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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 701-701
    Abstract: Background. Systemic inflammation is a pathogenic mechanism shared by infection and cancer. Mortality from Covid-19 is strongly linked to systemic cytokine excess. We investigated systemic inflammation as a driver of Covid-19 severity in patients with Covid-19 and cancer. Methods. Between 27/02 and 23/06/2020, OnCovid retrospectively accrued 1,318 consecutive European cancer patients with Covid-19. Patients with myeloma, leukemia, or insufficient data were excluded. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and prognostic index (PI) were evaluated for their prognostic potential, with the NLR, PLR, and PNI risk stratifications dichotomized around median values, and the pre-established risk categorizations from literature utilized for the mGPS and PI. Results. 1,071 eligible patients were randomly assorted into a training set (TS, n=529) and validation set (VS, n=542) matched for age (67.9±13.3 TS, 68.5±13.5 VS), presence of & gt;1 comorbidity (52.1% TS, 49.8% VS), development of & gt;1 Covid-19 complication (27% TS, 25.9% VS), and active malignancy at Covid-19 diagnosis (66.7% TS, 61.6% VS). Among all 1,071 patients, deceased patients tended to categorize into poor risk groups for the NLR, PNI, mGPS, and PI (P & lt;0.0001). Recovered patients fully normalised NLR, PNI, and mGPS to pre-Covid-19 diagnosis levels (P & lt;0.01). In the TS, higher mortality rates were associated with NLR & gt;6 (44.6% vs 28%, P & lt;0.0001), PNI & lt;40 (46.6% vs 20.9%, P & lt;0.0001), mGPS (50.6% for mGPS2 vs 30.4% and 11.4% for mGPS1 and 0, P & lt;0.0001), and PI (50% for PI2 vs 40% for PI1 and 9.1% for PI0, P & lt;0.0001). Findings were confirmed in the VS (P & lt;0.001 for all comparisons). Patients in poor risk categories had shorter median overall survival [OS] (NLR & gt;6 30 days 95%CI 1-63, PNI & lt;40 23 days 95%CI 10-35, mGPS2 20 days 95%CI 8-32, PI2 23 days 95%CI 1-56) compared to patients in good risk categories, for whom median OS was not reached (P & lt;0.001 for all comparisons). The PLR was not associated with survival. Analyses of survival in the VS confirmed the NLR (P & lt;0.0001), PNI (P & lt;0.0001), PI (P & lt;0.01), and mGPS (P & lt;0.001) as predictors of survival. In a multivariable Cox regression model including all inflammatory indices, the PNI was the only independent predictor in both TS and VS analysis (TS hazard ratio [HR] 1.97, 95%CI 1.19-3.26, P=0.008; VS HR 2.48, 95%CI 1.47-4.20, P=0.001). Estimates were adjusted for sex, age, comorbid burden, active malignancy, and receipt of anti-cancer therapy within 4 weeks of Covid-19 diagnosis. Conclusion. Systemic inflammation drives mortality from Covid-19. Hypoalbuminemia and lymphocytopenia as measured by the PNI are the most accurate predictors of outcome and enable repurposing of the PNI as the OnCovid Inflammatory Score (OIS) as a readily available biomarker of severity. Citation Format: Gino M. Dettorre, Saoirse Dolly, Angela Loizidou, John Chester, Amanda Jackson, Uma Mukherjee, Alberto Zambelli, Juan Aguilar-Company, Mark Bower, Christopher C. Sng, Ramon Salazar, Alexia Bertuzzi, Joan Brunet, Ricard Mesia, Ailsa Sita-Lumsden, Elia Seguí, Federica Biello, Daniele Generali, Salvatore Grisanti, Pavetha Seeva, Gianpiero Rizzo, Michela Libertini, Antonio Maconi, Charlotte Moss, Josep Tabernero, Beth Russell, Nadia Harbeck, Bruno Vincenzi, Rossella Bertulli, Diego Ottaviani, Raquel Liñan, Andrea Marrari, M. Carmen Carmona-García, Neha Chopra, Carlo Tondini, Oriol Mirallas, Valeria Tovazzi, Vittoria Fotia, Claudia Andrea Cruz, Nadia Saoudi-Gonzalez, Eudald Felip, Ariadna Roqué, Alvin J. Lee, Thomas Newsom-Davis, Andrea Patriarca, Lorenza Rimassa, Armando Santoro, Alessandra Gennari, Nikolaos Diamantis, David J. Pinato. The acute phase response identifies cancer patients with adverse outcomes from SARS-CoV-2 infection as quantified by the OnCovid Inflammatory Score [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 701.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 2
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. 3 ( 2021-03), p. e002277-
    Abstract: Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study. Methods In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets. Results We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p 〈 0.01), recovering in survivors to pre-COVID-19 levels. Patients in poorer risk categories for each index except the PLR exhibited higher mortality rates (p 〈 0.001) and shorter median overall survival in the training and validation sets (p 〈 0.01). Multivariable analyses revealed the OIS to be most independently predictive of survival (validation set HR 2.48, 95% CI 1.47 to 4.20, p=0.001; adjusted concordance index score 0.611). Conclusions Systemic inflammation is a validated prognostic domain in SARS-CoV-2-infected patients with cancer and can be used as a bedside predictor of adverse outcome. Lymphocytopenia and hypoalbuminemia as computed by the OIS are independently predictive of severe COVID-19, supporting their use for risk stratification. Reversal of the COVID-19-induced proinflammatory state is a putative therapeutic strategy in patients with cancer.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    Language: English
    Publisher: BMJ
    Publication Date: 2021
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  • 3
    In: International Immunology, Oxford University Press (OUP), Vol. 30, No. 8 ( 2018-07-24), p. 375-383
    Abstract: Acute myeloid leukemia (AML) remains a significant health problem, with poor outcomes despite chemotherapy and bone marrow transplants. Although one form of AML, acute promyelocytic leukemia (APL), is successfully treated with all-trans retinoic acid (ATRA), this drug is seemingly ineffective against all other forms of AML. Here, we show that ATRA up-regulates CD38 expression on AML blasts to sufficient levels that promote antibody-mediated fratricide following the addition of anti-CD38 daratumumab (DARA). The combination of ATRA plus DARA induced Fc-dependent conjugate formation and cytotoxicity among AML blasts in vitro. Combination treatment also led to reduction in tumor volume and resulted in increased overall survival in murine engraftment models of AML. These results suggest that, although ATRA does not induce differentiation of non-APL, it may be effective as a therapy in conjunction with DARA.
    Type of Medium: Online Resource
    ISSN: 0953-8178 , 1460-2377
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
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  • 4
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 6_Supplement ( 2021-03-15), p. S01-03-S01-03
    Abstract: We sought to determine parameters of the acute phase response, a feature of innate immunity activated by infectious noxae and cancer, deranged by Covid-19 and establish oncological indices’ prognostic potential for patients with concomitant cancer and Covid-19. Between 27/02 and 23/06/2020, OnCovid retrospectively accrued 1,318 consecutive referrals of patients with cancer and Covid-19 aged 18 from the U.K., Spain, Italy, Belgium, and Germany. Patients with myeloma, leukemia, or insufficient data were excluded. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), modified Glasgow prognostic score (mGPS), and prognostic index (PI) were evaluated for their prognostic potential, with the NLR, PLR, and PNI risk stratifications dichotomized around median values and the pre-established risk categorizations from literature utilized for the mGPS and PI. 1,071 eligible patients were randomly assorted into a training set (TS, n=529) and validation set (VS, n=542) matched for age (67.9±13.3 TS, 68.5±13.5 VS), presence of 1 comorbidity (52.1% TS, 49.8% VS), development of 1 Covid-19 complication (27% TS, 25.9% VS), and active malignancy at Covid-19 diagnosis (66.7% TS, 61.6% VS). Among all 1,071 patients, deceased patients tended to categorize into poor risk groups for the NLR, PNI, mGPS, and PI (P & lt;0.0001) with a return to pre-Covid-19 diagnosis NLR, PNI, and mGPS categorizations following recovery (P & lt;0.01). In the TS, higher mortality rates were associated with NLR & gt;6 (44.6% vs 28%, P & lt;0.0001), PNI & lt;40 (46.6% vs 20.9%, P & lt;0.0001), mGPS (50.6% for mGPS2 vs 30.4% and 11.4% for mGPS1 and 0, P & lt;0.0001), and PI (50% for PI2 vs 40% for PI1 and 9.1% for PI0, P & lt;0.0001). Findings were confirmed in the VS (P & lt;0.001 for all comparisons). Patients in poor risk categories had shorter median overall survival [OS], (NLR & gt;6 30 days 95%CI 1-63, PNI & lt;40 23 days 95%CI 10-35, mGPS2 20 days 95%CI 8-32, PI2 23 days 95%CI 1-56) compared to patients in good risk categories, for whom median OS was not reached (P & lt;0.001 for all comparisons). The PLR was not associated with survival. Analyses of survival in the VS confirmed the NLR (P & lt;0.0001), PNI (P & lt;0.0001), PI (P & lt;0.01), and mGPS (P & lt;0.001) as predictors of survival. In a multivariable Cox regression model including all inflammatory indices and pre-established prognostic factors for severe Covid-19 including sex, age, comorbid burden, malignancy status, and receipt of anti-cancer therapy at Covid-19 diagnosis, the PNI was the only factor to emerge with a significant hazard ratio [HR] in both TS and VS analysis (TS HR 1.97, 95%CI 1.19-3.26, P=0.008; VS HR 2.48, 95%CI 1.47-4.20, P=0.001). We conclude that systemic inflammation drives mortality from Covid-19 through hypoalbuminemia and lymphocytopenia as measured by the PNI and propose the PNI as the OnCovid Inflammatory Score (OIS) in this context. Citation Format: Gino M. Dettorre, Saoirse Dolly, Angela Loizidou, John Chester, Amanda Jackson, Uma Mukherjee, Alberto Zambelli, Juan Aguilar-Company, Mark Bower, Christopher C. T. Sng, Ramon Salazar, Alexia Bertuzzi, Joan Brunet, Ricard Mesia, Ailsa Sita-Lumsden, Elia Seguí, Federica Biello, Daniele Generali, Salvatore Grisanti, Pavetha Seeva, Gianpiero Rizzo, Michela Libertini, Antonio Maconi, Charlotte Moss, Beth Russell, Josep Tabernero, Nadia Harbeck, Bruno Vincenzi, Rossella Bertulli, Diego Ottaviani, Andrea Marrari, M. Carmen Carmona-García, Neha Chopra, Carlo Tondini, Oriol Mirallas, Valeria Tovazzi, Vittoria Fotia, Claudia A. Cruz, Nadia Saoudi-Gonzalez, Eudald Felip, Lorenza Scotti, Alvin J. X. Lee, Thomas Newsom-Davis, Andrea Patriarca, Lorenza Rimassa, Armando Santoro, Alessandra Gennari, Mieke Van Hemelrijck, Nikolaos Diamantis, David J. Pinato. The acute phase response identifies cancer patients with adverse outcomes from SARS-CoV-2 infection as quantified by the OnCovid Inflammatory Score [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr S01-03.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 5
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 7 ( 2020-04-01), p. 1988-1997
    Abstract: TLRs, a family of membrane-bound pattern recognition receptors found on innate immune cells, have been well studied in the context of cancer therapy. Activation of these receptors has been shown to induce inflammatory anticancer events, including differentiation and apoptosis, across a wide variety of malignancies. In contrast, intracellular pattern recognition receptors such as NOD-like receptors have been minimally studied. NOD2 is a member of the NOD-like receptor family that initiates inflammatory signaling in response to the bacterial motif muramyl dipeptide. In this study, we examined the influence of NOD2 in human acute myeloid leukemia (AML) cells, demonstrating that IFN-γ treatment upregulated the expression of NOD2 signaling pathway members SLC15A3 and SLC15A4, downstream signaling kinase RIPK2, and the NOD2 receptor itself. This priming allowed for effective induction of caspase-1–dependent cell death upon treatment with muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic ligand for NOD2. Furthermore, the combination of MTP-PE and IFN-γ on AML blasts generated an inflammatory cytokine profile and activated NK cells. In a murine model of AML, dual treatment with MTP-PE and IFN-γ led to a significant increase in mature CD27− CD11b+ NK cells as well as a significant reduction in disease burden and extended survival. These results suggest that NOD2 activation, primed by IFN-γ, may provide a novel therapeutic option for AML.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
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    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
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  • 6
    In: Therapeutic Advances in Medical Oncology, SAGE Publications, Vol. 13 ( 2021-01), p. 175883592110422-
    Abstract: Specialist palliative care team (SPCT) involvement has been shown to improve symptom control and end-of-life care for patients with cancer, but little is known as to how these have been impacted by the COVID-19 pandemic. Here, we report SPCT involvement during the first wave of the pandemic and compare outcomes for patients with cancer who received and did not receive SPCT input from multiple European cancer centres. Methods: From the OnCovid repository ( N = 1318), we analysed cancer patients aged ⩾18 diagnosed with COVID-19 between 26 February and 22 June 2020 who had complete specialist palliative care team data (SPCT+ referred; SPCT− not referred). Results: Of 555 eligible patients, 317 were male (57.1%), with a median age of 70 years (IQR 20). At COVID-19 diagnosis, 44.7% were on anti-cancer therapy and 53.3% had ⩾1 co-morbidity. Two hundred and six patients received SPCT input for symptom control (80.1%), psychological support (54.4%) and/or advance care planning (51%). SPCT+ patients had more ‘Do not attempt cardio-pulmonary resuscitation’ orders completed prior to (12.6% versus 3.7%) and during admission (50% versus 22.1%, p  〈  0.001), with more SPCT+ patients deemed suitable for treatment escalation (50% versus 22.1%, p  〈  0.001). SPCT involvement was associated with higher discharge rates from hospital for end-of-life care (9.7% versus 0%, p  〈  0.001). End-of-life anticipatory prescribing was higher in SPCT+ patients, with opioids (96.3% versus 47.1%) and benzodiazepines (82.9% versus 41.2%) being used frequently for symptom control. Conclusion: SPCT referral facilitated symptom control, emergency care and discharge planning, as well as high rates of referral for psychological support than previously reported. Our study highlighted the critical need of SPCTs for patients with cancer during the pandemic and should inform service planning for this population.
    Type of Medium: Online Resource
    ISSN: 1758-8359 , 1758-8359
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2021
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  • 7
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 10, No. 11 ( 2022-11), p. e005732-
    Abstract: As management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer. Methods In a joint analysis of ICI recipients from OnCovid ( NCT04393974 ) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19. Findings The study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR 30 ) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR 30 (4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, p 〈 0.0001), requirement of oxygen therapy (15.8% vs 41.5%, p=0.0030), COVID-19 complication rate (11.9% vs 34.6%, p=0.0040), with a reduced need for COVID-19-specific therapy (26.3% vs 57.9%, p=0.0004) compared with unvaccinated patients. Inverse probability of treatment weighting (IPTW)-fitted multivariable analysis, following a clustered-robust correction for the data source (OnCovid vs ESMO CoCARE), confirmed that vaccinated patients experienced a decreased risk of death at 30 days (adjusted OR, aOR 0.08, 95% CI 0.01 to 0.69). Overall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13–48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR 30 (10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 10 9  cells/L, p=0.0098). Conclusion Anti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2719863-7
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  • 8
    In: The Lancet Oncology, Elsevier BV, Vol. 24, No. 4 ( 2023-04), p. 335-346
    Type of Medium: Online Resource
    ISSN: 1470-2045
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2049730-1
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  • 9
    In: The Lancet Oncology, Elsevier BV, Vol. 23, No. 7 ( 2022-07), p. 865-875
    Type of Medium: Online Resource
    ISSN: 1470-2045
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2049730-1
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