المؤلفون: Helmink, Beth A, Reddy, Sangeetha M, Gao, Jianjun, Zhang, Shaojun, Basar, Rafet, Thakur, Rohit, Yizhak, Keren, Sade-Feldman, Moshe, Blando, Jorge, Han, Guangchun, Gopalakrishnan, Vancheswaran, Xi, Yuanxin, Zhao, Hao, Amaria, Rodabe N, Tawbi, Hussein A, Cogdill, Alex P, Liu, Wenbin, LeBleu, Valerie S, Kugeratski, Fernanda G, Patel, Sapna, Davies, Michael A, Hwu, Patrick, Lee, Jeffrey E, Gershenwald, Jeffrey E, Lucci, Anthony, Arora, Reetakshi, Woodman, Scott, Keung, Emily Z, Gaudreau, Pierre-Olivier, Reuben, Alexandre, Spencer, Christine N, Burton, Elizabeth M, Haydu, Lauren E, Lazar, Alexander J, Zapassodi, Roberta, Hudgens, Courtney W, Ledesma, Deborah A, Ong, SuFey, Bailey, Michael, Warren, Sarah, Rao, Disha, Krijgsman, Oscar, Rozeman, Elisa A, Peeper, Daniel, Blank, Christian U, Schumacher, Ton N, Butterfield, Lisa H, Zelazowska, Monika A, McBride, Kevin M, Kalluri, Raghu, Allison, James, Petitprez, Florent, Fridman, Wolf Herman, Sautès-Fridman, Catherine, Hacohen, Nir, Rezvani, Katayoun, Sharma, Padmanee, Tetzlaff, Michael T, Wang, Linghua, Wargo, Jennifer A

المصدر: Nature. 577(7791)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Immunization, Cancer, Vaccine Related, Genetics, B-Lymphocytes, Biomarkers, Tumor, Carcinoma, Renal Cell, Cell Cycle Checkpoints, Clone Cells, Dendritic Cells, Follicular, Gene Expression Regulation, Neoplastic, Humans, Immunologic Memory, Immunotherapy, Mass Spectrometry, Melanoma, Neoplasm Metastasis, Phenotype, Prognosis, RNA-Seq, Receptors, Immunologic, Single-Cell Analysis, T-Lymphocytes, Tertiary Lymphoid Structures, Transcriptome, General Science & Technology

الوصف: Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers1-10 and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity11-15, although these have been less well-studied in ICB treatment16. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling17 that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter18) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4q46q7kwTest

المؤلفون: Asare, Elliot A., Fisher, Sarah B., Chiang, Yi‐Ju, Haydu, Lauren E., Patel, Sameer H., Keung, Emily Z., Lucci, Anthony, Wargo, Jennifer, Gershenwald, Jeffrey E., Ross, Merrick I., Lee, Jeffrey. E.

المصدر: Journal of Surgical Oncology ; volume 128, issue 2, page 313-321 ; ISSN 0022-4790 1096-9098

الوصف: Background and Objectives Modern systemic therapy (immune checkpoint blockade [ICB], targeted therapy) has improved survival for patients with metastatic melanoma. The role of adrenal metastasectomy is not well characterized in this setting. Methods Consecutive patients treated with adrenalectomy 1/1/2007–1/1/2019 were retrospectively compared to patients treated with systemic therapy alone in the same time period. Overall survival and survival after adrenal metastasis were compared, prognostic factors associated with survival after adrenal metastasis development were evaluated. Results A total of 74 patients underwent adrenalectomy and were compared to 69 treated with systemic therapy alone. The most common indications for adrenalectomy were to render the patient disease‐free in the setting of isolated adrenal metastasis ( n = 32, 43.2%) or treatment of isolated progression in the setting of other stable/responding metastases ( n = 32, 43.2%). Patients treated surgically had longer survival (116.9 vs. 11.0 months after adrenal metastasis diagnosis, p < 0.001). On multivariate analysis, receipt of ICB (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: [0.40–0.95]) and selection for adrenalectomy (HR: 0.27, 95% CI: [0.17–0.42]) were the strongest factors associated with improved survival after adrenal metastasis diagnosis. Conclusions Selective application of adrenal metastasectomy is associated with prolonged survival benefit and remains an important consideration in the multidisciplinary management of patients with metastatic melanoma.

الإتاحة: https://doi.org/10.1002/jso.27267Test

المؤلفون: Amaria, Rodabe N., Postow, Michael, Burton, Elizabeth M., Tetzlaff, Michael T., Ross, Merrick I., Torres-Cabala, Carlos, Glitza, Isabella C., Duan, Fei, Milton, Denái R., Busam, Klaus, Simpson, Lauren, McQuade, Jennifer L., Wong, Michael K., Gershenwald, Jeffrey E., Lee, Jeffrey E., Goepfert, Ryan P., Keung, Emily Z., Fisher, Sarah B., Betof-Warner, Allison, Shoushtari, Alexander N., Callahan, Margaret, Coit, Daniel, Bartlett, Edmund K., Bello, Danielle, Momtaz, Parisa, Nicholas, Courtney, Gu, Aidi, Zhang, Xuejun, Korivi, Brinda Rao, Patnana, Madhavi, Patel, Sapna P., Diab, Adi, Lucci, Anthony, Prieto, Victor G., Davies, Michael A., Allison, James P., Sharma, Padmanee, Wargo, Jennifer A., Ariyan, Charlotte, Tawbi, Hussein A.

المصدر: Nature ; volume 615, issue 7953, page E23-E23 ; ISSN 0028-0836 1476-4687

مصطلحات موضوعية: Multidisciplinary

الإتاحة: https://doi.org/10.1038/s41586-023-05892-1Test
https://www.nature.com/articles/s41586-023-05892-1.pdfTest
https://www.nature.com/articles/s41586-023-05892-1Test

المؤلفون: Anzar, Irantzu, Malone, Brandon, Samarakoon, Pubudu, Vardaxis, Ioannis, Simovski, Boris, Fontenelle, Hugues, Meza-Zepeda, Leonardo A., Stratford, Richard, Keung, Emily Z., Burgess, Melissa, Tawbi, Hussein A., Myklebost, Ola, Clancy, Trevor

المساهمون: Merck Sharp and Dohme, Norges Forskningsråd

المصدر: Frontiers in Immunology ; volume 14 ; ISSN 1664-3224

مصطلحات موضوعية: Immunology, Immunology and Allergy

الوصف: Introduction Sarcomas are comprised of diverse bone and connective tissue tumors with few effective therapeutic options for locally advanced unresectable and/or metastatic disease. Recent advances in immunotherapy, in particular immune checkpoint inhibition (ICI), have shown promising outcomes in several cancer indications. Unfortunately, ICI therapy has provided only modest clinical responses and seems moderately effective in a subset of the diverse subtypes. Methods To explore the immune parameters governing ICI therapy resistance or immune escape, we performed whole exome sequencing (WES) on tumors and their matched normal blood, in addition to RNA-seq from tumors of 31 sarcoma patients treated with pembrolizumab. We used advanced computational methods to investigate key immune properties, such as neoantigens and immune cell composition in the tumor microenvironment (TME). Results A multifactorial analysis suggested that expression of high quality neoantigens in the context of specific immune cells in the TME are key prognostic markers of progression-free survival (PFS). The presence of several types of immune cells, including T cells, B cells and macrophages, in the TME were associated with improved PFS. Importantly, we also found the presence of both CD8+ T cells and neoantigens together was associated with improved survival compared to the presence of CD8+ T cells or neoantigens alone. Interestingly, this trend was not identified with the combined presence of CD8+ T cells and TMB; suggesting that a combined CD8+ T cell and neoantigen effect on PFS was important. Discussion The outcome of this study may inform future trials that may lead to improved outcomes for sarcoma patients treated with ICI.

الإتاحة: https://doi.org/10.3389/fimmu.2023.1226445Test

المؤلفون: Cass, Samuel, Cope, Brandon, Bishop, Andrew J., Chiang, Yi-Ju, Ashleigh Guadagnolo, B., Farooqi, Ahsan, Morrison, William, Witt, Russell G., Seervai, Riyad N.H., Garden, Adam S., Fuller, Clifton D., Goepfert, Ryan P., Ross, Merrick, Gershenwald, Jeffrey E., Wong, Michael, Aung, Phyu P., Keung, Emily Z., Mitra, Devarati

المساهمون: National Center for Advancing Translational Sciences

المصدر: Radiotherapy and Oncology ; volume 188, page 109892 ; ISSN 0167-8140

مصطلحات موضوعية: Radiology, Nuclear Medicine and imaging, Oncology, Hematology

الإتاحة: https://doi.org/10.1016/j.radonc.2023.109892Test
https://api.elsevier.com/content/article/PII:S0167814023897869?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0167814023897869?httpAccept=text/plainTest

المؤلفون: Traweek, Raymond S., Lyu, Heather G., Witt, Russell G., Snyder, Rebecca A., Nassif, Elise F., Krijgh, David D., Smith, Jeffrey M., Tilney, Gordon S., Feng, Chun, Chiang, Yi-Ju, Torres, Keila E., Roubaud, Margaret J., Scally, Christopher P., Hunt, Kelly K., Keung, Emily Z., Mericli, Alexander F., Roland, Christina L.

المصدر: Annals of Surgical Oncology: An Oncology Journal for Surgeons; Jun2024, Vol. 31 Issue 6, p4138-4147, 10p

مستخلص: Background: Although social vulnerability has been associated with worse postoperative and oncologic outcomes in other cancer types, these effects have not been characterized in patients with soft tissue sarcoma. This study evaluated the association of social vulnerability and oncologic outcomes. Methods: The authors conducted a single-institution cohort study of adult patients with primary and locally recurrent extremity or truncal soft tissue sarcoma undergoing resection between January 2016 and December 2021. The social vulnerability index (SVI) was measured on a low (SVI 1–39%, least vulnerable) to high (60–100%, most vulnerable) SVI scale. The association of SVI with overall survival (OS) and recurrence-free survival (RFS) was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. Results: The study identified 577 patients. The median SVI was 44 (interquartile range [IQR], 19–67), with 195 patients categorized as high SVI and 265 patients as low SVI. The median age, tumor size, histologic subtype, grade, comorbidities, stage, follow-up time, and perioperative chemotherapy and radiation utilization were similar between the high and low SVI cohorts. The patients with high SVI had worse OS (p = 0.07) and RFS (p = 0.016) than the patients with low SVI. High SVI was independently associated with shorter RFS in the multivariate analysis (hazard ratio, 1.64; 95% confidence interval, 1.06–2.54) but not with OS (HR, 1.47; 95% CI 0.84–2.56). Conclusion: High community-level social vulnerability appears to be independently associated with worse RFS for patients undergoing resection of extremity and truncal soft tissue sarcoma. The effect of patient and community-level social risk factors should be considered in the treatment of patients with extremity sarcoma. [ABSTRACT FROM AUTHOR]

: Copyright of Annals of Surgical Oncology: An Oncology Journal for Surgeons is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Nasr, Lewis F., Zoghbi, Marianne, Lazcano, Rossana, Nakazawa, Michael, Bishop, Andrew J., Farooqi, Ahsan, Mitra, Devarati, Guadagnolo, Beverly Ashleigh, Benjamin, Robert, Patel, Shreyaskumar, Ravi, Vinod, Araujo, Dejka M., Livingston, Andrew, Zarzour, Maria A., Conley, Anthony P., Ratan, Ravin, Somaiah, Neeta, Lazar, Alexander J., Roland, Christina, Keung, Emily Z.

المصدر: Cancers; May2024, Vol. 16 Issue 9, p1763, 17p

مصطلحات موضوعية: CANCER treatment, SARCOMA, PATIENT safety, MICROMETASTASIS, SCIENTIFIC observation, IMMUNOTHERAPY, PROGRAMMED death-ligand 1, RETROSPECTIVE studies, CANCER patients, DESCRIPTIVE statistics, IMMUNE checkpoint inhibitors, DRUG approval, LONGITUDINAL method, DRUG efficacy, PROGRESSION-free survival, SPECIALTY hospitals, OVERALL survival, EVALUATION, CHEMICAL inhibitors

مصطلحات جغرافية: TEXAS

الشركة/الكيان: UNITED States. Food & Drug Administration

مستخلص: Simple Summary: Undifferentiated pleomorphic sarcomas (UPSs) represent 10–20% of all soft tissue sarcomas (STSs) and have quickly emerged as one of the more immune-sensitive types. There are few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and those with other high-grade pleomorphic STSs. This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center intended to describe the efficacy and toxicity of ICB in this particular group of patients. We find that our outcomes are comparable to those in the published literature and pose a question regarding the need to further evaluate the optimal sequencing of radiotherapy and prior lines of systemic therapy. Background: Undifferentiated pleomorphic sarcomas (UPSs) are amongst the most common subtypes of soft-tissue sarcomas. Few real-world data on the use of immune checkpoint blockade (ICB) in UPS patients and other high-grade pleomorphic STS patients are available. Purpose: The purpose of our study is to describe the efficacy and toxicity of ICB in patients with advanced UPSs and other high-grade pleomorphic sarcomas treated at our institution. Methods: This is a retrospective, observational study of all patients with metastatic high-grade pleomorphic sarcomas treated with FDA-approved ICB at MD Anderson Cancer Center between 1 January 2015 and 1 January 2023. Patients included in trials for which results are not yet published were excluded. Results: Thirty-six patients with advanced/metastatic pleomorphic sarcomas were included. The median age was 52 years. A total of 26 patients (72%) had UPSs and 10 patients (28%) had other high-grade pleomorphic sarcomas. The median follow-up time was 8.8 months. The median PFS was 2.9 months. The 3-month PFS and 6-month PFS were 46% and 32%, respectively. The median OS was 12.9 months. The 12-month OS and 24-month OS were 53% and 29%, respectively. The best response, previous RT, and type of ICB treatment were significantly and independently associated with shorter PFS (p = 0.0012, p = 0.0019 and p = 0.036, respectively). No new safety signal was identified, and the toxicity was overall manageable with no toxic deaths and only four patients (11%) stopping treatment due to toxicity. Conclusions: Real-world retrospective data are consistent with the published literature, with a promising 6-month PFS of 32%. Partial or stable responders to ICB treatment have significantly improved PFS compared to progressors. [ABSTRACT FROM AUTHOR]

: Copyright of Cancers is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Fiziev, Petko, Akdemir, Kadir C, Miller, John P, Keung, Emily Z, Samant, Neha S, Sharma, Sneha, Natale, Christopher A, Terranova, Christopher J, Maitituoheti, Mayinuer, Amin, Samirkumar B, Martinez-Ledesma, Emmanuel, Dhamdhere, Mayura, Axelrad, Jacob B, Shah, Amiksha, Cheng, Christine S, Mahadeshwar, Harshad, Seth, Sahil, Barton, Michelle C, Protopopov, Alexei, Tsai, Kenneth Y, Davies, Michael A, Garcia, Benjamin A, Amit, Ido, Chin, Lynda, Ernst, Jason, Rai, Kunal

المصدر: Cell Reports. 19(4)

مصطلحات موضوعية: Biological Sciences, Human Genome, Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Acetylation, Cell Line, Cell Proliferation, Chromatin, Chromatin Immunoprecipitation, Disease-Free Survival, Epigenomics, Histone Deacetylase Inhibitors, Histone Deacetylases, Histones, Humans, Hydroxamic Acids, Kaplan-Meier Estimate, Melanoma, PTEN Phosphohydrolase, Principal Component Analysis, RNA Interference, RNA, Small Interfering, Signal Transduction, Vorinostat, CBP, ChIP-seq, DUSP5, HDAC, chromatin state, epigenome, histone modifications, melanoma, Biochemistry and Cell Biology, Medical Physiology, Biological sciences

الوصف: The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Through these results, we define functionally relevant chromatin states associated with melanoma progression.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0zj4h2swTest

المؤلفون: Roland, Christina L, Nassif Haddad, Elise F, Keung, Emily Z, Wang, Wei-Lien, Lazar, Alexander J, Lin, Heather, Chelvanambi, Manoj, Parra, Edwin R, Wani, Khalida, Guadagnolo, B Ashleigh, Bishop, Andrew J, Burton, Elizabeth M, Hunt, Kelly K, Torres, Keila E, Feig, Barry W, Scally, Christopher P, Lewis, Valerae O, Bird, Justin E, Ratan, Ravin, Araujo, Dejka, Zarzour, M Alexandra, Patel, Shreyaskumar, Benjamin, Robert, Conley, Anthony P, Livingston, J Andrew, Ravi, Vinod, Tawbi, Hussein A, Lin, Patrick P, Moon, Bryan S, Satcher, Robert L, Mujtaba, Bilal, Witt, Russell G, Traweek, Raymond S, Cope, Brandon, Lazcano, Rossana, Wu, Chia-Chin, Zhou, Xiao, Mohammad, Mohammad M, Chu, Randy A, Zhang, Jianhua, Damania, Ashish, Sahasrabhojane, Pranoti, Tate, Taylor, Callahan, Kate, Nguyen, Sa, Ingram, Davis, Morey, Rohini, Crosby, Shadarra, Mathew, Grace, Duncan, Sheila, Lima, Cibelle F, Blay, Jean-Yves, Fridman, Wolf Herman, Shaw, Kenna, Wistuba, Ignacio, Futreal, Andrew, Ajami, Nadim, Wargo, Jennifer A, Somaiah, Neeta

المصدر: Nat Cancer ; ISSN:2662-1347 ; Volume:5 ; Issue:4

الوصف: 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.

العلاقة: https://doi.org/10.1038/s43018-024-00726Test-z; https://pubmed.ncbi.nlm.nih.gov/38351182Test

الإتاحة: https://doi.org/10.1038/s43018-024-00726Test-z
https://pubmed.ncbi.nlm.nih.gov/38351182Test

المؤلفون: Awad, Ahmed, Pal, Koustav, Yevich, Steven, Kuban, Joshua D., Tam, Alda, Odisio, Bruno C., Gupta, Sanjay, Habibollahi, Peiman, Bishop, Andrew J., Conley, Anthony Paul, Somaiah, Neeta, Araujo, Dejka M., Zarzour, Maria Alejandra, Ratan, Ravin, Roland, Christina L., Keung, Emily Z., Huang, Steven Y., Sheth, Rahul A.

المصدر: Cancer ; ISSN 0008-543X 1097-0142

الوصف: Purpose To evaluate outcomes following percutaneous image‐guided ablation of soft tissue sarcoma metastases to the liver. Materials and Methods A single‐institution retrospective analysis of patients with a diagnosis of metastatic soft tissue sarcoma who underwent percutaneous image‐guided ablation of hepatic metastases between January 2011 and December 2021 was performed. Patients with less than 60 days of follow‐up after ablation were excluded. The primary outcome was local tumor progression‐free survival (LPFS). Secondary outcomes included overall survival, liver‐specific progression‐free survival. and chemotherapy‐free survival. Results Fifty‐five patients who underwent percutaneous ablation for 84 metastatic liver lesions were included. The most common histopathological subtypes were leiomyosarcoma (23/55), followed by gastrointestinal stromal tumor (22/55). The median treated liver lesions was 2 (range, 1–8), whereas the median size of metastases were 1.8 cm (0.3–8.7 cm). Complete response at 2 months was achieved in 90.5% of the treated lesions. LPFS was 83% at 1 year and 80% at 2 years. Liver‐specific progression‐free survival was 66% at 1 year and 40% at 2 years. The overall survival at 1 and 2 years was 98% and 94%. The chemotherapy‐free holiday from the start of ablation was 71.2% at 12 months. The complication rate was 3.6% (2/55); one of the complications was Common Terminology Criteria for Adverse Events grade 3 or higher. LPFS subgroup analysis for leiomyosarcoma versus gastrointestinal stromal tumor suggests histology‐agnostic outcomes (2 years, 89% vs 82%, p = .35). Conclusion Percutaneous image‐guided liver ablation of soft tissue sarcoma metastases is safe and efficacious.

الإتاحة: https://doi.org/10.1002/cncr.35330Test