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Bao Z, Jia N, Zhang Z, Hou C, Yao B, Li Y. Prospects for the application of pathological response rate in neoadjuvant therapy for gastric cancer. Front Oncol 2025; 15:1528529. [PMID: 40291912 PMCID: PMC12021903 DOI: 10.3389/fonc.2025.1528529] [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: 11/15/2024] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
With the annual increase in the incidence and mortality rates of gastric cancer, it has gradually become one of the significant threats to human health. Approximately 90% of gastric cancer patients are diagnosed with adenocarcinoma. Although the 5-year survival rate for early-stage gastric cancer can exceed 90%, due to its concealed symptoms, less than half of the patients are eligible for radical surgical treatment upon diagnosis. For gastric cancer patients receiving palliative treatment, the current expected survival time is only about one year. In China, the majority of gastric cancer patients, accounting for about 80% of the total, are in the locally advanced stage. For these patients, radical surgery remains the primary treatment option; however, surgery alone is often inadequate in controlling tumor progression. In the pivotal MAGIC study, the recurrence rate was as high as 75%, and similar results were obtained in the French ACCORD07-FFCD9703 study. Numerous clinical trials are currently exploring preoperative neoadjuvant therapy for patients with locally advanced gastric cancer. Data indicates that preoperative neoadjuvant therapy can not only reduce the size of the local tumor but also shrink surrounding lymph nodes, thereby downstaging the tumor and improving the R0 resection rate. Additionally, it can decrease tumor cell activity and eliminate potential micrometastases. The emergence of various immunotherapies has ushered in a new era for neoadjuvant treatment options for gastric cancer.
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Affiliation(s)
| | | | - Zhidong Zhang
- The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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2
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van den Berg PF, Bracun V, Noordman M, van der Meer P, Shi C, Oosting SF, Aboumsallem JP, de Wit S, Meijers WC, Jalving M, van Kruchten M, de Boer RA. Elevations of Cardiac Troponin in Patients Receiving Immune Checkpoint Inhibitors: Data From a Prospective Study. JACC. ADVANCES 2024; 3:101375. [PMID: 39583866 PMCID: PMC11584941 DOI: 10.1016/j.jacadv.2024.101375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 09/11/2024] [Accepted: 09/16/2024] [Indexed: 11/26/2024]
Abstract
Background Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of cancer. However, immune-related adverse events are prevalent in patients receiving ICI therapy. A serious immune-related adverse event is ICI-myocarditis, which is complex to diagnose given that the significance of early symptoms and biomarker trajectories, such as high-sensitivity troponin T (hs-TnT) are unclear. Objectives The purpose of the study was to evaluate kinetics of hs-TnT in cancer patients receiving ICI and to identify patients at risk of developing ICI-myocarditis. Methods This prospective, observational, single-center study included 164 patients receiving ICI therapy. Patients' history, demographics, and clinical characteristics, as well as survival statistics, were collected from electronic patient records and used to analyze associations between elevated hs-TnT (≥14 ng/L) and a significant rise in hs-TnT (100% rise from baseline, with an absolute value ≥2x upper limit of normal (ie, ≥28 ng/L) with ICI-myocarditis. Results We included 164 patients with a mean follow-up time of 1.60 ± 0.91 years. Melanoma was the most common type of cancer in the patient population, and most patients received treatment with programmed cell death protein 1 (PD-1). Twenty-six patients (16%) exhibited significant hs-TnT elevations, while 8 patients (5%) developed ICI-myocarditis. In 18 of 26 (69%) patients, ICI-myocarditis could not be diagnosed with certainty, while 10 of 26 (38%) patients had no other signs of symptoms of cardiac damage. All 8 myocarditis cases were preceded by significantly higher hs-TnT elevations than asymptomatic patients. Despite a high ICI-myocarditis incidence in our study population, cardiac mortality remained low (4%). Conclusions Significant hs-TnT elevations occur more often than previously reported, are often asymptomatic, and do not always lead to myocarditis diagnosis.
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Affiliation(s)
- Pieter F. van den Berg
- Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands
| | - Valentina Bracun
- Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands
| | - Michel Noordman
- Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands
| | - Peter van der Meer
- Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands
| | - Canxia Shi
- Erasmus Medical Center, Cardiovascular Institute, Thorax Center, Department of Cardiology, Rotterdam, the Netherlands
| | - Sjoukje F. Oosting
- Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands
| | | | - Sanne de Wit
- Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands
| | - Wouter C. Meijers
- Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands
- Erasmus Medical Center, Cardiovascular Institute, Thorax Center, Department of Cardiology, Rotterdam, the Netherlands
| | - Mathilde Jalving
- Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands
| | - Michel van Kruchten
- Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands
| | - Rudolf A. de Boer
- Erasmus Medical Center, Cardiovascular Institute, Thorax Center, Department of Cardiology, Rotterdam, the Netherlands
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Roland CL, Nassif Haddad EF, Keung EZ, Wang WL, Lazar AJ, Lin H, Chelvanambi M, Parra ER, Wani K, Guadagnolo BA, Bishop AJ, Burton EM, Hunt KK, Torres KE, Feig BW, Scally CP, Lewis VO, Bird JE, Ratan R, Araujo D, Zarzour MA, Patel S, Benjamin R, Conley AP, Livingston JA, Ravi V, Tawbi HA, Lin PP, Moon BS, Satcher RL, Mujtaba B, Witt RG, Traweek RS, Cope B, Lazcano R, Wu CC, Zhou X, Mohammad MM, Chu RA, Zhang J, Damania A, Sahasrabhojane P, Tate T, Callahan K, Nguyen S, Ingram D, Morey R, Crosby S, Mathew G, Duncan S, Lima CF, Blay JY, Fridman WH, Shaw K, Wistuba I, Futreal A, Ajami N, Wargo JA, Somaiah N. A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma. NATURE CANCER 2024; 5:625-641. [PMID: 38351182 DOI: 10.1038/s43018-024-00726-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 01/10/2024] [Indexed: 04/30/2024]
Abstract
Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.
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Affiliation(s)
- Christina L Roland
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Elise F Nassif Haddad
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Centre Léon-Bérard, University Claude Bernard Lyon I, Lyon, France
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Emily Z Keung
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Wei-Lien Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alexander J Lazar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Heather Lin
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Manoj Chelvanambi
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Edwin R Parra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Khalida Wani
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - B Ashleigh Guadagnolo
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew J Bishop
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elizabeth M Burton
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kelly K Hunt
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Keila E Torres
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Barry W Feig
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christopher P Scally
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Valerae O Lewis
- Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Justin E Bird
- Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ravin Ratan
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dejka Araujo
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - M Alexandra Zarzour
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shreyaskumar Patel
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robert Benjamin
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anthony P Conley
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - J Andrew Livingston
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vinod Ravi
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hussein A Tawbi
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Patrick P Lin
- Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bryan S Moon
- Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robert L Satcher
- Department of Orthopedic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bilal Mujtaba
- Department of Musculoskeletal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Russell G Witt
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Raymond S Traweek
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Brandon Cope
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rossana Lazcano
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chia-Chin Wu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiao Zhou
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mohammad M Mohammad
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Randy A Chu
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jianhua Zhang
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ashish Damania
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Pranoti Sahasrabhojane
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Taylor Tate
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kate Callahan
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sa Nguyen
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Davis Ingram
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rohini Morey
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shadarra Crosby
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Grace Mathew
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sheila Duncan
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cibelle F Lima
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jean-Yves Blay
- Centre Léon-Bérard, University Claude Bernard Lyon I, Lyon, France
| | - Wolf Herman Fridman
- Centre de Recherche des Cordeliers, Inserm, Université Paris-Cité, Equipe Labellisée Ligue Contre le Cancer, Paris, France
| | - Kenna Shaw
- Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ignacio Wistuba
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nadim Ajami
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jennifer A Wargo
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Neeta Somaiah
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Tang YH, Bergmann J, Vaidya D, Faraday N. Association of Preoperative Immune Checkpoint Inhibitor Therapy With Cardiopulmonary Instability and Organ Injury After High-Risk Surgery. Crit Care Explor 2024; 6:e1068. [PMID: 38562380 PMCID: PMC10984666 DOI: 10.1097/cce.0000000000001068] [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] [Indexed: 04/04/2024] Open
Abstract
OBJECTIVES To assess the relationship between prior exposure to immune checkpoint inhibitors (ICIs) and the risk of postoperative complications in cancer patients. DESIGN Single-center retrospective cohort study. INTERVENTIONS The main exposure was treatment with an FDA-approved ICI within 6 months before surgery. MEASUREMENTS AND MAIN RESULTS Exposure to ICIs and covariates was determined from the electronic health record. The primary outcome was a composite of postoperative complications, including prolonged pressor or oxygen dependence, kidney injury, or myocardial injury. Secondary outcomes included each subcomponent of the primary outcome. Of 7674 subjects with cancer admitted to the ICU after surgery, 247 were exposed to one or more ICIs in the 6 months before surgery. After propensity score matching, 197 ICI-exposed subjects were matched to 777 nonexposed. The composite outcome occurred in 70 of 197 (35.5%) ICI-exposed subjects and 251 of 777 (32.3%) nonexposed. There was no difference between exposed and nonexposed groups in the primary composite outcome (odds ratio [OR], 1.12; 95% CI, 0.80-1.58) by conditional logistic regression. Risk of the secondary outcome of prolonged pressor dependence was significantly higher in ICI-exposed subjects (OR, 1.64; 95% CI, 1.01-2.67). Risks of oxygen dependence (OR, 1.13; 95% CI, 0.75-1.73), kidney injury (OR, 1.15; 95% CI, 0.77-1.71), and myocardial injury (OR, 1.76; 95% CI, 1.00-3.10) were not significantly different. There was no difference between groups in the time to hospital discharge alive (p = 0.62). CONCLUSIONS Exposure to ICIs within 6 months before high-risk surgery was not associated with the composite outcome of cardiopulmonary instability or organ injury in patients with cancer. The potential for an association with the secondary outcomes of cardiac instability and injury is worthy of future study.
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Affiliation(s)
- Ying-Hung Tang
- Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD
| | - Jules Bergmann
- Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Dhananjay Vaidya
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Nauder Faraday
- Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD
- Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
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Dibajnia P, Cardenas LM, Lalani AKA. The emerging landscape of neo/adjuvant immunotherapy in renal cell carcinoma. Hum Vaccin Immunother 2023; 19:2178217. [PMID: 36775257 PMCID: PMC10026863 DOI: 10.1080/21645515.2023.2178217] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/14/2023] Open
Abstract
Adjuvant and neoadjuvant therapies that reduce the risk of renal cell carcinoma (RCC) recurrence remain an area of unmet need. Advances have been made in metastatic RCC recently by leveraging PD-1/PD-L1 immune checkpoint inhibitors (ICIs). These agents are currently being investigated in the adjuvant and neoadjuvant settings to determine if intervention early in the disease trajectory offers a clinically meaningful benefit. While a disease-free survival benefit has been demonstrated with pembrolizumab, results from other ICI studies have not been positive to date. More mature data from these studies are needed to determine whether there is a survival benefit to ICIs in the curative-intent setting. The success of ICIs has also ushered a new wave of studies combining ICIs with other agents such as targeted therapies and vaccines, which are in early stages of investigation. We review the current state of adjuvant/neoadjuvant therapy in RCC and highlight opportunities for ongoing study.
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Affiliation(s)
- Pooya Dibajnia
- Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, ON , Canada
| | - Luisa M Cardenas
- Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, ON , Canada
| | - Aly-Khan A Lalani
- Department of Oncology, Juravinski Cancer Centre, McMaster University, Hamilton, ON , Canada
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Feng Y, Zhang H, Ren Q, Li C, Liu S, Zheng C, Xia X. Contrast-enhanced CT parameters predict short-term tumor response in patients with hepatocellular carcinoma who received sequential combined anti-angiogenesis and immune checkpoint inhibitor treatment. Eur J Radiol 2023; 162:110784. [PMID: 36958125 DOI: 10.1016/j.ejrad.2023.110784] [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: 10/16/2022] [Revised: 03/06/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
PURPOSE To evaluate whether relative Hounsfield unit attenuation index (rHUAI) on contrast-enhanced computed tomography (CECT) can predict tumor response in advanced hepatocellular carcinoma (HCC) patients who received sequential combined treatment of immune checkpoint inhibitor (ICI) and anti-angiogenesis therapy. METHOD One hundred seventeen advanced HCC patients who underwent the sequential combined treatment in a tertiary hospital between March 2020 and December 2021 were allocated to prediction and validation cohorts (with a ratio of 2:1) based on the time of initial ICI treatment. rHUAI from the arterial to the portal-venous phase (rHU_ap) and from the portal-venous to the delayed phase (rHU_pd) was calculated. The optimal cut-off values (COVs) of rHU_ap and rHU_pd for predicting tumor response were identified using Youden's index. Univariate and multivariable analyses were performed to assess the relationship between the COVs and tumor response. The validity of COVs was verified in the validation cohort using the chi-square test and Cramer's V coefficient (V). RESULTS The optimal COVs of the two observers were 0.5316 and 0.3265 for rHU_ap, and -0.0208 and -0.0048 for rHU_pd, respectively. Multivariable analysis suggested that the COVs were independently associated with tumor response in the prediction cohort (rHU_ap, Odds ratio: 7.727 and 7.808, 95 % CI: 2.516-23.728 and 2.399-25.410, p value < 0.001 and 0.001; rHU_pd, Odds ratio: 0.034 and 0.011, 95 % CI: 0.002-0.600 and 0.001-0.209, p value of 0.021 and 0.003). In the validation cohort, the optimal COVs of rHU_ap had a moderate to a strong association with tumor response (V = 0.362-0.545, p < 0.05). The association between COVs of rHU_pd and tumor response was slight to strong (V = 0.24-0.545, p = 0.001 to 0.134). CONCLUSION rHUAI obtained from CECT has the potential as a non-invasive tool for predicting tumor response in advanced HCC patients who have received combined ICI and anti-angiogenesis treatment.
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Affiliation(s)
- Yiming Feng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Hui Zhang
- Department of Internal Medicine, Wuhan Hankou Hospital, 172 Zhaojiatiao Road, Wuhan City, Hubei Province 430011, China
| | - Qianqian Ren
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Changde Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Song Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Xiangwen Xia
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China.
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Liu W, Zhang T, Zhang Q, Li L, Xu C. A systematic review and meta-analysis of neoadjuvant chemoimmunotherapy in stage III non-small cell lung cancer. BMC Pulm Med 2022; 22:490. [PMID: 36582007 PMCID: PMC9798701 DOI: 10.1186/s12890-022-02292-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 12/20/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with different subtypes, multidisciplinary teams-led management, and a poor prognosis. Currently, the clinical benefits of stage III NSCLC in the neoadjuvant setting are still unclear. We performed a meta-analysis of published data on neoadjuvant chemoimmunotherapy in stage III NSCLC to systematically evaluate its efficacy and safety. METHODS We searched the databases to identify eligible studies of neoadjuvant chemoimmunotherapy for stage III NSCLC. The primary outcomes mainly included pathological and radiological response outcomes, the feasibility of surgery, and the safety of the regimen. The pathological and radiological response included the rate of major pathologic response (MPR), complete pathologic response (pCR), radiological response outcomes, and R0 resection; The feasibility included the rate of surgical resection, conversion to thoracotomy, surgical complications, pathological downstaging of clinical disease stage. The safety included the incidence of treatment-related adverse events (TRAEs) and severe adverse events (SAEs). R 4.1.3 software was conducted for data analysis, and p < 0.05 was considered statistically significant. RESULTS Nine trials containing a total of 382 populations were eligible for the meta-analysis, with the pooled surgical resection rate of 90%. Owing to the large heterogeneity of the single-rate meta-analysis, the random effect model was adopted. The estimated pooled prevalence of MPR was 56% (95%CI 0.39-0.72) and of pCR was 39% (95%CI 0.28-0.51). The pooled rate of TRAEs was 65% (95%CI 0.17-0.99) and SAEs was 24% (95%CI 0.05-0.49). CONCLUSION Compared to neoadjuvant chemotherapy or immunotherapy, neoadjuvant chemoimmunotherapy achieved more pathological and radiological relief, and has a high surgical resection rate and low risk of conversion to thoracotomy and surgical complications, with poor tolerance of toxicity but rarely developing life-threatening adverse events. In conclusion, neoadjuvant chemoimmunotherapy is suggested to be beneficial for stage III NSCLC.
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Affiliation(s)
- Wei Liu
- grid.89957.3a0000 0000 9255 8984Department of Respiratory Medicine, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, 215 Guangzhou Road, Nanjing, 210029 Jiangsu Province China ,Clinical Center of Nanjing Respiratory Diseases and Imaging, Nanjing, 210029 Jiangsu China
| | - Tiantian Zhang
- grid.89957.3a0000 0000 9255 8984Department of Respiratory Medicine, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, 215 Guangzhou Road, Nanjing, 210029 Jiangsu Province China ,Clinical Center of Nanjing Respiratory Diseases and Imaging, Nanjing, 210029 Jiangsu China
| | - Qian Zhang
- grid.89957.3a0000 0000 9255 8984Department of Respiratory Medicine, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, 215 Guangzhou Road, Nanjing, 210029 Jiangsu Province China ,Clinical Center of Nanjing Respiratory Diseases and Imaging, Nanjing, 210029 Jiangsu China
| | - Li Li
- grid.89957.3a0000 0000 9255 8984Department of Respiratory Medicine, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, 215 Guangzhou Road, Nanjing, 210029 Jiangsu Province China ,Clinical Center of Nanjing Respiratory Diseases and Imaging, Nanjing, 210029 Jiangsu China
| | - Chunhua Xu
- grid.89957.3a0000 0000 9255 8984Department of Respiratory Medicine, The Affiliated Nanjing Brain Hospital of Nanjing Medical University, 215 Guangzhou Road, Nanjing, 210029 Jiangsu Province China ,Clinical Center of Nanjing Respiratory Diseases and Imaging, Nanjing, 210029 Jiangsu China
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Long XY, Zhang S, Tang LS, Li X, Liu JY. Conversion therapy for advanced penile cancer with tislelizumab combined with chemotherapy: A case report and review of literature. World J Clin Cases 2022; 10:12305-12312. [PMID: 36483823 PMCID: PMC9724507 DOI: 10.12998/wjcc.v10.i33.12305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 09/15/2022] [Accepted: 10/26/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Locally advanced penile squamous cell carcinoma with unresectable inguinal lymph node metastasis has a poor prognosis, and surgical treatment alone offers limited benefits. Effective conversion therapy regimens are urgently needed.
CASE SUMMARY We describe a locally advanced penile squamous cell carcinoma patient with bulky, fixed inguinal lymph node metastasis complicated with genital skin ulcers who underwent inguinal lymph node dissection and achieved a pathological complete response with conversion therapy comprising immunotherapy plus chemotherapy.
CONCLUSION For unresectable locally advanced penile squamous cell carcinoma, neoadjuvant immunotherapy combined with chemotherapy is a potential treatment approach. Biomarkers of immunotherapy efficacy need to be explored, and clinical trials are needed to test these strategies.
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Affiliation(s)
- Xiang-Yu Long
- Department of Oncology, Guang’an People’s Hospital, Guang’an 638500, Sichuan Province, China
- Department of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shuang Zhang
- Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lian-Sha Tang
- Department of Biotherapy, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiang Li
- Department of Urology, West China Medical School, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ji-Yan Liu
- Department of Biotherapy, Sichuan University, Chengdu 610041, Sichuan Province, China
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9
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Lopci E, Hicks RJ, Dimitrakopoulou-Strauss A, Dercle L, Iravani A, Seban RD, Sachpekidis C, Humbert O, Gheysens O, Glaudemans AWJM, Weber W, Wahl RL, Scott AM, Pandit-Taskar N, Aide N. Joint EANM/SNMMI/ANZSNM practice guidelines/procedure standards on recommended use of [ 18F]FDG PET/CT imaging during immunomodulatory treatments in patients with solid tumors version 1.0. Eur J Nucl Med Mol Imaging 2022; 49:2323-2341. [PMID: 35376991 PMCID: PMC9165250 DOI: 10.1007/s00259-022-05780-2] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/22/2022] [Indexed: 12/13/2022]
Abstract
PURPOSE The goal of this guideline/procedure standard is to assist nuclear medicine physicians, other nuclear medicine professionals, oncologists or other medical specialists for recommended use of [18F]FDG PET/CT in oncological patients undergoing immunotherapy, with special focus on response assessment in solid tumors. METHODS In a cooperative effort between the EANM, the SNMMI and the ANZSNM, clinical indications, recommended imaging procedures and reporting standards have been agreed upon and summarized in this joint guideline/procedure standard. CONCLUSIONS The field of immuno-oncology is rapidly evolving, and this guideline/procedure standard should not be seen as definitive, but rather as a guidance document standardizing the use and interpretation of [18F]FDG PET/CT during immunotherapy. Local variations to this guideline should be taken into consideration. PREAMBLE The European Association of Nuclear Medicine (EANM) is a professional non-profit medical association founded in 1985 to facilitate worldwide communication among individuals pursuing clinical and academic excellence in nuclear medicine. The Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote science, technology and practical application of nuclear medicine. The Australian and New Zealand Society of Nuclear Medicine (ANZSNM), founded in 1969, represents the major professional society fostering the technical and professional development of nuclear medicine practice across Australia and New Zealand. It promotes excellence in the nuclear medicine profession through education, research and a commitment to the highest professional standards. EANM, SNMMI and ANZSNM members are physicians, technologists, physicists and scientists specialized in the research and clinical practice of nuclear medicine. All three societies will periodically put forth new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and improve service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. Each standard/guideline, representing a policy statement by the EANM/SNMMI/ANZSNM, has undergone a thorough consensus process, entailing extensive review. These societies recognize that the safe and effective use of diagnostic nuclear medicine imaging requires particular training and skills, as described in each document. These standards/guidelines are educational tools designed to assist practitioners in providing appropriate and effective nuclear medicine care for patients. These guidelines are consensus documents based on current knowledge. They are not intended to be inflexible rules or requirements of practice, nor should they be used to establish a legal standard of care. For these reasons and those set forth below, the EANM, SNMMI and ANZSNM caution against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question. The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals considering the unique circumstances of each case. Thus, there is no implication that an action differing from what is laid out in the guidelines/procedure standards, standing alone, is below standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources or advances in knowledge or technology subsequent to publication of the guidelines/procedure standards. The practice of medicine involves not only the science, but also the art of dealing with the prevention, diagnosis, alleviation and treatment of disease. The variety and complexity of human conditions make it impossible for general guidelines to consistently allow for an accurate diagnosis to be reached or a particular treatment response to be predicted. Therefore, it should be recognized that adherence to these standards/ guidelines will not ensure a successful outcome. All that should be expected is that practitioners follow a reasonable course of action, based on their level of training, current knowledge, clinical practice guidelines, available resources and the needs/context of the patient being treated. The sole purpose of these guidelines is to assist practitioners in achieving this objective. The present guideline/procedure standard was developed collaboratively by the EANM, the SNMMI and the ANZSNM, with the support of international experts in the field. They summarize also the views of the Oncology and Theranostics and the Inflammation and Infection Committees of the EANM, as well as the procedure standards committee of the SNMMI, and reflect recommendations for which the EANM and SNMMI cannot be held responsible. The recommendations should be taken into the context of good practice of nuclear medicine and do not substitute for national and international legal or regulatory provisions.
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Affiliation(s)
- E Lopci
- Nuclear Medicine Unit, IRCCS - Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milano, Italy.
| | - R J Hicks
- The Department of Medicine, St Vincent's Medical School, the University of Melbourne, Melbourne, Australia
| | - A Dimitrakopoulou-Strauss
- Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69210, Heidelberg, Germany
| | - L Dercle
- Department of Radiology, New York Presbyterian, Columbia University Irving Medical Center, New York, NY, USA
| | - A Iravani
- Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA
| | - R D Seban
- Department of Nuclear Medicine and Endocrine Oncology, Institut Curie, 92210, Saint-Cloud, France
- Laboratoire d'Imagerie Translationnelle en Oncologie, Inserm, Institut Curie, 91401, Orsay, France
| | - C Sachpekidis
- Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69210, Heidelberg, Germany
| | - O Humbert
- Department of Nuclear Medicine, Centre Antoine-Lacassagne, Université Côte d'Azur, Nice, France
- TIRO-UMR E 4320, Université Côte d'Azur, Nice, France
| | - O Gheysens
- Department of Nuclear Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), Brussels, Belgium
| | - A W J M Glaudemans
- Nuclear Medical Imaging Center, Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - W Weber
- Department of Nuclear Medicine, Klinikum Rechts Der Isar, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - R L Wahl
- Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA
| | - A M Scott
- Department of Molecular Imaging and Therapy, Austin Health, Studley Rd, Heidelberg, Victoria, 3084, Australia
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- Faculty of Medicine, University of Melbourne, Melbourne, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, Australia
| | - N Pandit-Taskar
- Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY, 10021, USA
| | - N Aide
- Nuclear Medicine Department, University Hospital, Caen, France
- INSERM ANTICIPE, Normandie University, Caen, France
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10
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Davern M, Donlon NE, O' Connell F, Sheppard AD, Hayes C, King R, Temperley H, Butler C, Bhardwaj A, Moore J, Bracken-Clarke D, Donohoe C, Ravi N, Reynolds JV, Maher SG, Conroy MJ, Lysaght J. Cooperation between chemotherapy and immune checkpoint blockade to enhance anti-tumour T cell immunity in oesophageal adenocarcinoma. Transl Oncol 2022; 20:101406. [PMID: 35366537 PMCID: PMC8976141 DOI: 10.1016/j.tranon.2022.101406] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/15/2022] [Accepted: 03/20/2022] [Indexed: 10/27/2022] Open
Abstract
Response rates to immune checkpoint blockade (ICB) remain low in oesophageal adenocarcinoma (OAC). Combining ICB with immunostimulatory chemotherapies to boost response rates is an attractive approach for converting 'cold' tumours into 'hot' tumours. This study profiled immune checkpoint (IC) expression on circulating and tumour-infiltrating T cells in OAC patients and correlated these findings with clinical characteristics. The effect of first-line chemotherapy regimens (FLOT and CROSS) on anti-tumour T cell immunity was assessed to help guide design of ICB and chemotherapy combinations in the first-line setting. The ability of ICB to enhance lymphocyte-mediated cytolysis of OAC cells in the absence and presence of post-FLOT and post-CROSS chemotherapy tumour cell secretome was assessed by a CCK-8 assay. Expression of ICs on T cells positively correlated with higher grade tumours and a subsequent poor response to neoadjuvant treatment. First-line chemotherapy regimens substantially altered IC expression profiles of T cells increasing PD-1, A2aR, KLRG-1, PD-L1, PD-L2 and CD160 and decreasing TIM-3 and LAG-3. In addition, pro-inflammatory T cell cytokine profiles were enhanced by first-line chemotherapy regimens. T cell activation status was significantly altered; both chemotherapy regimens upregulated co-stimulatory markers ICOS and CD69 yet downregulated co-stimulatory marker CD27. However, ICB attenuated chemotherapy-induced downregulation of CD27 on T cells and promoted differentiation of effector memory T cells into a terminally differentiated state. Importantly, dual nivolumab-ipilimumab treatment increased lymphocyte-mediated cytolysis of OAC cells, an effect further enhanced in the presence of post-FLOT tumour cell secretome. These findings justify a rationale to administer ICBs concurrently with first-line chemotherapies.
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Affiliation(s)
- Maria Davern
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, Ireland
| | - Noel E Donlon
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, Ireland
| | - Fiona O' Connell
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Andrew D Sheppard
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, Ireland
| | - Conall Hayes
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Ross King
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Hugo Temperley
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Christine Butler
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Anshul Bhardwaj
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Jenny Moore
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Dara Bracken-Clarke
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, Ireland
| | - Claire Donohoe
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Narayanasamy Ravi
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - John V Reynolds
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Stephen G Maher
- Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital, Trinity College Dublin, Dublin, Ireland
| | - Melissa J Conroy
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, Ireland
| | - Joanne Lysaght
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity St. James's Cancer Institute, Trinity Translational Medicine Institute, St. James's Hospital campus, Dublin 8, Ireland.
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11
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Wu D, Huang H, Zhang M, Li Z, Wang S, Yu Y, Fang Y, Jiang N, Miao H, Ma P, Tang Y, Li N. The global landscape of neoadjuvant and adjuvant anti-PD-1/PD-L1 clinical trials. J Hematol Oncol 2022; 15:16. [PMID: 35135567 PMCID: PMC8822713 DOI: 10.1186/s13045-022-01227-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/10/2022] [Indexed: 12/12/2022] Open
Abstract
The neoadjuvant and adjuvant anti-PD-1/PD-L1 treatment has been increasingly noticed. To summarize the global landscape of these clinical trials will provide essential data for all the stakeholders of drug development. Based on the Trialtrove database, a total of 668 clinical trials initiated by the end of 2020 were retrospectively analyzed. We found that a rising capability of global neoadjuvant and adjuvant anti-PD-1/PD-L1 clinical development has been achieved. High prevalent cancer types were extensively studied though the priorities in China and the United States were different. However, a lack of phase III trials and industry-sponsored trials was addressed. The confirmatory neoadjuvant trials were particularly insufficient, and the combination strategy mainly focused on chemotherapy. Thus, more public funding and accelerated regulatory strategies are needed in this field. Efforts should be made to confirm the benefit of neoadjuvant treatment and explore novel combination strategies.
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Affiliation(s)
- Dawei Wu
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huiyao Huang
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Minghui Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Ziwei Li
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shuhang Wang
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yue Yu
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuan Fang
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ning Jiang
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huilei Miao
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Peiwen Ma
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu Tang
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ning Li
- Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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12
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Liu Y, Gao Z, Zhang C, Liu X, Liu Z, Lin X, Qian B, Jin F, Shao G, Yang Z. Asynchrony of primary tumor and mediastinal lymph nodes response after neoadjuvant immunotherapy plus chemotherapy in a patient with stage IIIA non-small-cell lung cancer: a case report. Anticancer Drugs 2022; 33:e784-e788. [PMID: 34419961 PMCID: PMC8670334 DOI: 10.1097/cad.0000000000001204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 07/07/2021] [Indexed: 11/26/2022]
Abstract
With the rapid development of immunotherapy, the efficacy and feasibility of neoadjuvant immunotherapy for early resectable non-small-cell lung cancer (NSCLC) has been demonstrated. However, there are still difficulties and controversies in evaluating the efficacy of neoadjuvant immunotherapy. In our report, we described a 43-year-old female patient who was diagnosed with stage IIIA (cT1N2M0) pulmonary adenocarcinoma. After two cycles of neoadjuvant immunotherapy (sintilimab) combined with chemotherapy, according to imaging evaluation, the efficacy of the primary lesion was evaluated as stable disease and the mediastinal lymph nodes were evaluated as partial response. However, the postoperative pathological evaluation showed the primary lesion was pathological complete response and the mediastinal lymph nodes were major pathological response. This indicated that neoadjuvant chemo-immunotherapy was effective for both primary and mediastinal lymph nodes, but regression of the lesions was not synchronous. This study provided a complete process of neoadjuvant treatment, illustrating the effectiveness and safety of neoadjuvant chemo-immunotherapy to a certain extent. It is also suggested that the evaluation of neoadjuvant immunotherapy should be combined with imaging and pathology, and the primary tumor and lymph nodes should be evaluated, respectively.
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Affiliation(s)
| | | | - Chengbin Zhang
- Department of Pathology, The First Hospital of Jilin University, Changchun, Jilin, China
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13
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Nebhan CA, Johnson DB. Pembrolizumab in the adjuvant treatment of melanoma: efficacy and safety. Expert Rev Anticancer Ther 2021; 21:583-590. [PMID: 33504219 PMCID: PMC8238788 DOI: 10.1080/14737140.2021.1882856] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 01/26/2021] [Indexed: 10/22/2022]
Abstract
Introduction: Regional or distant metastases from melanoma may be surgically resected but remain at high-risk of recurrence. Over the last few years, several treatments have been approved to mitigate this risk. These include anti-PD-1 agents, specifically pembrolizumab and nivolumab.Areas covered: Herein, we will discuss the landscape of pembrolizumab safety and efficacy used in the adjuvant setting for high-risk, resected melanoma. We place this in context with other available adjuvant therapies, and discuss subgroup analyses.Expert opinion: Anti-PD-1 therapy with either pembrolizumab or nivolumab has become a standard of care for patients with resected stage III or IV melanoma. In our practice, we generally offer these agents (which have comparable safety and efficacy profiles) to patients with resected stage IIIb-IV melanoma regardless of BRAF mutation status.
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Affiliation(s)
- Caroline A. Nebhan
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center
| | - Douglas B. Johnson
- Department of Medicine, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center
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14
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Zhou S, Hao X, Yu D, Liu S, Cao X, Su C, Song X, Xiao N, Li Y, Yang W, Zhao D, Wang J, Liu Z, Xu S. [Preliminary Efficacy Evaluation of Neoadjuvant Immunotherapy Combined with
Chemotherapy in Resectable Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 24:420-425. [PMID: 34024062 PMCID: PMC8246389 DOI: 10.3779/j.issn.1009-3419.2021.102.13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
背景与目的 初步研究证实新辅助免疫联合化疗对可手术非小细胞肺癌近期疗效显著,但国内相关临床试验较少。本研究回顾性分析应用新辅助免疫治疗联合化疗的可手术Ib期-IIIb期非小细胞肺癌的临床病理资料,初步评估新辅助免疫治疗联合化疗的疗效及安全性。 方法 回顾性分析2019年11月-2020年12月期间于首都医科大学附属北京胸科医院胸外科治疗的临床分期Ib期-IIIb期的非小细胞肺癌患者20例,术前应用免疫联合化疗新辅助治疗,根据影像学和病理学方法分别评估疗效。 结果 全组患者新辅助治疗后影像学评估疗效,客观有效率(objective response rate, ORR)为85.0%(完全缓解4例,部分缓解13例),疾病稳定1例(5.0%),疾病进展2例(10.0%)。其中17例后续接受手术治疗,16例达到R0(no residual tumor)切除,1例R1(microscopic residual tumor)切除。术后病理评估:主要病理缓解率(major pathologic response, MPR)为47.1%(8/17),其中完全病理缓解率(complete pathologic response, CPR)为29.4%(5/17)。主要不良反应:免疫相关性肺炎(Ⅳ级)1例,Ⅲ级及以上血液学毒性9例(45.0%)。 结论 新辅助免疫联合化疗对于可手术的非小细胞肺癌近期疗效显著,具有一定的安全性及有效性。但新辅助免疫联合化疗的远期疗效、最佳周期数以及理想预测免疫治疗效果的标记物仍有待研究。
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Affiliation(s)
- Shijie Zhou
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Xuefeng Hao
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Daping Yu
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Shuku Liu
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Xiaoqing Cao
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Chongyu Su
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Xiaoyun Song
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Ning Xiao
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Yunsong Li
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Wei Yang
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Dan Zhao
- Department of Pathology,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Jinghui Wang
- Department of Medical Oncology,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China.,Cancer Research Center,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Zhidong Liu
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
| | - Shaofa Xu
- Department of Thoracic Surgery,
Beijing Chest Hospital, Capital Medical University, Beijing 101149, China
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15
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陈 思, 赵 泽, 龙 浩. [Application of Neoadjuvant Immuno-chemotherapy in NSCLC]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 24:284-292. [PMID: 33910277 PMCID: PMC8105607 DOI: 10.3779/j.issn.1009-3419.2021.102.10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 02/18/2021] [Accepted: 02/25/2021] [Indexed: 01/22/2023]
Abstract
Even patients after standard surgery and adjuvant chemotherapy still have a high risk of recurrence and metastasis. With the success of immunotherapy in advanced non-small cell lung cancer (NSCLC), the application of immunotherapy in locally advanced NSCLC has being investigated to reduce the recurrence and metastasis. Pre-clinical studies and several phase II clinical studies had provided theoretical support and clinical evidence for neoadjuvant immunotherapy for NSCLC. This review describes the mechanism of neoadjuvant immuno-chemotherapy, summarizes up-to-date clinical studies, and analyzes efficiency and feasibility of neoadjuvant immune monotherapy or immuno-chemotherapy. Results from four studies (NCT02259621, NEOSTAR, LCMC3 and ChiCTR-OIC-17013726) showed efficiency and feasibility of neoadjuvant anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) monotherapy. Neoadjuvant nivolumab plus ipilimumab achieved higher major pathological response rate than nivolumab monotherapy. However, the combination of nivolumab plus ipilimumab led to more severe adverse events as is seen in the NEOSTAR trial. Results from NCT02716038, SAKK 16/14 and NADIM studies suggest that the pathological response rate of neoadjuvant immune-chemotherapy is higher than neoadjuvant immune checkpoint inhibitor monotherapy. This review also elaborates the mechanism of chemotherapy combined with immunotherapy, and discusses the efficacy evaluation after neoadjuvant immunotherapy.
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Affiliation(s)
- 思 陈
- />510060 广州,中山大学肿瘤防治中心胸外科Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - 泽锐 赵
- />510060 广州,中山大学肿瘤防治中心胸外科Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
| | - 浩 龙
- />510060 广州,中山大学肿瘤防治中心胸外科Department of Thoracic Surgery, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China
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16
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Li J, Jiang Y, Wang J. Neoadjuvant immunotherapy for elderly patients with non-small-cell lung cancer: a case report and literature review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:182. [PMID: 33569484 PMCID: PMC7867947 DOI: 10.21037/atm-20-7767] [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] [Indexed: 11/08/2022]
Abstract
Although neoadjuvant immunotherapy has achieved remarkable results in the treatment of lung cancer, it is still infrequently applied in geriatric patients. We report on a 76-year-old male patient with a long-term history of heavy smoking presenting with cough and hemolysis. There was no related underlying disease or positive findings on physical examination. On July 23, 2019, his chest computed tomography (CT) showed small nodules in the upper lobe of the right lung and multiple enlarged lymph nodes in the mediastinum. Fiberoptic bronchoscopy showed a neoplasm in a subsegment of the upper lobe of the right lung. Following biopsy the patient was diagnosed with squamous cell carcinoma of the right upper lung, with lymph node metastasis in the mediastinum (CT1N2M0, IIIA). Between late July and mid-August of 2019, he received chemotherapy (TP regimen) combined immunotherapy for 2 cycles of preoperative neoadjuvant therapy. Three weeks later he underwent chest CT re-examination which revealed his focus was significantly shrunken in size, and multiple lymph nodes in the mediastinum and right hilum were smaller in comparison to the first examination. The patient then underwent thoracoscopic radical resection of the right upper lung cancer under general anesthesia and recovered uneventfully after surgery. The postoperative pathology examination showed complete response and no signs of recurrence were discovered on the 6 months follow up during which time the patient received immunotherapy on a monthly basis. We report on a case of immunotherapy in a geriatric patient with literature review which supports new treatment strategies for the treatment of elderly patients with lung cancer.
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Affiliation(s)
- Jianqiang Li
- Thoracic Surgery Department, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Youhua Jiang
- Thoracic Surgery Department, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jiangfeng Wang
- Thoracic Surgery Department, Institute of Cancer Research and Basic Medical Sciences of Chinese Academy of Sciences, Cancer Hospital of University of Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou, China
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17
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Albisinni S, Aoun F, Diamand R, Mjaess G, Esperto F, Martinez Chanza N, Roumeguère T, De Nunzio C. Systematic review of neoadjuvant therapy by immune checkpoint inhibitors before radical cystectomy: where do we stand? MINERVA UROL NEFROL 2020; 72:663-672. [DOI: 10.23736/s0393-2249.20.03833-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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18
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Rouanne M, Bajorin DF, Hannan R, Galsky MD, Williams SB, Necchi A, Sharma P, Powles T. Rationale and Outcomes for Neoadjuvant Immunotherapy in Urothelial Carcinoma of the Bladder. Eur Urol Oncol 2020; 3:728-738. [PMID: 33177001 DOI: 10.1016/j.euo.2020.06.009] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 06/14/2020] [Accepted: 06/24/2020] [Indexed: 12/17/2022]
Abstract
CONTEXT Immune therapy has emerged as a powerful treatment of metastatic urothelial carcinoma. Over 20 ongoing studies are exploring this strategy in the neoadjuvant setting in patients with localized muscle-invasive bladder cancer. OBJECTIVE To summarize the rationale and the clinical outcomes regarding the use of immune checkpoint blockade in the neoadjuvant setting before radical cystectomy. EVIDENCE ACQUISITION A systematic review of the literature in the MEDLINE database was performed. The central search strategy used the terms bladder cancer, urothelial carcinoma, mice, human, immunotherapy, neoadjuvant therapy, atezolizumab, pembrolizumab, durvalumab, nivolumab, avelumab, ipilimumab, and tremelimumab. The search was limited to publications between January 2008 and February 2020. Publicly available relevant abstracts from recent meetings were also included. EVIDENCE SYNTHESIS Phase II trials investigating neoadjuvant immune checkpoint blockade as a single agent before radical cystectomy reported a rate of pathological complete response (CR), ranging from 31% with an anti-PD-L1 monoclonal antibody (mAb) atezolizumab (n = 27/88) to 37% with anti-PD-1 mAb pembrolizumab (n = 42/114). Overall, 92% (n = 87/95) and 98% (n = 112/114) of the patients underwent radical cystectomy. Neoadjuvant immune checkpoint blockade did not delay planned surgery. Checkpoint inhibitor monotherapy was well tolerated, with no unexpected toxicity in the presurgical setting. Early phase I/II trials investigating neoadjuvant combination chemotherapy strategies with immune checkpoint blockers reported enhanced antitumor efficacy, with a pathological CR ranging from 33% to 50%. CONCLUSIONS Although limited clinical data are available on long-term survival, neoadjuvant immune checkpoint blockade demonstrated effective antitumor efficacy for localized muscle-invasive bladder cancer. Phase III trials are currently investigating this strategy in the presurgical setting. PATIENT SUMMARY Immunotherapy prior to surgery has been evaluated for patients with muscle-invasive bladder cancer. Although long-term survival benefit is unknown, such treatment strategy revealed a promising antitumor response rate for patients who underwent radical cystectomy. Ongoing prospective clinical trials will define the potential advantage of this approach over current cisplatin-based chemotherapeutic regimens alone or in combination.
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Affiliation(s)
- Mathieu Rouanne
- Department of Urology, Hôpital Foch, UVSQ-Université Paris-Saclay, Suresnes, France; INSERM U1015, Gustave Roussy Cancer Campus, Villejuif, France.
| | - Dean F Bajorin
- Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Raquibul Hannan
- Department of Radiation Oncology, Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Matthew D Galsky
- Division of Hematology and Oncology, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stephen B Williams
- Division of Urology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Andrea Necchi
- Department of Medical Oncology, Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy
| | - Padmanee Sharma
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Thomas Powles
- Experimental Cancer Medicine Centre Barts Cancer Institute, Queen Mary University of London, St Bartholomew's Hospital, London, UK
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19
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Yao Q, Gu L, Su R, Chen B, Cao H. Efficacy and safety of combination PD-1/PD-L1 checkpoint inhibitors for malignant solid tumours: A systematic review. J Cell Mol Med 2020; 24:13494-13506. [PMID: 33078904 PMCID: PMC7701512 DOI: 10.1111/jcmm.15991] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 09/18/2020] [Accepted: 09/29/2020] [Indexed: 12/20/2022] Open
Abstract
Treatment of multiple malignant solid tumours with programmed death (PD)-1/PD ligand (PD-L) 1 inhibitors has been reported. However, the efficacy and immune adverse effects of combination therapies are controversial. This meta-analysis was performed with PubMed, Web of Science, Medline, EMBASE and Cochrane Library from their inception until January 2020. Random-effect model was adopted because of relatively high heterogeneity. We also calculated hazard ratio (HR) of progression-free survival (PFS), overall survival (OS) and risk ratio (RR) of adverse events (AEs), the incidence of grade 3-5 AEs by tumour subgroup, therapeutic schedules and therapy lines. Nineteen articles were selected using the search strategy for meta-analysis. Combined PD-1/PD-L1 inhibitors prolonged OS and PFS (HR 0.72, P < 0.001) and (HR 0.66, P < 0.001). In addition, incidence of all-grade and grade 3-5 AEs was not significant in the two subgroup analyses (HR 1.01, P = 0.31) and (HR 1.10, P = 0.07), respectively. Our meta-analysis indicated that combination therapy with PD-1/PD-L1 inhibitors had greater clinical benefits and adverse events were not increased significantly.
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Affiliation(s)
- Qigu Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou CityChina
| | - Lihu Gu
- Department of General SurgeryHwaMei HospitalUniversity of Chinese Academy of SciencesNingbo CityChina
| | - Rong Su
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou CityChina
| | - Bangsheng Chen
- Emergency Medical CenterThe Second Hospital of YinzhouNingbo CityChina
| | - Hongcui Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou CityChina
- Zhejiang Provincial Key Laboratory for Diagnosis and Treatment of Aging and Physic‐chemical Injury DiseasesHangzhou CityChina
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20
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Mei KC, Liao YP, Jiang J, Chiang M, Khazaieli M, Liu X, Wang X, Liu Q, Chang CH, Zhang X, Li J, Ji Y, Melano B, Telesca D, Xia T, Meng H, Nel AE. Liposomal Delivery of Mitoxantrone and a Cholesteryl Indoximod Prodrug Provides Effective Chemo-immunotherapy in Multiple Solid Tumors. ACS NANO 2020; 14:13343-13366. [PMID: 32940463 PMCID: PMC8023019 DOI: 10.1021/acsnano.0c05194] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
We developed a custom-designed liposome carrier for codelivery of a potent immunogenic cell death (ICD) stimulus plus an inhibitor of the indoleamine 2,3-dioxygenase (IDO-1) pathway to establish a chemo-immunotherapy approach for solid tumors in syngeneic mice. The carrier was constructed by remote import of the anthraquinone chemotherapeutic agent, mitoxantrone (MTO), into the liposomes, which were further endowed with a cholesterol-conjugated indoximod (IND) prodrug in the lipid bilayer. For proof-of-principle testing, we used IV injection of the MTO/IND liposome in a CT26 colon cancer model to demonstrate the generation of a robust immune response, characterized by the appearance of ICD markers (CRT and HMGB-1) as well as evidence of cytotoxic cancer cell death, mediated by perforin and granzyme B. Noteworthy, the cytotoxic effects involved natural killer (NK) cell, which suggests a different type of ICD response. The immunotherapy response was significantly augmented by codelivery of the IND prodrug, which induced additional CRT expression, reduced number of Foxp3+ Treg, and increased perforin release, in addition to extending animal survival beyond the effect of an MTO-only liposome. The outcome reflects the improved pharmacokinetics of MTO delivery to the cancer site by the carrier. In light of the success in the CT26 model, we also assessed the platform efficacy in further breast cancer (EMT6 and 4T1) and renal cancer (RENCA) models, which overexpress IDO-1. Encapsulated MTO delivery was highly effective for inducing chemo-immunotherapy responses, with NK participation, in all tumor models. Moreover, the growth inhibitory effect of MTO was enhanced by IND codelivery in EMT6 and 4T1 tumors. All considered, our data support the use of encapsulated MTO delivery for chemo-immunotherapy, with the possibility to boost the immune response by codelivery of an IDO-1 pathway inhibitor.
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Affiliation(s)
- Kuo-Ching Mei
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Yu-Pei Liao
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Jinhong Jiang
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Michelle Chiang
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Mercedeh Khazaieli
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Xiangsheng Liu
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Xiang Wang
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Qi Liu
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Chong Hyun Chang
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Xiao Zhang
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
| | - Juan Li
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
| | - Ying Ji
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
| | - Brenda Melano
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Donatello Telesca
- Department of Biostatistics, University of California, Los Angeles, California, 90095, United States
| | - Tian Xia
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Huan Meng
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, 90095, United States
| | - Andre E. Nel
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California, 90095, United States
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21
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Zhang C, Zhang G, Sun N, Zhang Z, Xue L, Zhang Z, Yang H, Luo Y, Zheng X, Zhang Y, Yuan Y, Lei R, Yang Z, Zheng B, Wang L, Che Y, Wang F, Wang S, Gao S, Xue Q, Zhang Y, He J. An individualized immune signature of pretreatment biopsies predicts pathological complete response to neoadjuvant chemoradiotherapy and outcomes in patients with esophageal squamous cell carcinoma. Signal Transduct Target Ther 2020; 5:182. [PMID: 32883946 PMCID: PMC7471268 DOI: 10.1038/s41392-020-00221-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/20/2020] [Accepted: 06/04/2020] [Indexed: 12/24/2022] Open
Abstract
No clinically available biomarkers can predict pathological complete response (pCR) for esophageal squamous cell carcinomas (ESCCs) with neoadjuvant chemoradiotherapy (nCRT). Considering that antitumor immunity status is an important determinant for nCRT, we performed an integrative analysis of immune-related gene profiles from pretreatment biopsies and constructed the first individualized immune signature for pCR and outcome prediction of ESCCs through a multicenter analysis. During the discovery phase, 14 differentially expressed immune-related genes (DEIGs) with greater than a twofold change between pCRs and less than pCRs (
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Affiliation(s)
- Chaoqi Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Guochao Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Nan Sun
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Zhen Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Liyan Xue
- Department of Pathology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhihui Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Haijun Yang
- Department of Pathology, Anyang Cancer Hospital, The Fourth Affiliated Hospital of Henan University of Science and Technology, Anyang, 455000, Henan, China
| | - Yuejun Luo
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiaoli Zheng
- Department of Radiotherapy, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, Henan, China
| | - Yonglei Zhang
- Department of General Surgery, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450008, Henan, China
| | - Yufen Yuan
- Department of Pathology, Anyang Cancer Hospital, The Fourth Affiliated Hospital of Henan University of Science and Technology, Anyang, 455000, Henan, China
| | - Ruixue Lei
- Department of Pathology, Anyang Cancer Hospital, The Fourth Affiliated Hospital of Henan University of Science and Technology, Anyang, 455000, Henan, China
| | - Zhaoyang Yang
- Department of Pathology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Bo Zheng
- Department of Pathology, National Cancer Center/ National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Le Wang
- Department of Otology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Yun Che
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Feng Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Sihui Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shugeng Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qi Xue
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
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22
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Keung EZ, Gershenwald JE. Clinicopathological Features, Staging, and Current Approaches to Treatment in High-Risk Resectable Melanoma. J Natl Cancer Inst 2020; 112:875-885. [PMID: 32061122 PMCID: PMC7492771 DOI: 10.1093/jnci/djaa012] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 12/06/2019] [Accepted: 01/17/2020] [Indexed: 12/12/2022] Open
Abstract
The incidence of melanoma in the United States has been increasing over the past several decades. Prognosis largely depends on disease stage, with 5-year melanoma-specific survival ranging from as high as 99% in patients with stage I disease to less than 10% for some patients with stage IV (distant metastatic) disease. Fortunately, in the last 5-10 years, there have been remarkable treatment advances for patients with high-risk resectable melanoma, including approval of targeted and immune checkpoint blockade therapies. In addition, results of recent clinical trials have confirmed the importance of sentinel lymph node biopsy and continue to refine the approach to regional lymph node basin management. Lastly, the melanoma staging system was revised in the eighth edition AJCC Cancer Staging Manual, which was implemented on January 1, 2018. Here we discuss these changes and the clinicopathological features that confer high risk for locoregional and distant disease relapse and poor survival. Implications regarding the management of melanoma in the metastatic and adjuvant settings are discussed, as are future directions for neoadjuvant therapies.
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Affiliation(s)
- Emily Z Keung
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jeffrey E Gershenwald
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Melanoma and Skin Center, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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23
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Potentiating Antitumor Efficacy Through Radiation and Sustained Intratumoral Delivery of Anti-CD40 and Anti-PDL1. Int J Radiat Oncol Biol Phys 2020; 110:492-506. [PMID: 32768562 DOI: 10.1016/j.ijrobp.2020.07.2326] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/29/2020] [Accepted: 07/29/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE Mounting evidence demonstrates that combining radiation therapy (RT) with immunotherapy can reduce tumor burden in a subset of patients. However, conventional systemic delivery of immunotherapeutics is often associated with significant adverse effects, which force treatment cessation. The aim of this study was to investigate a minimally invasive therapeutics delivery approach to improve clinical response while attenuating toxicity. METHODS AND MATERIALS We used a nanofluidic drug-eluting seed (NDES) for sustained intratumoral delivery of combinational antibodies CD40 and PDL1. To enhance immune and tumor response, we combined the NDES intratumoral platform with RT to treat the 4T1 murine model of advanced triple negative breast cancer. We compared the efficacy of NDES against intraperitoneal administration, which mimics conventional systemic treatment. Tumor growth was recorded, and local and systemic immune responses were assessed via imaging mass cytometry and flow cytometry. Livers and lungs were histologically analyzed for evaluation of toxicity and metastasis, respectively. RESULTS The combination of RT and sustained intratumoral immunotherapy delivery of CD40 and PDL1 via NDES (NDES CD40/PDL1) showed an increase in both local and systemic immune response. In combination with RT, NDES CD40/PDL1 achieved significant tumor burden reduction and liver inflammation mitigation compared with systemic treatment. Importantly, our treatment strategy boosted the abscopal effect toward attenuating lung metastatic burden. CONCLUSIONS Overall, our study demonstrated superior efficacy of combination treatment with RT and sustained intratumoral immunotherapy via NDES, offering promise for improving therapeutic index and clinical response.
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24
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Najibi AJ, Mooney DJ. Cell and tissue engineering in lymph nodes for cancer immunotherapy. Adv Drug Deliv Rev 2020; 161-162:42-62. [PMID: 32750376 PMCID: PMC7736208 DOI: 10.1016/j.addr.2020.07.023] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/03/2020] [Accepted: 07/28/2020] [Indexed: 02/07/2023]
Abstract
In cancer, lymph nodes (LNs) coordinate tumor antigen presentation necessary for effective antitumor immunity, both at the levels of local cellular interactions and tissue-level organization. In this review, we examine how LNs may be engineered to improve the therapeutic outcomes of cancer immunotherapy. At the cellular scale, targeting the LNs impacts the potency of cancer vaccines, immune checkpoint blockade, and adoptive cell transfer. On a tissue level, macro-scale biomaterials mimicking LN features can function as immune niches for cell reprogramming or delivery in vivo, or be utilized in vitro to enable preclinical testing of drugs and vaccines. We additionally review strategies to induce ectopic lymphoid sites reminiscent of LNs that may improve antitumor T cell priming.
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Affiliation(s)
- Alexander J Najibi
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138
| | - David J Mooney
- John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA 02138.
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25
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Chua CYX, Ho J, Susnjar A, Lolli G, Di Trani N, Pesaresi F, Zhang M, Nance E, Grattoni A. Intratumoral Nanofluidic System for Enhancing Tumor Biodistribution of Agonist CD40 Antibody. ADVANCED THERAPEUTICS 2020. [DOI: 10.1002/adtp.202000055] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
| | - Jeremy Ho
- Department of Nanomedicine Houston Methodist Research Institute Houston TX 77030 USA
- Weill Cornell Medical College New York NY 10065 USA
| | - Antonia Susnjar
- Department of Nanomedicine Houston Methodist Research Institute Houston TX 77030 USA
| | - Graziano Lolli
- Department of Nanomedicine Houston Methodist Research Institute Houston TX 77030 USA
- Department of Mechanical and Aerospace Engineering Polytechnic of Turin Turin 10129 Italy
| | - Nicola Di Trani
- Department of Nanomedicine Houston Methodist Research Institute Houston TX 77030 USA
- University of Chinese Academy of Science (UCAS) Shijingshan, 19 Yuquan Road Beijing 100049 China
| | - Federica Pesaresi
- Department of Nanomedicine Houston Methodist Research Institute Houston TX 77030 USA
- Department of Electronics and Telecommunications Polytechnic of Turin Turin 10129 Italy
| | - Mengying Zhang
- Department of Chemical Engineering University of Washington Seattle WA 98195 USA
| | - Elizabeth Nance
- Department of Chemical Engineering University of Washington Seattle WA 98195 USA
| | - Alessandro Grattoni
- Department of Nanomedicine Houston Methodist Research Institute Houston TX 77030 USA
- Department of Surgery Houston Methodist Hospital Houston TX 77030 USA
- Department of Radiation Oncology Houston Methodist Hospital Houston TX 77030 USA
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26
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Wang S, Mao Y. [Progress in Neoadjuvant Immunotherapies for Resectable Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 23:371-380. [PMID: 32283581 PMCID: PMC7260379 DOI: 10.3779/j.issn.1009-3419.2020.103.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
可切除非小细胞肺癌(non-small cell lung cancer, NSCLC)是一种潜在可治愈性疾病。尽管外科手术仍然是可切除NSCLC的主要治疗手段,但仍有部分患者术后出现局部复发和远距离转移。因此,为改善长期生存效果术前术后辅助治疗可能仍有必要。免疫检查点抑制剂已经临床试验证实其治疗效果,目前已被批准用于转移性NSCLC或部分Ⅲ期局部晚期NSCLC的一线或二线使用。免疫治疗在晚期肺癌的显著疗效使研究者开始关注免疫治疗是否用于可切除非小细胞肺癌中的新辅助治疗。本文对免疫治疗作为可切除非小细胞肺癌的新辅助治疗的研究进行综述。
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Affiliation(s)
- Shuaibo Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yousheng Mao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Keung EZ, Burgess M, Salazar R, Parra ER, Rodrigues-Canales J, Bolejack V, Van Tine BA, Schuetze SM, Attia S, Riedel RF, Hu J, Okuno SH, Priebat DA, Movva S, Davis LE, Reed DR, Reuben A, Roland CL, Reinke D, Lazar AJ, Wang WL, Wargo JA, Tawbi HA. Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab. Clin Cancer Res 2020; 26:1258-1266. [PMID: 31900276 PMCID: PMC7731262 DOI: 10.1158/1078-0432.ccr-19-1824] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 09/17/2019] [Accepted: 12/23/2019] [Indexed: 12/23/2022]
Abstract
PURPOSE We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment. PATIENTS AND METHODS Pretreatment (n = 78) and 8-week on-treatment (n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti-PD-1 response. RESULTS Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8+ CD3+ PD-1+) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS). CONCLUSIONS We show that quantitative assessments of CD8+ CD3+ PD-1+ T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti-PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway.
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Affiliation(s)
- Emily Z Keung
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Melissa Burgess
- University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburg, Pennsylvania
| | - Ruth Salazar
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Edwin R Parra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jaime Rodrigues-Canales
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Brian A Van Tine
- Washington University in Saint Louis School of Medicine, St Louis, Missouri
| | | | | | - Richard F Riedel
- Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina
| | - James Hu
- University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California
| | | | - Dennis A Priebat
- Washington Cancer Institute at Medstar Washington Hospital Center, Washington DC
| | - Sujana Movva
- Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Lara E Davis
- Oregon Health and Science University, Portland, Oregon
| | - Damon R Reed
- Department of Interdisciplinary Cancer Management and Sarcoma Department, H. Lee Moffitt Cancer Center, Tampa, Florida
| | - Alexandre Reuben
- Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christina L Roland
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Denise Reinke
- SARC (Sarcoma Alliance for Research through Collaboration), Ann Arbor, Michigan
| | - Alexander J Lazar
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wei-Lien Wang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jennifer A Wargo
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Hussein A Tawbi
- Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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28
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Topalian SL, Taube JM, Pardoll DM. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 2020; 367:eaax0182. [PMID: 32001626 PMCID: PMC7789854 DOI: 10.1126/science.aax0182] [Citation(s) in RCA: 687] [Impact Index Per Article: 137.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 12/23/2019] [Indexed: 12/15/2022]
Abstract
Cancer immunotherapies that target the programmed cell death 1 (PD-1):programmed death-ligand 1 (PD-L1) immune checkpoint pathway have ushered in the modern oncology era. Drugs that block PD-1 or PD-L1 facilitate endogenous antitumor immunity and, because of their broad activity spectrum, have been regarded as a common denominator for cancer therapy. Nevertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing research efforts are focused on improving patient outcomes. Using anti-PD-1 or anti-PD-L1 treatment against earlier stages of cancer is hypothesized to be one such solution. This Review focuses on the development of neoadjuvant (presurgical) immunotherapy in the era of PD-1 pathway blockade, highlighting particular considerations for biological mechanisms, clinical trial design, and pathologic response assessments. Findings from neoadjuvant immunotherapy studies may reveal pathways, mechanisms, and molecules that can be cotargeted in new treatment combinations to increase anti-PD-1 and anti-PD-L1 efficacy.
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Affiliation(s)
- Suzanne L Topalian
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
| | - Janis M Taube
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
- Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Drew M Pardoll
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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Abstract
Anticancer immunotherapies involving the use of immune-checkpoint inhibitors or adoptive cellular transfer have emerged as new therapeutic pillars within oncology. These treatments function by overcoming or relieving tumour-induced immunosuppression, thereby enabling immune-mediated tumour clearance. While often more effective and better tolerated than traditional and targeted therapies, many patients have innate or acquired resistance to immunotherapies. Cancer immunoediting is the process whereby the immune system can both constrain and promote tumour development, which proceeds through three phases termed elimination, equilibrium and escape. Throughout these phases, tumour immunogenicity is edited, and immunosuppressive mechanisms that enable disease progression are acquired. The mechanisms of resistance to immunotherapy seem to broadly overlap with those used by cancers as they undergo immunoediting to evade detection by the immune system. In this Review, we discuss how a deeper understanding of the mechanisms underlying the cancer immunoediting process can provide insight into the development of resistance to immunotherapies and the strategies that can be used to overcome such resistance.
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Raufi AG, Almhanna K. Immune checkpoint inhibitors for esophageal cancer: are we moving in the right direction? ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:S102. [PMID: 31576309 DOI: 10.21037/atm.2019.04.82] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Affiliation(s)
- Alexander G Raufi
- Department of GI Oncology, Columbia University Medical Center, New York, NY, USA
| | - Khaldoun Almhanna
- Department of Hematology/Oncology, Lifespan Cancer Institute, Providence, RI, USA
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31
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Liu J, O'Donnell JS, Yan J, Madore J, Allen S, Smyth MJ, Teng MWL. Timing of neoadjuvant immunotherapy in relation to surgery is crucial for outcome. Oncoimmunology 2019; 8:e1581530. [PMID: 31069141 DOI: 10.1080/2162402x.2019.1581530] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 02/04/2019] [Accepted: 02/06/2019] [Indexed: 12/31/2022] Open
Abstract
Adjuvant immunotherapies targeting CTLA4 or PD-1 recently demonstrated efficacy in the treatment of earlier stages of human cancer. We previously demonstrated using mouse spontaneous metastasis models that neoadjuvant immunotherapy and surgery was superior, compared to surgery and adjuvant immunotherapy, in eradicating the lethal metastatic disease. However, the optimal scheduling between neoadjuvant immunotherapy and surgery and how it impacts on efficacy and development of immune-related adverse events (irAEs) remains undefined. Using orthotopic 4T1.2 and E0771 mouse models of spontaneously metastatic mammary cancer, we varied the schedule and duration of neoadjuvant immunotherapies and surgery and examined how it impacted on long-term survival. In two tumor models, we demonstrated that a short duration (4-5 days) between first administration of neoadjuvant immunotherapy and resection of the primary tumor was necessary for optimal efficacy, while extending this duration (10 days) abrogated immunotherapy efficacy. However, efficacy was also lost if neoadjuvant immunotherapy was given too close to surgery (2 days). Interestingly, an additional 4 adjuvant doses of treatment following a standard 2 doses of neoadjuvant immunotherapy, did not significantly improve overall tumor-free survival regardless of the combination treatment (anti-PD-1+anti-CD137 or anti-CTLA4+anti-PD-1). Furthermore, biochemical immune-related adverse events (irAEs) increased in tumor-bearing mice that received the additional adjuvant immunotherapy. Overall, our data suggest that shorter doses of neoadjuvant immunotherapy scheduled close to the time of surgery may optimize effective anti-tumor immunity and reduce severe irAEs.
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Affiliation(s)
- Jing Liu
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Jake S O'Donnell
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.,Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.,School of Medicine, University of Queensland, Herston, Australia
| | - Juming Yan
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.,School of Medicine, University of Queensland, Herston, Australia
| | - Jason Madore
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Stacey Allen
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
| | - Mark J Smyth
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.,School of Medicine, University of Queensland, Herston, Australia
| | - Michele W L Teng
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia.,School of Medicine, University of Queensland, Herston, Australia
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Keung EZ, Gershenwald JE. The eighth edition American Joint Committee on Cancer (AJCC) melanoma staging system: implications for melanoma treatment and care. Expert Rev Anticancer Ther 2019; 18:775-784. [PMID: 29923435 DOI: 10.1080/14737140.2018.1489246] [Citation(s) in RCA: 358] [Impact Index Per Article: 59.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The eighth edition of the American Joint Committee on Cancer (AJCC) melanoma staging system was implemented in the United States on 1 January 2018. Areas covered: This article provides an overview of important changes in the eighth edition AJCC staging system from the seventh edition based on analyses of a large international melanoma database. The clinical implications of these changes for melanoma treatment are also discussed. Expert commentary: A standardized and contemporary cancer staging system that facilitates accurate risk stratification is essential to guide patient treatment. The eighth edition of the AJCC staging system is currently the most widely accepted approach to melanoma staging and classification at initial diagnosis.
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Affiliation(s)
- Emily Z Keung
- a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
| | - Jeffrey E Gershenwald
- a Department of Surgical Oncology , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.,b Melanoma and Skin Center , The University of Texas MD Anderson Cancer Center , Houston , TX , USA
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33
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Pignot G, Loriot Y, Kamat AM, Shariat SF, Plimack ER. Effect of Immunotherapy on Local Treatment of Genitourinary Malignancies. Eur Urol Oncol 2019; 2:355-364. [PMID: 31277773 DOI: 10.1016/j.euo.2019.01.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 12/09/2018] [Accepted: 01/07/2019] [Indexed: 12/28/2022]
Abstract
CONTEXT Management of metastatic genitourinary malignancies has recently been transformed through the use of immune checkpoint inhibitors. The best way to integrate them into local treatment paradigms is still under investigation. OBJECTIVE To systematically evaluate evidence regarding the use of immunotherapy in the treatment of local disease, in both the perioperative and the metastatic setting. EVIDENCE ACQUISITION We performed a critical review of PubMed and ClinicalTrials.gov according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. Prospective and retrospective studies between 2011 and 2018 were included. Twenty-four publications were selected for inclusion, including 10 on urothelial carcinoma, seven on renal cell carcinoma, six on prostate cancer, and one on germ-cell cancer. EVIDENCE SYNTHESIS Prospective early-phase trials investigating neoadjuvant immunotherapy prior to cystectomy in urothelial carcinoma suggest a high rate of pathological complete response, from 29% with atezolizumab to 39.5% with pembrolizumab. Several neoadjuvant and adjuvant trials are still ongoing in bladder, renal, and prostate cancers, before or after surgery. The combination of immunotherapy and radiotherapy is being explored and could offer an interesting strategy for definitive treatment modality with curative intent. Finally, in metastatic disease, delayed local treatment could be discussed after immunotherapy in selected patients with an excellent radiographic response. CONCLUSIONS Little evidence exists on the oncological impact of immunotherapy on the local treatment of genitourinary malignancies, but preliminary results are encouraging and many prospective trials are ongoing. PATIENT SUMMARY In this study, we review recent advances in immunotherapy and its role in local treatment. Immunotherapy is evaluated before or after surgery, or in combination with radiotherapy for localized disease. Ongoing trials will bring clarity on the local downstaging effect of immunotherapy and its association with oncological and functional outcomes.
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Affiliation(s)
- Géraldine Pignot
- Institut Paoli-Calmettes, Chirurgie Oncologique 2, Marseille, France.
| | - Yohann Loriot
- Institut Gustave Roussy, Institut National de la Santé et de la Recherche Médicale U981, University of Paris Saclay, Villejuif, France
| | - Ashish M Kamat
- Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Elizabeth R Plimack
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
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34
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Dahl O, Brydøy M. The pioneers behind immune checkpoint blockers awarded the Nobel Prize in physiology or medicine 2018. Acta Oncol 2019; 58:1-8. [PMID: 30698061 DOI: 10.1080/0284186x.2018.1555375] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Olav Dahl
- Department of Clinical Science Faculty of Medicine, University of Bergen, Bergen, Norway
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
| | - Marianne Brydøy
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
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35
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Fransen MF, Schoonderwoerd M, Knopf P, Camps MG, Hawinkels LJ, Kneilling M, van Hall T, Ossendorp F. Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy. JCI Insight 2018; 3:124507. [PMID: 30518694 DOI: 10.1172/jci.insight.124507] [Citation(s) in RCA: 267] [Impact Index Per Article: 38.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/29/2018] [Indexed: 12/14/2022] Open
Abstract
PD-1/PD-L1 checkpoint therapy for cancer is commonly considered to act by reactivating T cells in the tumor microenvironment. Here, we present data from 2 mouse tumor models demonstrating an essential involvement of tumor-draining lymph nodes in PD-1 and PD-L1 therapeutic efficacy. Immune activation induced by checkpoint treatment was predominantly observed in the tumor-draining, but not nondraining, lymph nodes and was reflected in local accumulation of CD8+ T cells. Surgical resection of these lymph nodes, but not contralateral lymph nodes, abolished therapy-induced tumor regressions and was associated with decreased immune infiltrate in the tumor microenvironment. Moreover, inhibitor FTY720, which locks lymphocytes in lymph organs, also abrogated checkpoint therapy, suggesting that the tumor-draining lymph nodes function as sites of T cell invigoration required for checkpoint blockade therapy. Now that PD-1/PD-L1 checkpoint treatment is applied in earlier clinical stages of cancer, our preclinical data advocate for enrolling patients with their tumor-draining lymph nodes still in place, to optimally engage the antitumor immune response and thereby enhance clinical benefit.
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Affiliation(s)
- Marieke F Fransen
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | | | - Philipp Knopf
- Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | - Marcel Gm Camps
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | | | - Manfred Kneilling
- Department of Preclinical Imaging and Radiopharmacy, Werner Siemens Imaging Center, Eberhard Karls University Tuebingen, Tuebingen, Germany.,Department of Dermatology, Eberhard Karls University Tuebingen, Tuebingen, Germany
| | | | - Ferry Ossendorp
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Leiden, Netherlands
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36
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Balch CM. Revolutionary Advances in Immunotherapy for Melanoma Are Coming into the Surgical Arena: Are We Ready? Ann Surg Oncol 2018; 25:1803-1806. [PMID: 29752603 DOI: 10.1245/s10434-018-6516-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Indexed: 01/07/2023]
Affiliation(s)
- Charles M Balch
- University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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