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Article ; Online: Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes.

Binder, Moritz / Szalat, Raphael E / Talluri, Srikanth / Fulciniti, Mariateresa / Avet-Loiseau, Hervé / Parmigiani, Giovanni / Samur, Mehmet K / Munshi, Nikhil C

Nature communications

2024 Volume 15, Issue 1, Page(s) 4139

Abstract: The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of ... ...

Abstract	The natural history of multiple myeloma is characterized by its localization to the bone marrow and its interaction with bone marrow stromal cells. The bone marrow stromal cells provide growth and survival signals, thereby promoting the development of drug resistance. Here, we show that the interaction between bone marrow stromal cells and myeloma cells (using human cell lines) induces chromatin remodeling of cis-regulatory elements and is associated with changes in the expression of genes involved in the cell migration and cytokine signaling. The expression of genes involved in these stromal interactions are observed in extramedullary disease in patients with myeloma and provides the rationale for survival of myeloma cells outside of the bone marrow microenvironment. Expression of these stromal interaction genes is also observed in a subset of patients with newly diagnosed myeloma and are akin to the transcriptional program of extramedullary disease. The presence of such adverse stromal interactions in newly diagnosed myeloma is associated with accelerated disease dissemination, predicts the early development of therapeutic resistance, and is of independent prognostic significance. These stromal cell induced transcriptomic and epigenomic changes both predict long-term outcomes and identify therapeutic targets in the tumor microenvironment for the development of novel therapeutic approaches.
MeSH term(s)	Multiple Myeloma/genetics ; Multiple Myeloma/pathology ; Multiple Myeloma/metabolism ; Humans ; Chromatin Assembly and Disassembly ; Tumor Microenvironment/genetics ; Cell Line, Tumor ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cells/pathology ; Gene Expression Regulation, Neoplastic ; Transcription, Genetic ; Bone Marrow Cells/metabolism ; Cell Movement/genetics ; Stromal Cells/metabolism ; Stromal Cells/pathology ; Female ; Male
Language	English
Publishing date	2024-05-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47793-5
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Article ; Online: Light chain amyloidosis associated with Waldenström macroglobulinemia: treatment and survival outcomes.

Gustine, Joshua N / Szalat, Raphael E / Staron, Andrew / Joshi, Tracy / Mendelson, Lisa / Sloan, J Mark / Sanchorawala, Vaishali

Haematologica

2023 Volume 108, Issue 6, Page(s) 1680–1684

MeSH term(s)	Humans ; Waldenstrom Macroglobulinemia/complications ; Waldenstrom Macroglobulinemia/diagnosis ; Waldenstrom Macroglobulinemia/drug therapy ; Amyloidosis ; Immunoglobulin Light Chains
Chemical Substances	Immunoglobulin Light Chains
Language	English
Publishing date	2023-06-01
Publishing country	Italy
Document type	Letter
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2022.282264
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Article ; Online: Predictive factors of outcomes in patients with AL amyloidosis treated with daratumumab.

Szalat, Raphael E / Gustine, Joshua / Sloan, J Mark / Edwards, Camille V / Sanchorawala, Vaishali

American journal of hematology

2021 Volume 97, Issue 1, Page(s) 79–89

Abstract: Daratumumab as a single agent (sDARA) or in combination with chemotherapies (cDARA) leads to impressive hematologic and organ responses in AL amyloidosis. However, predictive factors associated with outcomes, and optimal duration of therapy remain ... ...

Abstract	Daratumumab as a single agent (sDARA) or in combination with chemotherapies (cDARA) leads to impressive hematologic and organ responses in AL amyloidosis. However, predictive factors associated with outcomes, and optimal duration of therapy remain unclear. We analyzed 107 patients with AL amyloidosis treated with daratumumab between 2017 and 2020. The median overall survival (OS) was not reached while the median major organ deterioration progression free survival (MOD-PFS) was 36 months in the sDARA cohort and not reached in the cDARA cohort, respectively. Hematologic response > VGPR was achieved in 81% of patients receiving sDARA and 86% of patients treated with cDARA. Several predictive factors were identified on a univariate analysis, including NTproBNP >8500 pg/mL but only achievement of at least VGPR and presence of 1q21 gain were independently associated with MOD-PFS and OS on a multivariate analysis. Finally, patients receiving > 12 cycles had significantly longer MOD-PFS (30 vs.13 months; (p = .0018) and OS (NR vs. 15 months; p < .0001). NTproBNP > 8500 pg/mL, presence of 1q21 gain and shorter duration of therapy (≤ 12 cycles) are strong negative predictive factors for outcomes with daratumumab therapy in AL amyloidosis.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/therapeutic use ; Antineoplastic Agents, Immunological/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Female ; Humans ; Immunoglobulin Light-chain Amyloidosis/diagnosis ; Immunoglobulin Light-chain Amyloidosis/drug therapy ; Male ; Middle Aged ; Prognosis ; Progression-Free Survival ; Prospective Studies ; Survival Analysis ; Treatment Outcome
Chemical Substances	Antibodies, Monoclonal ; Antineoplastic Agents, Immunological ; daratumumab (4Z63YK6E0E)
Language	English
Publishing date	2021-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	196767-8
ISSN	1096-8652 ; 0361-8609
ISSN (online)	1096-8652
ISSN	0361-8609
DOI	10.1002/ajh.26399
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Article ; Online: Genomic Instability in Multiple Myeloma.

Alagpulinsa, David A / Szalat, Raphael E / Poznansky, Mark C / Shmookler Reis, Robert J

Trends in cancer

2020 Volume 6, Issue 10, Page(s) 858–873

Abstract: Genomic instability (GIN), an increased tendency to acquire genomic alterations, is a cancer hallmark. However, its frequency, underlying causes, and disease relevance vary across different cancers. Multiple myeloma (MM), a plasma cell malignancy, ... ...

Abstract	Genomic instability (GIN), an increased tendency to acquire genomic alterations, is a cancer hallmark. However, its frequency, underlying causes, and disease relevance vary across different cancers. Multiple myeloma (MM), a plasma cell malignancy, evolves through premalignant phases characterized by genomic abnormalities. Next-generation sequencing (NGS) methods are deconstructing the genomic landscape of MM across the continuum of its development, inextricably linking malignant transformation and disease progression with increasing acquisition of genomic alterations, and illuminating the mechanisms that generate these alterations. Although GIN drives disease evolution, it also creates vulnerabilities such as dependencies on 'superfluous' repair mechanisms and the induction of tumor-specific antigens that can be targeted. We review the mechanisms of GIN in MM, the associated vulnerabilities, and therapeutic targeting strategies.
MeSH term(s)	Animals ; Genomic Instability ; Humans ; Multiple Myeloma/genetics ; Multiple Myeloma/therapy
Language	English
Publishing date	2020-05-30
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2852626-0
ISSN	2405-8025 ; 2405-8033 ; 2405-8033
ISSN (online)	2405-8025 ; 2405-8033
ISSN	2405-8033
DOI	10.1016/j.trecan.2020.05.006
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Article ; Online: Recent common human coronavirus infection protects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: A Veterans Affairs cohort study.

Fillmore, Nathanael R / Szalat, Raphael E / La, Jennifer / Branch-Elliman, Westyn / Monach, Paul A / Nguyen, Vinh / Samur, Mehmet K / Brophy, Mary T / Do, Nhan V / Munshi, Nikhil C

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 46, Page(s) e2213783119

MeSH term(s)	Humans ; SARS-CoV-2 ; Cohort Studies ; Veterans ; COVID-19/prevention & control ; Middle East Respiratory Syndrome Coronavirus
Language	English
Publishing date	2022-11-07
Publishing country	United States
Document type	Letter ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2213783119
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Article ; Online: Lack of differential impact of del17p on survival in African Americans compared with White patients with multiple myeloma: a VA study.

Fillmore, Nathanael R / Cirstea, Diana / Munjuluri, Anusha / Yameen, Hassan / Yellapragada, Sarvari V / Do, Nhan V / Brophy, Mary T / Szalat, Raphael E / Munshi, Nikhil C

Blood advances

2021 Volume 5, Issue 18, Page(s) 3511–3514

Abstract: Multiple myeloma (MM) is a heterogeneous disease that has an increased incidence in African Americans (AAs). We previously observed that, with equal access to health care, younger AA patients (age < 65 years) have superior overall survival (OS) compared ... ...

Abstract	Multiple myeloma (MM) is a heterogeneous disease that has an increased incidence in African Americans (AAs). We previously observed that, with equal access to health care, younger AA patients (age < 65 years) have superior overall survival (OS) compared with younger White patients. Because MM prognosis is influenced by 17p deletion (del17p), we investigated racial differences in its occurrence and impact in a large cohort of MM patients from the Veterans Affairs (VA) system. Among 2243 VA patients with MM for whom del17p data were available, del17p was present in 8.83% of all patients, with a significantly lower prevalence in AAs (5.56%) compared with Whites (10.52%; P < .001). The difference was even more pronounced among younger AAs (<65 years) vs younger Whites (4.34% vs 9.8%, respectively; P = .004). However, we did not observe any significant difference in survival between AA and White patients with del17p, regardless of age category, suggesting that del17p carries a poor prognosis across race and age. Interestingly, among patients without del17p, we still noted a significantly superior OS in younger AAs compared with younger Whites (7.75 vs 5.10 years; P = .042). Our study shows a lower incidence of del17p in AAs but suggests that the survival advantage for younger AAs is primarily due to factors other than del17p.
MeSH term(s)	African Americans ; Aged ; Cohort Studies ; Humans ; Multiple Myeloma/genetics ; Prognosis ; Whites
Language	English
Publishing date	2021-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2020004001
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Zs.A 7153: Show issues

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Article ; Online: Predictors of hematologic response and survival with stem cell transplantation in AL amyloidosis: A 25-year longitudinal study.

Gustine, Joshua N / Staron, Andrew / Szalat, Raphael E / Mendelson, Lisa M / Joshi, Tracy / Ruberg, Frederick L / Siddiqi, Omar / Gopal, Deepa M / Edwards, Camille V / Havasi, Andrea / Kaku, Michelle / Lau, K H Vincent / Berk, John L / Sloan, J Mark / Sanchorawala, Vaishali

American journal of hematology

2022 Volume 97, Issue 9, Page(s) 1189–1199

Abstract: High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was ... ...

Abstract	High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived >20 years. On multivariable analysis, dFLC >180 mg/L and BM plasma cells >10% were independently associated with shorter EFS, whereas BNP >81 pg/mL, troponin I > 0.1 ng/mL, and serum creatinine >2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC >180 mg/L and BMPC% >10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p < .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis.
MeSH term(s)	Amyloidosis/complications ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Immunoglobulin Light-chain Amyloidosis ; Longitudinal Studies ; Melphalan/therapeutic use ; Stem Cell Transplantation ; Transplantation, Autologous ; Treatment Outcome
Chemical Substances	Melphalan (Q41OR9510P)
Language	English
Publishing date	2022-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	196767-8
ISSN	1096-8652 ; 0361-8609
ISSN (online)	1096-8652
ISSN	0361-8609
DOI	10.1002/ajh.26641
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Article ; Online: Prevalence and Outcome of COVID-19 Infection in Cancer Patients: A National Veterans Affairs Study.

Fillmore, Nathanael R / La, Jennifer / Szalat, Raphael E / Tuck, David P / Nguyen, Vinh / Yildirim, Cenk / Do, Nhan V / Brophy, Mary T / Munshi, Nikhil C

Journal of the National Cancer Institute

2020 Volume 113, Issue 6, Page(s) 691–698

Abstract: Background: Emerging data suggest variability in susceptibility and outcome to coronavirus disease 2019 (COVID-19) infection. Identifying risk factors associated with infection and outcomes in cancer patients is necessary to develop healthcare ... ...

Abstract	Background: Emerging data suggest variability in susceptibility and outcome to coronavirus disease 2019 (COVID-19) infection. Identifying risk factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations. Methods: We analyzed electronic health records of the US Veterans Affairs Healthcare System and assessed the prevalence of COVID-19 infection in cancer patients. We evaluated the proportion of cancer patients tested for COVID-19 who were positive, as well as outcome attributable to COVID-19, and stratified by clinical characteristics including demographics, comorbidities, cancer treatment, and cancer type. All statistical tests are 2-sided. Results: Of 22 914 cancer patients tested for COVID-19, 1794 (7.8%) were positive. The prevalence of COVID-19 was similar across age. Higher prevalence was observed in African American (15.0%) compared with White (5.5%; P < .001) and in patients with hematologic malignancy compared with those with solid tumors (10.9% vs 7.8%; P < .001). Conversely, prevalence was lower in current smokers and patients who recently received cancer therapy (<6 months). The COVID-19-attributable mortality was 10.9%. Higher attributable mortality rates were observed in older patients, those with higher Charlson comorbidity score, and in certain cancer types. Recent (<6 months) or past treatment did not influence attributable mortality. Importantly, African American patients had 3.5-fold higher COVID-19-attributable hospitalization; however, they had similar attributable mortality as White patients. Conclusion: Preexistence of cancer affects both susceptibility to COVID-19 infection and eventual outcome. The overall COVID-19-attributable mortality in cancer patients is affected by age, comorbidity, and specific cancer types; however, race or recent treatment including immunotherapy do not impact outcome.
MeSH term(s)	COVID-19/epidemiology ; Humans ; Neoplasms/complications ; Prevalence ; Risk Factors ; United States ; United States Department of Veterans Affairs
Keywords	covid19
Language	English
Publishing date	2020-11-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djaa159
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Article ; Online: Prevalence and outcome of Covid-19 infection in cancer patients: a national VA study

Fillmore, Nathanael R / La, Jennifer / Szalat, Raphael E / Tuck, David P / Nguyen, Vinh / Yildirim, Cenk / Do, Nhan V / Brophy, Mary T / Munshi, Nikhil C

medRxiv

Abstract: Background: Emerging data suggest variability in susceptibility and outcome to Covid-19 infection. Identifying the risk-factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations. Methods: We ... ...

Abstract	Background: Emerging data suggest variability in susceptibility and outcome to Covid-19 infection. Identifying the risk-factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations. Methods: We analyzed electronic health records of the US National Veterans Administration healthcare system and assessed the prevalence of Covid-19 infection in cancer patients. We evaluated the proportion of cancer patients tested for Covid-19 and their confirmed positivity, with clinical characteristics, and outcome, and stratified by demographics, comorbidities, cancer treatment and cancer type. Results: Of 22914 cancer patients tested for Covid-19, 1794 (7.8%) were positive. The prevalence of Covid-19 was similar across all ages. Higher prevalence was observed in African-American (AA) (15%) compared to white (5.5%; P<.001), in Hispanic vs non-Hispanic population and in patients with hematologic malignancy compared to those with solid tumors (10.9% vs 7.7%; P<.001). Conversely, prevalence was lower in current smoker patients, patients with other co-morbidities and having recently received cancer therapy (<6 months). The Covid-19 attributable mortality was 10.9%. Highest mortality rates were observed in older patients, those with renal dysfunction, higher Charlson co-morbidity score and with certain cancer types. Recent (<6 months) or past treatment did not influence mortality. Importantly, AA patients had 3.5-fold higher Covid-19 attributable hospitalization, however had similar mortality rate as white patients. Conclusion: Pre-existence of cancer affects both susceptibility to Covid-19 infection and eventual outcome. The overall Covid-19 attributable mortality in cancer patients is affected by age, co-morbidity and specific cancer types, however, race or recent treatment including immunotherapy does not impact outcome.
Keywords	covid19
Language	English
Publishing date	2020-08-24
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2020.08.21.20177923
Database	COVID19

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Article: Prevalence and outcome of COVID-19 infection in cancer patients: a national Veterans Affairs study

Fillmore, Nathanael R / La, Jennifer / Szalat, Raphael E / Tuck, David P / Nguyen, Vinh / Yildirim, Cenk / Do, Nhan V / Brophy, Mary T / Munshi, Nikhil C

J. natl. cancer inst

Abstract: BACKGROUND: Emerging data suggest variability in susceptibility and outcome to COVID-19 infection. Identifying risk-factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations. METHODS: We analyzed ...

Abstract	BACKGROUND: Emerging data suggest variability in susceptibility and outcome to COVID-19 infection. Identifying risk-factors associated with infection and outcomes in cancer patients is necessary to develop healthcare recommendations. METHODS: We analyzed electronic health records of the US Veterans Affairs healthcare system and assessed the prevalence of COVID-19 infection in cancer patients. We evaluated the proportion of cancer patients tested for COVID-19 who were positive, as well as outcome attributable to COVID-19, and stratified by clinical characteristics including demographics, comorbidities, cancer treatment and cancer type. All statistical tests are two-sided. RESULTS: Of 22914 cancer patients tested for COVID-19, 1794 (7.8%) were positive. The prevalence of COVID-19 was similar across age. Higher prevalence was observed in African-American (AA) (15.0%) compared to White (5.5%; P<.001) and in patients with hematologic malignancy compared to those with solid tumors (10.9% vs 7.8%; P<.001). Conversely, prevalence was lower in current smokers and patients who recently received cancer therapy (<6 months). The COVID-19 attributable mortality was 10.9%. Higher attributable mortality rates were observed in older patients, those with higher Charlson comorbidity score, and in certain cancer types. Recent (<6 months) or past treatment did not influence attributable mortality. Importantly, AA patients had 3.5-fold higher COVID-19 attributable hospitalization, however had similar attributable mortality as White patients. CONCLUSION: Pre-existence of cancer affects both susceptibility to COVID-19 infection and eventual outcome. The overall COVID-19 attributable mortality in cancer patients is affected by age, comorbidity and specific cancer types, however, race or recent treatment including immunotherapy does not impact outcome.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #838367
Database	COVID19

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