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de Boissieu P, Chevret S. Misleading Reporting of a Negative Randomized Clinical Trial May Affect Clinical Practice. J Clin Oncol 2025; 43:354-355. [PMID: 39383491 DOI: 10.1200/jco.24.01104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/01/2024] [Indexed: 10/11/2024] Open
Affiliation(s)
- Paul de Boissieu
- Paul de Boissieu, PhD, Drug Assessment Division, Haute Autorité de Santé, Saint-Denis La Plaine, France; and Sylvie Chevret, MD, PhD, Membre titulaire de la Commission de la Transparence, Haute Autorité de Santé, Saint-Denis La Plaine, France, ECSTRRA team, UMR1153, Inserm, Paris Cité Université, Paris, France
| | - Sylvie Chevret
- Paul de Boissieu, PhD, Drug Assessment Division, Haute Autorité de Santé, Saint-Denis La Plaine, France; and Sylvie Chevret, MD, PhD, Membre titulaire de la Commission de la Transparence, Haute Autorité de Santé, Saint-Denis La Plaine, France, ECSTRRA team, UMR1153, Inserm, Paris Cité Université, Paris, France
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Das S, Samaddar S. Recent Advances in the Clinical Translation of Small-Cell Lung Cancer Therapeutics. Cancers (Basel) 2025; 17:255. [PMID: 39858036 PMCID: PMC11764476 DOI: 10.3390/cancers17020255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/03/2025] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
Small-cell lung cancer (SCLC) is a recalcitrant form of cancer, representing 15% of lung cancer cases globally. SCLC is classified within the range of neuroendocrine pulmonary neoplasms, exhibiting shared morphologic, ultrastructural, immunohistochemical, and molecular genomic features. It is marked by rapid proliferation, a propensity for early metastasis, and an overall poor prognosis. The current conventional therapies involve platinum-etoposide-based chemotherapy in combination with immunotherapy. Nonetheless, the rapid emergence of therapeutic resistance continues to pose substantial difficulties. The genomic profiling of SCLC uncovers significant chromosomal rearrangements along with a considerable mutation burden, typically involving the functional inactivation of the tumor suppressor genes TP53 and RB1. Identifying biomarkers and evaluating new treatments is crucial for enhancing outcomes in patients with SCLC. Targeted therapies such as topoisomerase inhibitors, DLL3 inhibitors, HDAC inhibitors, PARP inhibitors, Chk1 inhibitors, etc., have introduced new therapeutic options for future applications. In this current review, we will attempt to outline the key molecular pathways that play a role in the development and progression of SCLC, together with a comprehensive overview of the most recent advancements in the development of novel targeted treatment strategies, as well as some ongoing clinical trials against SCLC, with the goal of improving patient outcomes.
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Affiliation(s)
- Subhadeep Das
- Department of Biochemistry, Purdue University, BCHM A343, 175 S. University Street, West Lafayette, IN 47907, USA
- Purdue University Institute for Cancer Research, Purdue University, Hansen Life Sciences Research Building, Room 141, 201 S. University Street, West Lafayette, IN 47907, USA
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Odeniran PO, Madlala P, Mkhwanazi NP, Soliman MES. Camptothecin and Its Derivatives from Traditional Chinese Medicine in Combination with Anticancer Therapy Regimens: A Systematic Review and Meta-Analysis. Cancers (Basel) 2024; 16:3802. [PMID: 39594757 PMCID: PMC11593076 DOI: 10.3390/cancers16223802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 11/04/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Background/Objectives: Camptothecin (CPT) and its derivatives, irinotecan and topotecan, are integral components of cancer chemotherapy, often used in combination therapies. This meta-analysis evaluates the efficacy of CPT-based combination treatments in cancer patients. Methods: We systematically searched the literature database using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist for articles published between 2000 and 2022. Published studies were retrieved through an electronic search on the Web of Science, PubMed, and Google Scholar databases. A total of 138 studies were downloaded and examined, and 71 eligible studies were selected for meta-analysis after excluding studies that did not meet the inclusion criteria. Results: Ultimately, a total of 71 studies were included in the analysis, comprising non-small cell lung cancer (NSCLC), colorectal cancer (COLRC), oesophageal/gastric cancer (O/GC), and small cell lung cancer (SCLC). For NSCLC, the objective response rate (RR) was 31.8% (95% CI: 27.3-37.1%, p = 0.025), with irinotecan plus cisplatin showing significantly higher efficacy compared to other irinotecan-based combinations. In COLRC, irinotecan and 5-fluorouracil/leucovorin plus bevacizumab demonstrated superior efficacy with a RR of 44% (95% CI: 34-58, p < 0.001) and minimal haematological toxicity. In O/GC, irinotecan-based combinations showed an average RR of 43% (95% CI: 27-70, p < 0.001) and average overall survival (OS) and progression-free survival (PFS) rates of 10.2 and 5.5 months, respectively. For SCLC, irinotecan-based combinations had a higher control response than topotecan-based ones, while the latter exhibited higher rates of stable and progressive disease. The overall RR for SCLC was 45% (95% CI: 34.3-60.2, p < 0.001). Conclusions: The existing evidence underscored the potential of CPT-based combination therapy in various cancers. Among the various combinations discussed in this analysis, irinotecan plus cisplatin demonstrated the highest objective RR in 12 trials focused on NSCLC. This study provides valuable insights into potential treatment strategies for various types of cancer, emphasising the importance of personalised and tailored approaches to maximise efficacy and minimise adverse effects.
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Affiliation(s)
- Paul O. Odeniran
- Department of Veterinary Parasitology and Entomology, University of Ibadan, Ibadan 200001, Nigeria;
| | - Paradise Madlala
- HIV Pathogenesis Programme, School of Laboratory Medicine and Medical Science, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Nompumelelo P. Mkhwanazi
- HIV Pathogenesis Programme, School of Laboratory Medicine and Medical Science, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Mahmoud E. S. Soliman
- Molecular Bio-Computation and Drug Design Lab, School of Health Sciences, University of Kwazulu-Natal, Durban 4000, South Africa
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Shim JS, Kim Y, Yuh T, Lee JB, Kim HR, Hong MH, Cho BC, Lim SM. Real-World Outcomes with Lurbinectedin in Second Line and Beyond for Extensive Stage Small Cell Lung Cancer in Korea. LUNG CANCER (AUCKLAND, N.Z.) 2024; 15:149-159. [PMID: 39494146 PMCID: PMC11531734 DOI: 10.2147/lctt.s485320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 10/18/2024] [Indexed: 11/05/2024]
Abstract
Purpose Small-cell lung cancer (SCLC) accounts for approximately 10-15% of all lung cancers and is characterized by a high recurrence rate, early metastasis, and poor prognosis. Before the FDA approved lurbinectedin for SCLC that progressed on or after platinum-based chemotherapy in 2020, topotecan was the sole second-line option associated with hematological toxicities and modest efficacy. Lurbinectedin received conditional approval in Korea in September 2022 for metastatic SCLC progression, with the same indications. Real-world data on its efficacy remains scarce owing to its recent implementation. Patients and Methods Patients with metastatic SCLC who progressed on or after first-line therapy (n = 51) at Yonsei Cancer Center, Seoul, received lurbinectedin at 3.2 mg/m². Efficacy data, including tumor response, progression, survival, and demographics, were recorded. Results A total of fifty-one patients received lurbinectedin between April 2023 and March 2024, with thirty-four patients being eligible for the assessment. At diagnosis, approximately one-third of the patients were female, 3% had a poor performance status with an Eastern Cooperative Oncology Group Performance Score (ECOG PS ≥ 2), and the median age was 68. Most patients (80%) had extensive disease. Overall objective response rate (ORR) and disease control rate (DCR) were 20% and 47%, respectively. The median progression-free survival (PFS) was 2.8 months, and the median overall survival (OS) was 3.3 months. Never smokers showed prolonged OS compared with current/former smokers (Smokers; 3.0 vs 7.3 months). Common adverse effects were nausea (53%), loss of appetite (24%), general weakness (18%), anemia (29%), neutropenia (12%), dizziness (6%), alopecia (6%), thrombocytopenia (3%), and pneumonia (3%). Overall, 24% of the patients experienced grade ≥3 adverse events (AEs), with the most common being anemia (9%) and neutropenia (9%). Conclusion Real-world data suggest that lurbinectedin is a viable option for patients with SCLC who have progressed on or after platinum-based chemotherapy.
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Affiliation(s)
- Joo Sung Shim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Youhyun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Taeho Yuh
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jii Bum Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hye Ryun Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Min Hee Hong
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byoung Chul Cho
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sun Min Lim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
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Du Y, Liu XY, Si XY, Zhang XT, Zhou JY, Wang Y, Chen MJ, Zhang L. Comparative efficacy and safety of anlotinib and topotecan as second-line treatment in small cell lung cancer: a retrospective cohort study. Transl Lung Cancer Res 2024; 13:1518-1529. [PMID: 39118888 PMCID: PMC11304151 DOI: 10.21037/tlcr-24-274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/27/2024] [Indexed: 08/10/2024]
Abstract
Background Small cell lung cancer (SCLC) presents considerable challenges regarding the availability of second-line treatment options, which remain limited. The paucity of effective therapeutic choices at this setting emphasizes the urgent requirement for rigorous research and investigation into novel treatment strategies. To address this clinical gap, the current study aimed to compare the efficacy and safety of anlotinib with the standard second-line treatment, topotecan, in patients with relapsed SCLC. Methods This retrospective collected data from SCLC patients who received either anlotinib or topotecan as second-line treatment. The primary endpoints were progression-free survival (PFS), while the secondary endpoints included the overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety assessment. Results The study included 46 SCLC patients, with 20 receiving anlotinib and 26 receiving topotecan as second-line treatment. The anlotinib group showed a significantly longer median PFS compared to the topotecan group [5.6 vs. 2.2 months; hazard ratio (HR) =0.50; 95% confidence interval (CI): 0.27-0.92; P=0.02]. However, there was no statistically significant difference in OS between the two groups (9.1 vs. 7.7 months; HR =0.88; 95% CI: 0.46-1.70; P=0.71). The ORRs were 20.0% and 7.7% (P=0.48), and the DCRs were 70.0% and 23.1% (P=0.007) for the anlotinib and topotecan groups, respectively. Treatment-related adverse events (TRAEs) occurred in 13 patients (65.0%) in the anlotinib group and 20 (76.9%) in the topotecan group (P=0.49). Conclusions Anlotinib shows the potential to extend PFS and manageable adverse events (AEs) compared to topotecan in the second-line setting for relapsed SCLC.
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Affiliation(s)
- Yang Du
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiao-Yan Liu
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiao-Yan Si
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiao-Tong Zhang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jing-Ya Zhou
- Medical Record Department, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yi Wang
- Medical Record Department, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Min-Jiang Chen
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Li Zhang
- Department of Respiratory and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Su HH, Lin ES, Huang YH, Lien Y, Huang CY. Inhibition of SARS-CoV-2 Nsp9 ssDNA-Binding Activity and Cytotoxic Effects on H838, H1975, and A549 Human Non-Small Cell Lung Cancer Cells: Exploring the Potential of Nepenthes miranda Leaf Extract for Pulmonary Disease Treatment. Int J Mol Sci 2024; 25:6120. [PMID: 38892307 PMCID: PMC11173125 DOI: 10.3390/ijms25116120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 05/27/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
Carnivorous pitcher plants from the genus Nepenthes are renowned for their ethnobotanical uses. This research explores the therapeutic potential of Nepenthes miranda leaf extract against nonstructural protein 9 (Nsp9) of SARS-CoV-2 and in treating human non-small cell lung carcinoma (NSCLC) cell lines. Nsp9, essential for SARS-CoV-2 RNA replication, was expressed and purified, and its interaction with ssDNA was assessed. Initial tests with myricetin and oridonin, known for targeting ssDNA-binding proteins and Nsp9, respectively, did not inhibit the ssDNA-binding activity of Nsp9. Subsequent screenings of various N. miranda extracts identified those using acetone, methanol, and ethanol as particularly effective in disrupting Nsp9's ssDNA-binding activity, as evidenced by electrophoretic mobility shift assays. Molecular docking studies highlighted stigmast-5-en-3-ol and lupenone, major components in the leaf extract of N. miranda, as potential inhibitors. The cytotoxic properties of N. miranda leaf extract were examined across NSCLC lines H1975, A549, and H838, focusing on cell survival, apoptosis, and migration. Results showed a dose-dependent cytotoxic effect in the following order: H1975 > A549 > H838 cells, indicating specificity. Enhanced anticancer effects were observed when the extract was combined with afatinib, suggesting synergistic interactions. Flow cytometry indicated that N. miranda leaf extract could induce G2 cell cycle arrest in H1975 cells, potentially inhibiting cancer cell proliferation. Gas chromatography-mass spectrometry (GC-MS) enabled the tentative identification of the 19 most abundant compounds in the leaf extract of N. miranda. These outcomes underscore the dual utility of N. miranda leaf extract in potentially managing SARS-CoV-2 infection through Nsp9 inhibition and offering anticancer benefits against lung carcinoma. These results significantly broaden the potential medical applications of N. miranda leaf extract, suggesting its use not only in traditional remedies but also as a prospective treatment for pulmonary diseases. Overall, our findings position the leaf extract of N. miranda as a promising source of natural compounds for anticancer therapeutics and antiviral therapies, warranting further investigation into its molecular mechanisms and potential clinical applications.
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Affiliation(s)
- Hsin-Hui Su
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan City 717, Taiwan
| | - En-Shyh Lin
- Department of Beauty Science, National Taichung University of Science and Technology, Taichung City 403, Taiwan
| | - Yen-Hua Huang
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung City 402, Taiwan
| | - Yi Lien
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Cheng-Yang Huang
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung City 402, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung City 402, Taiwan
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Lee CY, Chen YC, Huang YH, Lien Y, Huang CY. Cytotoxicity and Multi-Enzyme Inhibition of Nepenthes miranda Stem Extract on H838 Human Non-Small Cell Lung Cancer Cells and RPA32, Elastase, Tyrosinase, and Hyaluronidase Proteins. PLANTS (BASEL, SWITZERLAND) 2024; 13:797. [PMID: 38592804 PMCID: PMC10974603 DOI: 10.3390/plants13060797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/07/2024] [Accepted: 03/07/2024] [Indexed: 04/11/2024]
Abstract
The carnivorous pitcher plants of the genus Nepenthes have long been known for their ethnobotanical applications. In this study, we prepared various extracts from the pitcher, stem, and leaf of Nepenthes miranda using 100% ethanol and assessed their inhibitory effects on key enzymes related to skin aging, including elastase, tyrosinase, and hyaluronidase. The cytotoxicity of the stem extract of N. miranda on H838 human lung carcinoma cells were also characterized by effects on cell survival, migration, proliferation, apoptosis induction, and DNA damage. The cytotoxic efficacy of the extract was enhanced when combined with the chemotherapeutic agent 5-fluorouracil (5-FU), indicating a synergistic effect. Flow cytometry analysis suggested that the stem extract might suppress H838 cell proliferation by inducing G2 cell cycle arrest, thereby inhibiting carcinoma cell proliferation. Gas chromatography-mass spectrometry (GC-MS) enabled the tentative identification of the 15 most abundant compounds in the stem extract of N. miranda. Notably, the extract showed a potent inhibition of the human RPA32 protein (huRPA32), critical for DNA replication, suggesting a novel mechanism for its anticancer action. Molecular docking studies further substantiated the interaction between the extract and huRPA32, highlighting bioactive compounds, especially the two most abundant constituents, stigmast-5-en-3-ol and plumbagin, as potential inhibitors of huRPA32's DNA-binding activity, offering promising avenues for cancer therapy. Overall, our findings position the stem extract of N. miranda as a promising source of natural compounds for anticancer therapeutics and anti-skin-aging treatments, warranting further investigation into its molecular mechanisms and potential clinical applications.
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Affiliation(s)
- Ching-Yi Lee
- Department of Internal Medicine, Tao Yuan General Hospital, Ministry of Health and Welfare, Taoyuan 330, Taiwan
| | - Yu-Cheng Chen
- Department of Internal Medicine, Tao Yuan General Hospital, Ministry of Health and Welfare, Taoyuan 330, Taiwan
| | - Yen-Hua Huang
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung City 402, Taiwan
| | - Yi Lien
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Cheng-Yang Huang
- Department of Biomedical Sciences, Chung Shan Medical University, Taichung City 402, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung City 402, Taiwan
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Chen C, Chen M, Bai Y, Li Y, Peng J, Yao B, Feng J, Zhou JG, Ma H. A Single-Arm Multi-Center Phase II Clinical Trial of Cadonilimab (anti-PD-1/CTLA-4) in Combination with or without Conventional Second-Line Treatment for Patients with Extensive Stage Small Cell Lung Cancer. Technol Cancer Res Treat 2024; 23:15330338241249690. [PMID: 38706247 PMCID: PMC11072065 DOI: 10.1177/15330338241249690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/07/2024] Open
Abstract
BACKGROUND Cadonilimab (AK104) is a bispecific IgG-single-chain Fv fragment (ScFv) antibody that binds to PD-1 and CTLA-4. Cadonilimab has shown encouraging anti-tumour activity and a favourable safety profile in several tumour types. In second-line treatment, there is no defined standard of care for patients with extensive-stage small-cell lung cancer (ES-SCLC). Cadonilimab is expected to show substantial clinical efficacy. OBJECTIVE To assess the antitumor activity and safety of cadonilimab monotherapy or combination with conventional therapy in ES-SCLC patients who failed first-line treatment. METHODS In this multicenter, open-label, phase II study, ES-SCLC patients who had failed first-line treatment, also aged 18 years to 70 years with histologically or cytologically confirmed ES-SCLC, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0-2 were eligible. Patients will receive cadonilimab 10 mg/kg every three weeks (Q3 W) among 24 months until progressive disease (PD) or adverse events (AE) discovery. The primary endpoint is progression-free survival (PFS). TRIAL REGISTRATION NCT05901584.
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Affiliation(s)
- Can Chen
- Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Minjun Chen
- Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Yuju Bai
- Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Yajun Li
- Department of Oncology, The First People's Hospital of Zunyi, Zunyi, Guizhou, China
| | - Jie Peng
- Department of Oncology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, Guizhou, China
| | - Biao Yao
- Department of Oncology, Tongren People's Hospital, Tongren, Guizhou, China
| | - Jiangping Feng
- Department of Oncology, Xingyi People's Hospital, Xingyi, Guizhou, China
| | - Jian-Guo Zhou
- Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Hu Ma
- Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
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Ezzedine R, Canellas A, Naltet C, Wislez M, Azarian R, Seferian A, Giroux Leprieur E. Evaluation of Real-Life Chemoimmunotherapy Combination in Patients with Metastatic Small Cell Lung Carcinoma (SCLC): A Multicentric Case-Control Study. Cancers (Basel) 2023; 15:4593. [PMID: 37760561 PMCID: PMC10526821 DOI: 10.3390/cancers15184593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
The current first-line standard treatment for advanced small cell lung cancer (SCLC) is a combination of chemotherapy and immunotherapy. However, few efficacy data are available in a real-life settings, including frail patients. The aim of this study is to describe the real-life efficacy of chemoimmunotherapy in an unselected SCLC population. We conducted a retrospective multicenter study, which compared two cohorts of patients with treatment-naive metastatic SCLC treated in six academic centers in the Greater Paris area. Cohort 1 included patients treated with chemotherapy between January 2017 and December 2018, and cohort 2 included patients treated with chemoimmunotherapy between January 2019 and December 2020. A total of 153 consecutive patients were included (cohort 1: n = 96; cohort 2: n = 57). Clinical characteristics were similar between the two cohorts. Overall survival (OS) was statistically higher in cohort 2 (median survival 15.47 months) than in cohort 1 (median survival 9.5 months) (p = 0.0001). OS for patients with a performance status ≥2 and for patients ≥70 years old was not statistically different between the two cohorts. Chemoimmunotherapy efficacy was better compared to chemotherapy alone in case of brain or liver metastases. In conclusion, the combination of chemoimmunotherapy in metastatic SCLC appears to provide a real-life OS benefit. Dedicated clinical trials are needed to test this strategy in patients with impaired performance status or advanced age.
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Affiliation(s)
- Rémy Ezzedine
- Department of Respiratory Diseases and Thoracic Oncology, APHP—Hôpital Ambroise Paré, 92104 Boulogne-Billancourt, France;
| | - Anthony Canellas
- Department of Respiratory Diseases and Thoracic Oncology, APHP—Hôpital Tenon, 75020 Paris, France;
| | - Charles Naltet
- Department of Respiratory Diseases, Hôpital Paris Saint Joseph, 75014 Paris, France;
| | - Marie Wislez
- Thoracic Oncology Unit, Pulmonology Department, APHP—Hôpital Cochin, Université Paris Cité, 75006 Paris, France;
| | - Reza Azarian
- Department of Respiratory Diseases, Hôpital Mignot, 78150 Le Chesnay, France;
| | - Andrei Seferian
- Department of Respiratory Diseases, APHP—Hôpital Bicêtre, 94270 Le Kremlin-Bicêtre, France;
| | - Etienne Giroux Leprieur
- Department of Respiratory Diseases and Thoracic Oncology, APHP—Hôpital Ambroise Paré, 92104 Boulogne-Billancourt, France;
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Paz-Ares L, Champiat S, Lai WV, Izumi H, Govindan R, Boyer M, Hummel HD, Borghaei H, Johnson ML, Steeghs N, Blackhall F, Dowlati A, Reguart N, Yoshida T, He K, Gadgeel SM, Felip E, Zhang Y, Pati A, Minocha M, Mukherjee S, Goldrick A, Nagorsen D, Hashemi Sadraei N, Owonikoko TK. Tarlatamab, a First-in-Class DLL3-Targeted Bispecific T-Cell Engager, in Recurrent Small-Cell Lung Cancer: An Open-Label, Phase I Study. J Clin Oncol 2023; 41:2893-2903. [PMID: 36689692 PMCID: PMC10414718 DOI: 10.1200/jco.22.02823] [Citation(s) in RCA: 146] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/04/2023] [Accepted: 01/13/2023] [Indexed: 01/24/2023] Open
Abstract
PURPOSE Small-cell lung cancer (SCLC) is an aggressive malignancy with limited treatments. Delta-like ligand 3 (DLL3) is aberrantly expressed in most SCLC. Tarlatamab (AMG 757), a bispecific T-cell engager molecule, binds both DLL3 and CD3 leading to T-cellb-mediated tumor lysis. Herein, we report phase I results of tarlatamab in patients with SCLC. PATIENTS AND METHODS This study evaluated tarlatamab in patients with relapsed/refractory SCLC. The primary end point was safety. Secondary end points included antitumor activity by modified RECIST 1.1, overall survival, and pharmacokinetics. RESULTS By July 19, 2022, 107 patients received tarlatamab in dose exploration (0.003 to 100 mg; n = 73) and expansion (100 mg; n = 34) cohorts. Median prior lines of anticancer therapy were 2 (range, 1-6); 49.5% received antiprogrammed death-1/programmed death ligand-1 therapy. Any-grade treatment-related adverse events occurred in 97 patients (90.7%) and grade b % 3 in 33 patients (30.8%). One patient (1%) had grade 5 pneumonitis. Cytokine release syndrome was the most common treatment-related adverse event, occurring in 56 patients (52%) including grade 3 in one patient (1%). Maximum tolerated dose was not reached. Objective response rate was 23.4% (95% CI, 15.7 to 32.5) including two complete and 23 partial responses. The median duration of response was 12.3 months (95% CI, 6.6 to 14.9). The disease control rate was 51.4% (95% CI, 41.5 to 61.2). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.1 to 5.4) and 13.2 months (95% CI, 10.5 to not reached), respectively. Exploratory analysis suggests that selecting for increased DLL3 expression can result in increased clinical benefit. CONCLUSION In patients with heavily pretreated SCLC, tarlatamab demonstrated manageable safety with encouraging response durability. Further evaluation of this promising molecule is ongoing.
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Affiliation(s)
- Luis Paz-Ares
- Hospital Universitario 12 de Octubre, CNIO-H120 Lung Cancer Unit, Ciberonc and Universidad Complutense, Madrid, Spain
| | - Stephane Champiat
- Gustave Roussy, DC(c)partement d'Innovation ThC(c)rapeutique et d'Essais PrC(c)coces (DITEP), Villejuif, France
| | - W. Victoria Lai
- Thoracic Oncology Service, Department of Medicine, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Hiroki Izumi
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Ramaswamy Govindan
- Divisions of Hematology and Oncology, Washington University Medical School, St Louis, MO
| | - Michael Boyer
- Department of Medical Oncology, Chris O'Brien Lifehouse, Camperdown, NSW, Australia
| | - Horst-Dieter Hummel
- Translational Oncology/Early Clinical Trial Unit (ECTU), Comprehensive Cancer Center Mainfranken, University Hospital Wuerzburg, Wuerzburg, Germany
| | | | | | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Fiona Blackhall
- Department of Medical Oncology, The Christie NHS Foundation Trust, Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Afshin Dowlati
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH
| | - Noemi Reguart
- Department of Medical Oncology, Thoracic Oncology Unit, IDIBAPS, Hospital Clinic, University of Barcelona School of Medicine, Barcelona, Spain
| | - Tatsuya Yoshida
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kai He
- Division of Medical Oncology, James Thoracic Oncology Center, The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | | | - Enriqueta Felip
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain
| | | | | | | | | | | | | | | | - Taofeek K. Owonikoko
- UPMC Hillman Cancer Center, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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11
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Bailly C, Vergoten G. Interaction of Camptothecin Anticancer Drugs with Ribosomal Proteins L15 and L11: A Molecular Docking Study. Molecules 2023; 28:molecules28041828. [PMID: 36838813 PMCID: PMC9967338 DOI: 10.3390/molecules28041828] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 01/31/2023] [Accepted: 02/13/2023] [Indexed: 02/17/2023] Open
Abstract
The antitumor drug topotecan (TPT) is a potent inhibitor of topoisomerase I, triggering DNA breaks lethal for proliferating cancer cells. The mechanism is common to camptothecins SN38 (the active metabolite of irinotecan) and belotecan (BLT). Recently, TPT was shown to bind the ribosomal protein L15, inducing an antitumor immune activation independent of topoisomerase I. We have modeled the interaction of four camptothecins with RPL15 derived from the 80S human ribosome. Two potential drug-binding sites were identified at Ile135 and Phe129. SN38 can form robust RPL15 complexes at both sites, whereas BLT essentially gave stable complexes with site Ile135. The empirical energy of interaction (ΔE) for SN38 binding to RPL15 is similar to that determined for TPT binding to the topoisomerase I-DNA complex. Molecular models with the ribosomal protein L11 sensitive to topoisomerase inhibitors show that SN38 can form a robust complex at a single site (Cys25), much more stable than those with TPT and BLT. The main camptothecin structural elements implicated in the ribosomal protein interaction are the lactone moiety, the aromatic system and the 10-hydroxyl group. The study provides guidance to the design of modulators of ribosomal proteins L11 and L15, both considered anticancer targets.
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Affiliation(s)
- Christian Bailly
- Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Faculté de Pharmacie, University of Lille, 3 rue du Professeur Laguesse, BP-83, F-59006 Lille, France
- CNRS, Inserm, CHU Lille, UMR9020-U1277—CANTHER—Cancer Heterogeneity Plasticity and Resistance to Therapies, University of Lille, F-59000 Lille, France
- OncoWitan, Consulting Scientific Office, Wasquehal, F-59290 Lille, France
- Correspondence:
| | - Gérard Vergoten
- Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Faculté de Pharmacie, University of Lille, 3 rue du Professeur Laguesse, BP-83, F-59006 Lille, France
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12
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Stefani A, Piro G, Schietroma F, Strusi A, Vita E, Fiorani S, Barone D, Monaca F, Sparagna I, Valente G, Ferrara MG, D’Argento E, Di Salvatore M, Carbone C, Tortora G, Bria E. Unweaving the mitotic spindle: A focus on Aurora kinase inhibitors in lung cancer. Front Oncol 2022; 12:1026020. [PMID: 36387232 PMCID: PMC9647054 DOI: 10.3389/fonc.2022.1026020] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/17/2022] [Indexed: 07/30/2023] Open
Abstract
Lung cancer is one of the most aggressive malignancies, classified into two major histological subtypes: non-small cell lung cancer (NSCLC), that accounts for about 85% of new diagnosis, and small cell lung cancer (SCLC), the other 15%. In the case of NSCLC, comprehensive genome sequencing has allowed the identification of an increasing number of actionable targets, which have become the cornerstone of treatment in the advanced setting. On the other hand, the concept of oncogene-addiction is lacking in SCLC, and the only innovation of the last 30 years has been the introduction of immune checkpoint inhibitors in extensive stage disease. Dysregulation of cell cycle is a fundamental step in carcinogenesis, and Aurora kinases (AURKs) are a family of serine/threonine kinases that play a crucial role in the correct advance through the steps of the cycle. Hyperexpression of Aurora kinases is a common protumorigenic pathway in many cancer types, including NSCLC and SCLC; in addition, different mechanisms of resistance to anticancer drugs rely on AURK expression. Hence, small molecule inhibitors of AURKs have been developed in recent years and tested in several malignancies, with different results. The aim of this review is to analyze the current evidences of AURK inhibition in lung cancer, starting from preclinical rationale to finish with clinical trials available up to now.
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Affiliation(s)
- Alessio Stefani
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Geny Piro
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesco Schietroma
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alessandro Strusi
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Emanuele Vita
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Simone Fiorani
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Diletta Barone
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Federico Monaca
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Ileana Sparagna
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giustina Valente
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Miriam Grazia Ferrara
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Ettore D’Argento
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Mariantonietta Di Salvatore
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Carmine Carbone
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giampaolo Tortora
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Emilio Bria
- Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
- Section of Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
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13
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Sun SJ, Han JD, Liu W, Wu ZY, Zhao X, Yan X, Jiao SC, Fang J. Sequential chemotherapy and icotinib as first-line treatment for advanced epidermal growth factor receptor-mutated non-small cell lung cancer. World J Clin Cases 2022; 10:6069-6081. [PMID: 35949840 PMCID: PMC9254173 DOI: 10.12998/wjcc.v10.i18.6069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 03/13/2022] [Accepted: 04/15/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Icotinib could have potential effect and tolerability when used sequentially with chemotherapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC).
AIM To evaluate the efficacy and safety of chemotherapy followed by icotinib maintenance therapy as first-line treatment for advanced EGFR-mutated NSCLC.
METHODS This multicenter, open-label, pilot randomized controlled trial enrolled 68 EGFR-mutated stage IIIB/IV NSCLC patients randomized 2:3 to the icotinib alone and chemotherapy + icotinib groups.
RESULTS The median progression-free survival in the icotinib alone and chemotherapy + icotinib groups was 8.0 mo (95%CI: 3.84-11.63) and 13.4 mo (95%CI: 10.18-16.33), respectively (P = 0.0249). No significant differences were found in the curative effect when considering different cycles of chemotherapy or chemotherapy regimen (all P > 0.05).
CONCLUSION A sequential combination of chemotherapy and EGFR-tyrosine kinase inhibitor is feasible for stage IV EGFR-mutated NSCLC patients.
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Affiliation(s)
- Sheng-Jie Sun
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Jin-Di Han
- Department of Internal Oncology of Chest, Beijing Cancer Hospital, Beijing 100142, China
| | - Wei Liu
- Peking Cancer Hospital Palliative Care Center, Beijing Cancer Hospital, Beijing 100142, China
| | - Zhi-Yong Wu
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Xiao Zhao
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Xiang Yan
- Department of Medical Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Shun-Chang Jiao
- Department of Oncology, The Fifth Medical Center of General Hospital of Chinese People's Liberation Army, Beijing 100039, China
| | - Jian Fang
- Department of Internal Oncology of Chest, Beijing Cancer Hospital, Beijing 100142, China
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14
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Ganti AKP, Loo BW, Bassetti M, Blakely C, Chiang A, D'Amico TA, D'Avella C, Dowlati A, Downey RJ, Edelman M, Florsheim C, Gold KA, Goldman JW, Grecula JC, Hann C, Iams W, Iyengar P, Kelly K, Khalil M, Koczywas M, Merritt RE, Mohindra N, Molina J, Moran C, Pokharel S, Puri S, Qin A, Rusthoven C, Sands J, Santana-Davila R, Shafique M, Waqar SN, Gregory KM, Hughes M. Small Cell Lung Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:1441-1464. [PMID: 34902832 DOI: 10.6004/jnccn.2021.0058] [Citation(s) in RCA: 234] [Impact Index Per Article: 58.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The "Summary of the Guidelines Updates" section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.
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Affiliation(s)
| | | | | | | | | | | | | | - Afshin Dowlati
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | | | | | | | - John C Grecula
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Christine Hann
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | | | | | | | - Robert E Merritt
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Nisha Mohindra
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | - Cesar Moran
- The University of Texas MD Anderson Cancer Center
| | | | - Sonam Puri
- Huntsman Cancer Institute at the University of Utah
| | - Angel Qin
- University of Michigan Rogel Cancer Center
| | | | - Jacob Sands
- Dana Farber/Brigham and Women's Cancer Center
| | | | | | - Saiama N Waqar
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
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