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المؤلفون: Ashish V. Chintakuntlawar, Lisa A. Kottschade, Alexandra Higgins, Ronald S. Go, Anna Schwecke, Uma Thanarajasingam, Paul J. Hampel, Yiyi Yan, Antoine N. Saliba, Lionel A. Kankeu Fonkoua, Harry E Fuentes-Bayne, Anuhya Kommalapati, Xavier Andrade-Gonzalez, Evandro D. Bezerra, Aref Al-Kali, Alexandra P. Wolanskyj-Spinner, Yanyan Lou, Gita Thanarajasingam, Sagar Rakshit, Candido E. Rivera, Matthew S. Block, Katharine A. Price, Zhuoer Xie, Ariela L. Marshall, Daniel S. Childs
المصدر: American Journal of Hematology. 96
مصطلحات موضوعية: Adult, Male, business.industry, Immune checkpoint inhibitors, MEDLINE, Context (language use), Hematology, Middle Aged, Bioinformatics, Hematologic Diseases, Immune system, Humans, Medicine, Female, Immunotherapy, business, Adverse effect, Immune Checkpoint Inhibitors, Aged
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المؤلفون: Svetomir N. Markovic, Yiyi Yan, Edwin A. Burgstaler, Jacob J. Orme, Matthew K. Ball, Mathew S Block, Aaron S. Mansfield, Roxana S. Dronca, Sean S. Park, Susan M. Harrington, Elizabeth Ann L. Enninga, Fabrice Lucien-Matteoni, Heather Dale, Jeffrey L. Winters, Haidong Dong
المصدر: Journal for Immunotherapy of Cancer
مصطلحات موضوعية: Adult, Male, Cancer Research, medicine.medical_treatment, ADAM10, Immunology, Pharmacology, PD-L1 Positive, B7-H1 Antigen, programmed cell death 1 receptor, Extracellular Vesicles, In vivo, PD-L1, mental disorders, Extracellular, medicine, Immunology and Allergy, Humans, Aged, Clinical/Translational Cancer Immunotherapy, biology, Plasma Exchange, Chemistry, Melanoma, Cancer, tumor escape, Immunotherapy, Middle Aged, medicine.disease, receptors, immunologic, Oncology, translational medical research, biology.protein, Molecular Medicine, Female, immunotherapy
الوصف: BackgroundTrans-acting programmed death-ligand 1 (PD-L1) derives from malignant cells in three known forms. High levels of secreted splice variant PD-L1 (sPD-L1), ADAM10/ADAM17-shed sPD-L1, and PD-L1-positive extracellular vesicles (evPD-L1) each predict poor prognosis and limited response to PD-(L)1 checkpoint inhibitors in cancer. To our knowledge, no clinical intervention has reduced any of these circulating forms of extracellular PD-L1. Here, we explore therapeutic plasma exchange (TPE) as a treatment to reduce circulating extracellular PD-L1.ResultsIn patients with melanoma, sPD-L1 levels above 0.277 ng/mL predicted inferior overall survival. In patients undergoing TPE for non-malignant indications, each TPE session removed a mean 70.8% sPD-L1 and 73.1% evPD-L1 detectable in plasma. TPE also reduced total and ADAM10-positive extracellular vesicles.ConclusionHere, we report the first known clinical intervention to remove either sPD-L1 or evPD-L1 from plasma in vivo. TPE reduces plasma sPD-L1 and evPD-L1 in vivo and may have a role in treatment with immunotherapy. TPE may also prove useful in patients with other extracellular vesicle-related conditions.
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المؤلفون: Jarrett J. Failing, Anagha Bangalore Kumar, Robert R. McWilliams, Svetomir N. Markovic, Roxana S. Dronca, Matthew S. Block, Ying Li, Jonas Paludo, Lisa A. Kottschade, Yiyi Yan, Jesus Vera Aguilera, Henan Zhang, Haidong Dong
المصدر: Melanoma Research
مصطلحات موضوعية: 0301 basic medicine, Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Skin Neoplasms, Disease Response, medicine.medical_treatment, Original Articles: Clinical research, Dermatology, chemotherapy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Chemoimmunotherapy, Internal medicine, medicine, Humans, Young adult, Lung cancer, Immune Checkpoint Inhibitors, Melanoma, Aged, Chemotherapy, business.industry, Immunotherapy, Middle Aged, medicine.disease, Confidence interval, Blockade, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, chemoimmunotherapy, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, immunotherapy, therapy-responsive T-cells, business
الوصف: Supplemental Digital Content is available in the text.
Management of PD-1 blockade resistance in metastatic melanoma (MM) remains challenging. Immunotherapy or chemotherapy alone provides limited benefit in this setting. Chemo-immunotherapy (CIT) has demonstrated favorable efficacy and safety profiles in lung cancer. Our pre-clinical study showed that in MM patients who have failed PD-1 blockade, the addition of chemotherapy increases CX3CR1+ therapy-responsive CD8+ T-cells with enhanced anti-tumor activity, resulting in improved clinical response. Here, we examined the clinical outcomes of CIT in MM patients after PD-1 blockade failure and the treatment-related changes in CX3CR1+ therapy-responsive CD8+ T-cells. We reviewed MM patients seen between January 2012 and June 2018 who failed anti-PD-1-based therapy and received subsequent CIT, immune checkpoint inhibitors (ICI) or chemotherapy alone. Overall survival (OS), objective response rate (ORR), event-free survival (EFS), and toxicities were assessed. Among 60 patients, 33 received CIT upon disease progression on PD-1 blockade. At a median follow-up of 3.9 years, the CIT group had a median OS of 3.5 years [95% confidence interval (CI) 1.7–NR] vs. 1.8 years (95% CI 0.9–2; P = 0.002) for those who received subsequent ICI (n = 9) or chemotherapy alone (n = 18), with ORR of 59% vs. 15% (P = 0.0003), respectively. The median EFS was 7.6 months (95% CI 6–10) following CIT vs. 3.4 months (95% CI 2.8–4.1; P = 0.0005) following ICI or chemotherapy alone. Therapy-responsive CX3CR1+CD8+ T-cells showed dynamic increase with successful CIT. CIT showed favorable clinical outcomes and acceptable safety profile in PD-1 blockade-resistant patients. CX3CR1+CD8+ therapy-responsive T-cells can be potentially used for monitoring disease response to CIT.URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5a513e0df05dc28790966ff365e4f988
https://pubmed.ncbi.nlm.nih.gov/32404734 -
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المؤلفون: Alexandra B. Gonzalez, Yiyi Yan, Jennifer M. Racz, Tina J. Hieken, James W. Jakub, Lisa A. Kottschade, Svetomir N. Markovic, Matthew S. Block
المصدر: Journal of Surgical Oncology. 117:1164-1169
مصطلحات موضوعية: Male, medicine.medical_specialty, medicine.medical_treatment, Disease, Systemic therapy, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, 030212 general & internal medicine, Progression-free survival, Stage (cooking), Melanoma, Neoadjuvant therapy, Aged, Retrospective Studies, Advanced melanoma, business.industry, Advanced stage, General Medicine, Middle Aged, Prognosis, Response to treatment, Neoadjuvant Therapy, Surgery, Survival Rate, Oncology, Chemotherapy, Adjuvant, 030220 oncology & carcinogenesis, Female, Neoplasm Recurrence, Local, business, Follow-Up Studies
الوصف: Background Patients with regionally advanced melanoma are at high risk of distant failure and unlikely to be cured by surgery alone. Neoadjuvant therapy may provide benefit in these patients. Objectives To evaluate our experience with neoadjuvant systemic therapy in high-risk stage III patients. Methods Retrospective review of patients with advanced stage III disease who received neoadjuvant therapy between August 2009 and August 2016 at Mayo Clinic Rochester. Results Twenty-three cases met our inclusion criteria, 16 with resectable disease and 7 with unresectable disease. No patients with resectable disease and one patient with borderline resectable disease progressed regionally, prohibiting surgical resection. Five of seven patients with unresectable disease were down-staged to a resectable state. Six of twenty-three (26%) had a CR and five are alive at last follow-up. Fifteen of twenty three patients (65%) progressed with a median progression free survival of 11 months; however, the 5 year overall survival estimate was 84%. Conclusions Neoadjuvant systemic therapy is a reasonable approach for patients with advanced but resectable/borderline resectable disease and the risk of losing regional control is low. Our data also suggest some patients with unresectable disease will be converted to resectable and a complete clinical response to treatment can be obtained in approximately one quater of patients.
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المؤلفون: Yiyi Yan, Thanh P. Ho, Sudhakar K. Venkatesh, Hani S. Alkhatib
المصدر: Journal of Oncology Practice. 15:675-676
مصطلحات موضوعية: Male, Oncology, medicine.medical_specialty, medicine.diagnostic_test, Oncology (nursing), business.industry, Biopsy, Health Policy, medicine.medical_treatment, Hepatic Veno-Occlusive Disease, MEDLINE, Immunotherapy, Middle Aged, Internal medicine, medicine, Humans, business, Melanoma
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::eb1981d387989bf8c8d794377dcfdd52
https://doi.org/10.1200/jop.19.00276 -
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المؤلفون: Svetomir N. Markovic, Yiyi Yan, Lisa A. Kottschade, Tina J. Hieken, Jerry D. Brewer, Anagha Bangalore Kumar, James W. Jakub, Matthew S. Block, Ana I. Velazquez, Clark C. Otley, Jesus Vera Aguilera, Robert R. McWilliams
المصدر: Dermatologic therapy. 32(2)
مصطلحات موضوعية: Oncology, Adult, Male, medicine.medical_specialty, Skin Neoplasms, MEDLINE, Dermatology, Text mining, Internal medicine, medicine, Biomarkers, Tumor, Humans, Melanoma, Aged, Retrospective Studies, L-Lactate Dehydrogenase, business.industry, Extramural, Retrospective cohort study, General Medicine, Middle Aged, medicine.disease, Prognosis, Female, business, Serum lactate dehydrogenase level
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المؤلفون: Jesus, Vera, Jonas, Paludo, Lisa, Kottschade, Jessica, Brandt, Yiyi, Yan, Matthew, Block, Robert, McWilliams, Roxana, Dronca, Charles, Loprinzi, Axel, Grothey, Svetomir N, Markovic
المصدر: Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 27(10)
مصطلحات موضوعية: Male, Fever, Pyridones, Imidazoles, Pyrimidinones, Middle Aged, Enzyme Activation, Antineoplastic Combined Chemotherapy Protocols, Mutation, Oximes, Humans, Mitogen-Activated Protein Kinases, Colchicine, Melanoma
الوصف: The most common adverse event (AE) of dabrafenib and trametinib (DT) is pyrexia, which has been reported to occur in up to 71% of patients. Pyrexia resulted in therapy discontinuation in up to 26% of patients that otherwise were benefiting from the treatment. Little is known about the pathogenesis and optimal management of this common AE. We hypothesized that the etiology of pyrexia in patients treated with DT could be extrapolated from DT-related cutaneous adverse effects in which a paradoxical MAPK pathway activation has been identified. Based on preliminary data by our group suggesting an upregulation of the mitogen-activated protein kinases (MAPKs) in human lymphocytes exposed to dabrafenib and trametinib, specifically elevated expression of phosphorylated JNK (p-JNK), p38 MAPK (p-p38 MAPK), and ERK5 (p-ERK5), we hypothesized that the mechanism of MAPK pathway activation with DT therapy is similar to that reported in patients with familial Mediterranean fever (FMF), a rare, inherited condition characterized by episodes of fever and rash that responds exceedingly well to colchicine-based therapy in which the MAPK pathway is hyper-activated. Based on this association, our group explored the use of oral colchicine for the treatment of DT-associated pyrexia in five patients with metastatic melanoma.
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المؤلفون: Svetomir N. Markovic, Luis F. Porrata, Jarrett J. Failing, Yiyi Yan
المصدر: Melanoma research. 27(6)
مصطلحات موضوعية: Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Adolescent, Lymphocyte, Dermatology, Pembrolizumab, Antibodies, Monoclonal, Humanized, Monocytes, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Lymphocytes, Melanoma, Aged, Retrospective Studies, Aged, 80 and over, business.industry, Hazard ratio, Retrospective cohort study, Middle Aged, medicine.disease, Prognosis, Confidence interval, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Monoclonal, Biomarker (medicine), Female, business, 030215 immunology
الوصف: The peripheral blood lymphocyte-to-monocyte ratio (LMR) has been associated with prognosis in many malignancies including metastatic melanoma. However, it has not been studied in patients treated with immune checkpoint inhibitors. In this study, we analyzed the baseline LMR with progression-free survival (PFS) and overall survival (OS) in metastatic melanoma patients treated with pembrolizumab. A total of 133 patients with metastatic melanoma treated with pembrolizumab were included in this retrospective study. LMR was calculated from pretherapy peripheral blood counts and the optimal cutoff value was determined by a receiver operator characteristic curve. PFS and OS were evaluated using the Kaplan-Meier method and multivariate Cox proportional hazard modeling. Patients with an LMR of at least 1.7 showed improved PFS (hazard ratio=0.55; 95% confidence interval: 0.34-0.92; P=0.024) and OS (hazard ratio=0.29; 95% confidence interval: 0.15-0.59; P=0.0007). The baseline LMR is associated with PFS and OS in metastatic melanoma patients treated with pembrolizumab, and could represent a convenient and cost-effective prognostic biomarker. Validation of these findings in an independent cohort is needed.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::49e2b0b9348a4013038a41ae7189f2c3
https://pubmed.ncbi.nlm.nih.gov/29016387 -
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المؤلفون: Yiyi Yan, Xin Liu, Siyu Cao, Jin Sung Jang, Ying Li, Wendy E. Bindeman, Aaron S. Mansfield, Jin Jen, Sean S. Park, Svetomir N. Markovic, Susan M. Harrington, Roxana S. Dronca, Pritha Chanana, Alex A. Adjei, Haidong Dong
المصدر: JCI insight. 3(8)
مصطلحات موضوعية: 0301 basic medicine, Male, ATP Binding Cassette Transporter, Subfamily B, Paclitaxel, medicine.medical_treatment, Programmed Cell Death 1 Receptor, CX3C Chemokine Receptor 1, Antineoplastic Agents, CD8-Positive T-Lymphocytes, Granzymes, Carboplatin, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Cancer immunotherapy, Chemoimmunotherapy, Neoplasms, Medicine, Cytotoxic T cell, Animals, Humans, Melanoma, Chemotherapy, business.industry, Cytotoxins, Perforin, General Medicine, Immune checkpoint, Granzyme B, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Cancer research, Drug Therapy, Combination, Female, Immunotherapy, business, CD8, Research Article
الوصف: Although immune checkpoint inhibitors have resulted in durable clinical benefits in a subset of patients with advanced cancer, some patients who did not respond to initial anti-PD-1 therapy have been found to benefit from the addition of salvage chemotherapy. However, the mechanism responsible for the successful chemoimmunotherapy is not completely understood. Here we show that a subset of circulating CD8+ T cells expressing the chemokine receptor CX3CR1 are able to withstand the toxicity of chemotherapy and are increased in patients with metastatic melanoma who responded to chemoimmunotherapy (paclitaxel and carboplatin plus PD-1 blockade). These CX3CR1+CD8+ T cells have effector memory phenotypes and the ability to efflux chemotherapy drugs via the ABCB1 transporter. In line with clinical observation, our preclinical models identified an optimal sequencing of chemoimmunotherapy that resulted in an increase of CX3CR1+CD8+ T cells. Taken together, we found a subset of PD-1 therapy-responsive CD8+ T cells that were capable of withstanding chemotherapy and executing tumor rejection with their unique abilities of drug efflux (ABCB1), cytolytic activity (granzyme B and perforin), and migration to and retention (CX3CR1 and CD11a) at tumor sites. Future strategies to monitor and increase the frequency of CX3CR1+CD8+ T cells may help to design effective chemoimmunotherapy to overcome cancer resistance to immune checkpoint blockade therapy.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::876984572c4fae2775374a44a408b1f4
https://pubmed.ncbi.nlm.nih.gov/29669928 -
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المؤلفون: Pekka Ellonen, Thomas L. Olson, Thomas P. Loughran, Olli Kallioniemi, Hanna Rajala, Caroline A. Heckman, Satu Mustjoki, Samuli Eldfors, Andy Awwad, Emma I. Andersson, Sonja Lagström, Michael J. Clemente, Arjan J. van Adrichem, Kimmo Porkka, Heikki Kuusanmäki, Yiyi Yan, Jaroslaw P. Maciejewski, Dan Zhang, Andres Jerez, Krister Wennerberg
المصدر: Blood. 121:4541-4550
مصطلحات موضوعية: Male, animal structures, Transcription, Genetic, Somatic cell, Large granular lymphocytic leukemia, Immunology, STAT5B, chemical and pharmacologic phenomena, Biology, Biochemistry, Cohort Studies, src Homology Domains, 03 medical and health sciences, 0302 clinical medicine, STAT5 Transcription Factor, medicine, Humans, Cytotoxic T cell, Missense mutation, Exome, Genetic Testing, Phosphorylation, STAT5, Aged, 030304 developmental biology, 0303 health sciences, Lymphoid Neoplasia, Tumor Suppressor Proteins, food and beverages, Cell Biology, Hematology, Middle Aged, medicine.disease, Molecular biology, Protein Structure, Tertiary, 3. Good health, Leukemia, Large Granular Lymphocytic, Leukemia, Mutagenesis, 030220 oncology & carcinogenesis, Mutation, Cancer research, biology.protein, Female, Dimerization, hormones, hormone substitutes, and hormone antagonists, HeLa Cells
الوصف: Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells or natural killer cells. Recently, somatic mutations in the signal transducer and activator of transcription 3 (STAT3) gene were discovered in 28% to 40% of LGL leukemia patients. By exome and transcriptome sequencing of 2 STAT3 mutation-negative LGL leukemia patients, we identified a recurrent, somatic missense mutation (Y665F) in the Src-like homology 2 domain of the STAT5b gene. Targeted amplicon sequencing of 211 LGL leukemia patients revealed 2 additional patients with STAT5b mutations (N642H), resulting in a total frequency of 2% (4 of 211) of STAT5b mutations across all patients. The Y665F and N642H mutant constructs increased the transcriptional activity of STAT5 and tyrosine (Y694) phosphorylation, which was also observed in patient samples. The clinical course of the disease in patients with the N642H mutation was aggressive and fatal, clearly different from typical LGL leukemia with a relatively favorable outcome. This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia.
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c2c5dd567d7dac01114c33c7b92464d9
https://doi.org/10.1182/blood-2012-12-474577
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