Immunosenescence (iSenescence) correlates with progression (PD) to PD-(L)1 inhibitors (IO) and not to platinum-chemotherapy (PCT) in advanced non-small cell lung cancer (aNSCLC) patients (pts)

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Tres medici, duo athei? The Physician as Atheist and the Medicalization of the Soul

Until recently, examinations of the ‘mind-body problem’ in historical context paid only cursory attention to its specifically medical dimension, if at all. At best, some ‘folk physiology’ was entertained, usually to laugh at it (the pineal gland, animal spirits). Conversely, historians of neuroscience or of artificial intelligence (Jeannerod 1985, Dupuy 2000) often present figures like La Mettrie as heroic early cases of ‘naturalization’, giving an experimental basis to materialism: their symmetrically inverse mistake is to take professions of medical authority too literally (although there are genuine cases where all of the above does coalesce – where ‘actors’ categories mysteriously transcend historiographic projections –, such as Hieronymus Gaub’s reflections on the ‘regimen of the mind’ in the mid-eighteenth century, or, more theoretically, Guillaume Lamy’s Epicurean-inflected Anatomical Discourses on the Soul, eighty years earlier). Contrary to the denial of the relevance of medicine in early modern philosophy, as regards issues such as the body-soul (then body-mind) relation among others, it seems patently difficult to separate medical theory, medically nourished philosophical speculation, and metaphysics. This is the case, whether in Descartes, Gaub, the ‘animist’ Georg-Ernest Stahl, or materialists such as Guillaume Lamy and La Mettrie: medicine, or rather ‘a certain idea of medicine’, is everywhere. Here I focus on the motif of a radical medicine – a medical precursor of the Radical Enlightenment (Israel 2001, 2006, 2007), symbolized negatively by the slogan, tres medici, duo athei, or ‘where there are three doctors, there are two atheists’, i.e. medicine as a basis for atheism. This theme runs through various works of medical or medico-theological propaganda: Thomas Browne’s 1643 De religio medici begins with Browne regretting rumors of doctors being atheists as the “general scandal of my Profession”; Germain de Bezançon’s 1677 Les médecins à la censure works hard at rebutting the saying, “Bon Physicien, mauvais chrétien.” But these are examples of the fear of a radical medicine – a medicine that denies the existence of an immortal soul, or even defends materialism and atheism. Are there positive statements of this doctrine? Indeed, attacks on it are much more common than statements identifying with it, like medical versions of natural theology in general. In fact, just as there were theologically motivated medical works, there were also medically motivated works of radical or heretical theology, like William Coward’s Second Thoughts on the Human Soul (Coward 1702, building on Overton 1644), which engaged in polemics concerning the nature of the soul – mortal or immortal? (Thomson 2008). Parallel to the mortalist trend, but flowing into a common genre of radical, medico-materialist texts (sometimes anonymous, such as L’Âme Matérielle, from the 1720s) are at least two other strands of radical medicine: a post-Cartesian focus on medicina mentis and the nature of the mind (Henricus Regius, Hieronymus Gaub, Antoine Le Camus), and an Epicurean medicine, in which mind and body are organismically united, with an additional hedonistic component, notably in Lamy, Mandeville and La Mettrie (Wright 1991, Wolfe and van Esveld 2014). The focus on a medicine of the mind (Corneanu, ms. 2013) is obviously connected to a ‘medicalization of the soul’: there was a body-soul problem in and for medicine, a sort of medicalized ‘pneumatology’. Radical medicine is located somewhere in between the early forms of ‘naturalization’ or ‘medicalization’ of the soul and the pose of scientific neutrality that is characteristic of early nineteenth-century medicine (as in Cabanis, Bichat or Bernard): it is a short-lived episode. I seek to reconstruct this intellectual figure, in which mortalist, post-Cartesian and Epicurean strands intersect and sometimes come together. I suggest that medically influenced materialism in the Radical Enlightenment (e.g. in the later French cases, La Mettrie, Ménuret and Diderot), is different from later, more experimentally focused and more quantitatively oriented forms of medical materialism, precisely because of its radical dimension. This radical medicine often insists on vitality, as opposed to “anatomie cadavérique”: it is vital and hedonistic, a medicine concerned with maintaining bodily pleasure.Until recently, examinations of the 'mind-body problem' in historical context paid only cursory attention to its specifically medical dimension, if at all. At best, some 'folk physiology' was entertained, usually to laugh at it (the pineal gland, animal spirits). Conversely, historians of neuroscience or of artificial intelligence (Jeannerod M, The brain machine. The development of neurophysiological thought, trans. D. Urion, Harvard University Press, Cambridge, 1985; Dupuy J-P, The mechanization of the mind: on the origins of cognitive science, trans. M.B. DeBevoise, Princeton University Press, Princeton, 2000) often present figures like La Mettrie as heroic early cases of 'naturalization', giving an experimental basis to materialism: their symmetrically inverse mistake is to take professions of medical authority too literally (although there are genuine cases where all of the above does coalesce where 'actors' categories mysteriously transcend historiographic projections -, such as Hieronymus Gaub's reflections on the 'regimen of the mind' in the mid-eighteenth century, or, more theoretically, Guillaume Lamy's Epicurean-inflected Anatomical Discourses on the Soul, eighty years earlier). Contrary to the denial of the relevance of medicine in early modern philosophy, as regards issues such as the body-soul (then body-mind) relation among others, it seems patently difficult to separate medical theory, medically nourished philosophical speculation, and metaphysics. This is the case, whether in Descartes, Gaub, the 'animist' Georg-Ernest Stahl, or materialists such as Guillaume Lamy and La Mettrie: medicine, or rather 'a certain idea of medicine', is everywhere.Here I focus on the motif of a radical medicine - a medical precursor of the Radical Enlightenment (Israel J, Radical enlightenment. Philosophy and the making of modernity, 1650-1750, Oxford University Press, Oxford, 2001; Israel J, Enlightenment contested. Oxford University Press, Oxford, 2006, Israel J, Enlightenment, radical enlightenment and the "medical revolution" of the late seventeenth and eighteenth centuries. In: Grell OP, Cunningham A (ed) Medicine and religion in enlightenment Europe. Ashgate, Aldershot, pp 5-28, 2007), symbolized negatively by the slogan, tres medici, duo athei, or 'where there are three doctors, there are two atheists', i.e. medicine as a basis for atheism. This theme runs through various works of medical or medico-theological propaganda: Thomas Browne's 1643 De religio medici begins with Browne regretting rumors of doctors being atheists as the "general scandal of my Profession"; Germain de Bezancon's 1677 Les medecins a la censure works hard at rebutting the saying, "Bon Physicien, mauvais chretien." But these are examples of the fear of a radical medicine - a medicine that denies the existence of an immortal soul, or even defends materialism and atheism. Are there positive statements of this doctrine? Indeed, attacks on it are much more common than statements identifying with it, like medical versions of natural theology in general.In fact, just as there were theologically motivated medical works, there were also medically motivated works of radical or heretical theology, like William Coward's Second Thoughts on the Human Soul (Coward W, Second thoughts on the human soul. R. Basset, London, 1702, building on Overton 1644), which engaged in polemics concerning the nature of the soul - mortal or immortal? (Thomson A, Bodies of thought: science, religion, and the soul in the early enlightenment. Oxford University Press, Oxford, 2008). Parallel to the mortalist trend, but flowing into a common genre of radical, medico-materialist texts (sometimes anonymous, such as L'Ame Materielle, from the 1720s) are at least two other strands of radical medicine: a post-Cartesian focus on medicina mentis and the nature of the mind (Henricus Regius, Hieronymus Gaub, Antoine Le Camus), and an Epicurean medicine, in which mind and body are organismically united, with an additional hedonistic component, notably in Lamy, Mandeville and La Mettrie (Wright JP, Locke, Willis, and the seventeenth-century epicurean soul. In: Osler MJ (ed) Atoms, Pneuma, and Tranquillity: Epicurean and stoic themes in European thought. Cambridge University Press, Cambridge, pp 239-258, 1991; Wolfe CT, van Esveld M, The material soul: strategies for naturalising the soul in an early modern epicurean context. In: Kambaskovic D (ed) Conjunctions: body, soul and mind from Plato to the enlightenment. Springer, Dordrecht, pp 371-421, 2014). The focus on a medicine of the mind (Corneanu, (ms. 2013), The care of the whole man: medicine and theology in the late renaissance, 2013) is obviously connected to a 'medicalization of the soul': there was a body-soul problem in and for medicine, a sort of medicalized 'pneumatology'. Radical medicine is located somewhere in between the early forms of 'naturalization' or 'medicalization' of the soul and the pose of scientific neutrality that is characteristic of early nineteenth-century medicine (as in Cabanis, Bichat or Bernard): it is a short-lived episode. I seek to reconstruct this intellectual figure, in which mortalist, post-Cartesian and Epicurean strands intersect and sometimes come together. I suggest that medically influenced materialism in the Radical Enlightenment (e.g. in the later French cases, La Mettrie, Menuret and Diderot), is different from later, more experimentally focused and more quantitatively oriented forms of medical materialism, precisely because of its radical dimension. This radical medicine often insists on vitality, as opposed to "anatomie cadaverique": it is vital and hedonistic, a medicine concerned with maintaining bodily pleasure

NIVOREN GETUG-AFU 26 translational study: Baseline peripheral cytokines predict survival in metastatic clear cell renal carcinoma (RCC) treated with nivolumab

International audienc

Immunosenescence (iSenescence) correlates with disease progression in advanced non-small cell lung cancer (aNSCLC) patients treated with PD-(L)1 inhibitors (IO)

BACKGROUND: iSenescence is a progressive remodeling of immune functions with a multifactorial etiology (i.e. aging, chronic inflammation, cancer). Although the absence of CD28 and the expression of CD57 and Killer-cell lectin-like receptor G1 (KLRG1) on peripheral T-lymphocytes are potential hallmarks of iSenescence, the characterization of such phenotype in IO-treated aNSCLC patients and the correlation with clinical characteristics and benefit from immunotherapy are currently unknown. [...

Immunosenescence Correlates with Poor Outcome from PD-(L)1 Blockade but Not Chemotherapy in Non-Small Cell Lung Cancer (NSCLC)[P1.04-31]

BACKGROUND : CD28, CD57 and KLRG1 on circulating T-lymphocytes have been identified as markers of immunosenescence. The characterization of a senescent immune phenotype (SIP) in advanced NSCLC (aNSCLC) and its impact on anti-PD(L)-1 (IO) or platinum-based chemotherapy (PCT) treatments are unknown. [...

Immunosenescence Correlates with Progression upon PD-(L)-1 Blockade (IO) in Advanced Non-Small Cell Lung Cancer (aNSCLC) Patients [P1.01-18]

BACKGROUND : Immunosenescence is a progressive remodeling of immune functions with a multifactorial etiology (i.e. aging, chronic inflammation, cancer). Although a CD28-CD57+KLRG1+ phenotype on peripheral T-lymphocytes is a potential hallmark of immunosenescence, the characterization of such phenotype in IO-treated NSCLC patients and the correlation with clinical characteristics and benefit from immunotherapy are unknown. [...

Circulating T-cell Immunosenescence in Patients with Advanced Non-small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy

Purpose: CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non-small cell lung cancer (aNSCLC) is unknown.Experimental Design: The percentage of CD28(-), CD57(+), KLRG1(+) among CD8(+) T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cutoff was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8(+) T cells were assessed in vitro.Results: In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8(+) T cells proliferation, lower IL2 and higher TNF alpha and IFN gamma production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.Conclusions: Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT