-adjusted life year (QALY). The ICER is $14,306/QALY for CXR versus $117,683/QALY for CCT while PET/CT is never cost effective (Table). Sensitivity analyses demonstrated CCT becomes the preferred imaging modality as the lifetime risk of DR increases beyond 38% or as the societal WTP increases beyond $130,000/QALY. Conclusions: Optimal DR surveillance imaging for Stage II-III extremity STS should be individualized based on patients’ risks for DR. CXR, or CCT at more protracted intervals, may be preferred for lower risk patients (i.e. DR risk less than 38%), whereas CCT may be preferred for higher risk patients (i.e. DR risk greater than 38%). These findings can help refine guidelines to reduce resource overutilization during surveillance of sarcoma patients. [Table: see text]
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- 2017
42. Images in clinical medicine. FLT3 Mutation and acute myelogenous leukemia with leukostasis
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Katherine A, Thornton and Mark, Levis
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Male ,Leukemia, Myeloid, Acute ,Fatal Outcome ,fms-Like Tyrosine Kinase 3 ,Gene Duplication ,Humans ,Middle Aged ,Leukostasis - Published
- 2007
43. TRANSIENT ANALYSIS OF CAPACITOR SWITCHING IN UNBALANCED DISTRIBUTION SYSTEM WITH HARMONIC DISTORTION
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Adly A. Girgis, Elham B. Makram, and Katherine P. Thornton
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Total harmonic distortion ,Engineering ,business.industry ,Decoupling capacitor ,law.invention ,Distribution system ,Capacitor ,Matrix (mathematics) ,law ,Control theory ,Frequency domain ,Harmonic ,Boundary value problem ,Electrical and Electronic Engineering ,business - Abstract
The wide application of shunt capacitor banks in distribution systems for economic reasons, have raised concern about over-voltage transients and harmonic magnification in unbalanced distribution systems. This paper introduces a new method for transient analysis during capacitor switching. Presence of harmonic sources, unbalance in feeder configuration, and combinations of single-and three-phase loads are accounted for. The new method is a frequency domain-based approach using a three-phase Z-Bus algorithm. The paper reviews the concepts of the building algorithm of a three-phase Z-bus matrix in the complex frequency domain. Untransposed feeders and different types of loads are considered. Finally, the boundary conditions for different capacitor switching cases and the results with harmonic distortion are reported.
- Published
- 1989
44. Selection of lines to be switched to eliminate overloaded lines using a Z-matrix method
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Elham B. Makram, Katherine P. Thornton, and Homer E. Brown
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Engineering ,Schedule ,business.industry ,Economic dispatch ,Energy Engineering and Power Technology ,law.invention ,Electric power system ,Electric power transmission ,law ,Electrical network ,Control system ,Electronic engineering ,Power-flow study ,Electrical and Electronic Engineering ,business ,Z-matrix (chemistry) - Abstract
There are many ways in which a system can be adjusted to compensate for an overloaded line. Earlier studies have shown that shifts in generation or phase shifter adjustments can be calculated to correct an overload. These corrections are based on an analytical solution of the system. Many algorithms have been developed to use these techniques in optimal power flow solutions. Generation schedules are based on economic dispatch and any deviation from the proper schedule to eliminate overloads will result in an increase in production costs. There have been a considerable number of papers in the literature that have presented methods of solving large problems, such as the power system load flow problem, using different approaches with a large amount of numbers in storage and more computer time. Methods have been developed to identify overloaded lines and to select one or more lines to be removed in order to reduce the overload in a power system. Recent research in reference [1] indicated that a simple method of redirecting power flow to reduce the overload in a line is to selectively switch the network. A line can be added to or removed from the system in order to cause a shift in the power flow and to eliminate the overload. The selection of a line to be switched is a complicated process. The addition or removal of a line must not cause any other overloads on the system as it eliminates the original overload.
- Published
- 1989
45. Whole-Exome Capture and Sequencing Identifies HEATR2 Mutation as a Cause of Primary Ciliary Dyskinesia
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Katherine C. Thornton, Margaret W. Leigh, Emily H. Turner, Benjamin T. Levinson, Deborah A. Nickerson, Maimoona A. Zariwala, Laura G. Van Arendonk, Amjad Horani, Philip V. Bayly, Kate S. Wilson, Susan K. Dutcher, Joseph C. Giacalone, Alison J. Albee, Todd E. Druley, Steven L. Brody, Thomas Ferkol, Michael R. Knowles, Anand C. Patel, and Jay Shendure
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Adult ,Male ,Absent outer dynein arms ,Dynein ,Respiratory System ,Mutation, Missense ,Chromosome Disorders ,Genes, Recessive ,Gene mutation ,Biology ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Report ,medicine ,Genetics ,Humans ,Genetics(clinical) ,Exome ,Genetic Predisposition to Disease ,Child ,Genetics (clinical) ,Exome sequencing ,030304 developmental biology ,Primary ciliary dyskinesia ,0303 health sciences ,Kartagener Syndrome ,Cilium ,Infant ,Proteins ,Epithelial Cells ,Axonemal Dyneins ,Sequence Analysis, DNA ,medicine.disease ,Motile cilium ,Female ,030217 neurology & neurosurgery ,Chlamydomonas reinhardtii - Abstract
Motile cilia are essential components of the mucociliary escalator and are central to respiratory-tract host defenses. Abnormalities in these evolutionarily conserved organelles cause primary ciliary dyskinesia (PCD). Despite recent strides characterizing the ciliome and sensory ciliopathies through exploration of the phenotype-genotype associations in model organisms, the genetic bases of most cases of PCD remain elusive. We identified nine related subjects with PCD from geographically dispersed Amish communities and performed exome sequencing of two affected individuals and their unaffected parents. A single autosomal-recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function. Airway epithelial cells isolated from PCD-affected individuals had markedly reduced HEATR2 levels, absent dynein arms, and loss of ciliary beating. MicroRNA-mediated silencing of the orthologous gene in Chlamydomonas reinhardtii resulted in absent outer dynein arms, reduced flagellar beat frequency, and decreased cell velocity. These findings were recapitulated by small hairpin RNA-mediated knockdown of HEATR2 in airway epithelial cells from unaffected donors. Moreover, immunohistochemistry studies in human airway epithelial cells showed that HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly. The identification of HEATR2 contributes to the growing number of genes associated with PCD identified in both individuals and model organisms and shows that exome sequencing in family studies facilitates the discovery of novel disease-causing gene mutations.
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46. Population-based rare variant detection via pooled exome or custom hybridization capture with or without individual indexing
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Michael A. Province, Allie Y. Li, Andrew L. Young, Katherine C. Thornton, Benjamin T. Levinson, Todd E. Druley, Andrew E. O. Hughes, Enrique Ramos, Francesco Vallania, and Sara E. Chasnoff
- Subjects
Male ,lcsh:QH426-470 ,lcsh:Biotechnology ,Population ,Genomics ,Biology ,Multiplexed capture ,Polymorphism, Single Nucleotide ,Sensitivity and Specificity ,DNA sequencing ,Nuclear Family ,03 medical and health sciences ,Nucleic acid thermodynamics ,0302 clinical medicine ,Gene Frequency ,lcsh:TP248.13-248.65 ,Genetics ,Humans ,Genomic library ,Exome ,Genetic Testing ,education ,Exome sequencing ,Alleles ,030304 developmental biology ,Gene Library ,Oligonucleotide Array Sequence Analysis ,Indexed capture ,0303 health sciences ,education.field_of_study ,Methodology Article ,Nucleic Acid Hybridization ,SPLINTER ,Rare variants ,lcsh:Genetics ,Hybridization capture ,Female ,DNA microarray ,Sequence Alignment ,030217 neurology & neurosurgery ,Algorithms ,Software ,Biotechnology - Abstract
Background Rare genetic variation in the human population is a major source of pathophysiological variability and has been implicated in a host of complex phenotypes and diseases. Finding disease-related genes harboring disparate functional rare variants requires sequencing of many individuals across many genomic regions and comparing against unaffected cohorts. However, despite persistent declines in sequencing costs, population-based rare variant detection across large genomic target regions remains cost prohibitive for most investigators. In addition, DNA samples are often precious and hybridization methods typically require large amounts of input DNA. Pooled sample DNA sequencing is a cost and time-efficient strategy for surveying populations of individuals for rare variants. We set out to 1) create a scalable, multiplexing method for custom capture with or without individual DNA indexing that was amenable to low amounts of input DNA and 2) expand the functionality of the SPLINTER algorithm for calling substitutions, insertions and deletions across either candidate genes or the entire exome by integrating the variant calling algorithm with the dynamic programming aligner, Novoalign. Results We report methodology for pooled hybridization capture with pre-enrichment, indexed multiplexing of up to 48 individuals or non-indexed pooled sequencing of up to 92 individuals with as little as 70 ng of DNA per person. Modified solid phase reversible immobilization bead purification strategies enable no sample transfers from sonication in 96-well plates through adapter ligation, resulting in 50% less library preparation reagent consumption. Custom Y-shaped adapters containing novel 7 base pair index sequences with a Hamming distance of ≥2 were directly ligated onto fragmented source DNA eliminating the need for PCR to incorporate indexes, and was followed by a custom blocking strategy using a single oligonucleotide regardless of index sequence. These results were obtained aligning raw reads against the entire genome using Novoalign followed by variant calling of non-indexed pools using SPLINTER or SAMtools for indexed samples. With these pipelines, we find sensitivity and specificity of 99.4% and 99.7% for pooled exome sequencing. Sensitivity, and to a lesser degree specificity, proved to be a function of coverage. For rare variants (≤2% minor allele frequency), we achieved sensitivity and specificity of ≥94.9% and ≥99.99% for custom capture of 2.5 Mb in multiplexed libraries of 22–48 individuals with only ≥5-fold coverage/chromosome, but these parameters improved to ≥98.7 and 100% with 20-fold coverage/chromosome. Conclusions This highly scalable methodology enables accurate rare variant detection, with or without individual DNA sample indexing, while reducing the amount of required source DNA and total costs through less hybridization reagent consumption, multi-sample sonication in a standard PCR plate, multiplexed pre-enrichment pooling with a single hybridization and lesser sequencing coverage required to obtain high sensitivity.
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