death

Programmed death ligand 1 in glioblastoma

Programmed death ligand 1 in glioblastoma

Reports of programmed death ligand 1 (PD-L1) expression in glioblastoma are highly variable (ranging from 6% to 88%) and its role as a prognostic marker has yielded conflicting results.

Data points to a putative role for PD-L1 expression in glioblastoma biology, which correlates to poor patient overall survival, as well as with a general systemic inflammatory status and immunosuppression 1).

A 5% PD-L1 expression cut-off identified a subset of glioblastoma that is associated with a worse clinical outcome. This association remained significant within the newly defined IDH wildtype classification. These findings could have implications for patient stratification in future clinical trials of PD-1/PD-L1 blockade 2).

For patients receiving Dendritic cell vaccine adjuvant therapy, better outcomes are predicted in patients with younger age, with TILs or PBMCs with lower PD-1+/CD8+ ratio, with gross tumor resection, and receiving CCRT 3).

In a retrospective cohort of 115 consecutive patients with GBM, PD-L1 expression was determined using immunohistochemistry (IHC). Membranous and fibrillary PD-L1 staining of any intensity in > 5% neoplastic cells and tumour infiltrating immune cells (TIIs) was considered positive staining. In addition, isocitrate dehydrogenase 1 (IDH-1) (R132H) expression and cluster of differentiation 3 (CD3)-positive T-cell infiltration were investigated using IHC. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation assay and fluorescence in situ hybridization (FISH) for the assessment of 1p/19q deletion were performed. Expression of PD-L1 in tumour cells and TIIs was found in 37 (32.2%) and 6 (5.2%) patients, respectively. Kaplan-Meier analysis indicated that PD-L1 expression in tumour cells was significantly associated with poor overall survival (OS) (P = 0.017), though multivariate Cox analysis did not confirm this association (hazard ratio 1.204; P = 0.615). PD-L1 expression in TIIs did not correlate with the patient prognosis (P = 0.545). In addition, MGMT methylation and IDH-1 (R132H) expression were associated with a better prognosis (P < 0.001 and P = 0.024, respectively). The expression of PD-L1 was associated with CD3-positive T-cell infiltration (P < 0.001), and IDH-1 wild type status (P = 0.008). A deeper insight into PD-L1 expression could help to ensure the success of future immunotherapy in GBM. Our study suggested that PD-L1 target therapy might be beneficial for PD-L1-expressing GBM patients with a poor prognosis 4).

Immunotherapies for glioblastoma multiforme including PD1/PD-L1 inhibition are currently tested in ongoing clinical trials. The purpose of a study was to investigate the molecular background of PD-L1 expression in glioblastoma multiforme and to find associated pathway activation and genetic alterations. Heiland et al., show that PD-L1 is up-regulated in IDH1/2 wildtype glioblastoma multiforme compared to lower-grade gliomas. In addition, a strong association of PD-L1 with the mesenchymal expression subgroup was observed. Consistent with that, NF1 mutation and corresponding activation of the MAPK pathway was strongly connected to PD-L1 expression. The findings may explain different response to PD-L1 inhibition of patients in ongoing trials and may help to select patients that may profit of immunotherapy in the future 5).

1)

Noronha C, Ribeiro AS, Taipa R, Leitão D, Schmitt F, Reis J, Faria C, Paredes J. PD-L1 tumor expression is associated with poor prognosis and systemic immunosuppression in glioblastoma. J Neurooncol. 2022 Jan 23. doi: 10.1007/s11060-021-03907-3. Epub ahead of print. PMID: 35066764.
2)

Pratt D, Dominah G, Lobel G, Obungu A, Lynes J, Sanchez V, Adamstein N, Wang X, Edwards NA, Wu T, Maric D, Giles AJ, Gilbert MR, Quezado M, Nduom EK. Programmed Death Ligand 1 Is a Negative Prognostic Marker in Recurrent Isocitrate Dehydrogenase-Wildtype Glioblastoma. Neurosurgery. 2018 Jul 12. doi: 10.1093/neuros/nyy268. [Epub ahead of print] PubMed PMID: 30011045.
3)

Jan CI, Tsai WC, Harn HJ, Shyu WC, Liu MC, Lu HM, Chiu SC, Cho DY. Predictors of Response to Autologous Dendritic Cell Therapy in Glioblastoma Multiforme. Front Immunol. 2018 May 29;9:727. doi: 10.3389/fimmu.2018.00727. eCollection 2018. PubMed PMID: 29910795; PubMed Central PMCID: PMC5992384.
4)

Lee KS, Lee K, Yun S, Moon S, Park Y, Han JH, Kim CY, Lee HS, Choe G. Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma. J Neurooncol. 2018 Feb;136(3):453-461. doi: 10.1007/s11060-017-2675-6. Epub 2017 Nov 16. PubMed PMID: 29147863.
5)

Heiland DH, Haaker G, Delev D, Mercas B, Masalha W, Heynckes S, Gäbelein A, Pfeifer D, Carro MS, Weyerbrock A, Prinz M, Schnell O. Comprehensive analysis of PD-L1 expression in glioblastoma multiforme. Oncotarget. 2017 Feb 2. doi: 10.18632/oncotarget.15031. [Epub ahead of print] PubMed PMID: 28178682.

Brain death

Brain death

The published World Brain Death Project aims in alleviating inconsistencies in clinical guidelines and practice in the determination of death by neurologic criteria. However, critics have taken issue with a number of epistemic and metaphysical assertions that critics argue are either false, ad hoc, or confused.

Lazaridis disscussed the nature of a definition of death; the plausibility of neurologic criteria as a sensible social, medical, and legal policy; and within a Rawlsian liberal framework, reasons for personal choice or accommodation among neurologic and circulatory definitions. Declaration of human death cannot rest on contested metaphysics or unmeasurable standards, instead it should be regarded as a plausible and widely accepted social construct that conforms to best available and pragmatic medical science and practice. The definition(s) and criteria should be transparent, publicly justifiable, and potentially allow for the accommodation of reasonable choice. This is an approach that situates the definition of death as a political matter. The approach anticipates that no conceptualization of death can claim universal validity, since this is a question that cannot be settled solely on biologic or scientific grounds, rather it is a matter of normative preference, socially constructed and historically contingent 1).

The concept of brain death has periodically come under criticism 2).

Confirmatory tests for the diagnosis of brain death in addition to clinical findings may shorten observation time required in some countries and may add certainty to the diagnosis under specific circumstances.

The current U.S. approach to determining death was developed in response to the emergence of technologies that made the traditional standard of cardiopulmonary death problematic. In 1968, an ad hoc committee at Harvard Medical School published an influential article arguing for extending the concept of death to patients in an “irreversible coma.“ 3). The emerging neurologic criteria for death defined it in terms of loss of the functional activity of the brain stem and cerebral cortex. Although clinical criteria were developed in the 1960s, it took more than a decade for consensus over a rationale for the definition to emerge. In 1981, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research provided a philosophical definition of brain death in terms of the loss of the critical functions of the organism as a whole 4).

Shortly thereafter, the National Conference of Commissioners on Uniform State Laws produced the Uniform Determination of Death Act, which has been adopted in 45 states and recognized in the rest through judicial opinion 5).

Computed tomography angiography for brain death

see Computed tomography angiography for brain death.

S100B

Changes in S100B protein, especially the levels of this dimer 48 hours after trauma can be used as marker to predict brain death. Alongside other known prognostic factors such as age, GCS and diameters of the pupils, however, this factor individually can not conclusive predict the patient’s clinical course and incidence of brain death. However, it is suitable to use GCS, CT scan, clinical symptoms and biomarkers together for a perfect prediction of brain death 6).

Near-Infrared Spectroscopy

Near-Infrared Spectroscopy for Brain death

Gadolinium-enhanced magnetic resonance angiography

The practicability of Gadolinium-enhanced magnetic resonance angiography to confirm cerebral circulatory arrest was assessed after the diagnosis of brain death in 15 patients using a 1.5 Tesla MRI scanner. In all 15 patients extracranial blood flow distal to the external carotid arteries was undisturbed. In 14 patients no contrast medium was noted within intracerebral vessels above the proximal level of the intracerebral arteries. In one patient more distal segments of the anterior and middle cerebral arteries (A3 and M3) were filled with contrast medium. Gadolinium-enhanced MRA may be considered conclusive evidence of cerebral circulatory arrest, when major intracranial vessels fail to fill with contrast medium while extracranial vessels show normal blood flow 7).

The level of knowledge of medical students at Centro Universitário Lusíada – UNILUS- Santos (SP), Brazil, regarding brain death and transplantation is limited, which could be the result of inadequate education during medical school 8).

Criteria

Brain death criteria.

Case reports

In a editorial, Hibi et al., aimed to provide an outline of the world history of liver transplantation (LT), with a special focus on the innovation, development, and current controversies of living donor (LD) LT from East Asian and Western perspectives. In 1963, Starzl et al. (University of Colorado, U.S.) performed the world’s first human LT for a 3-year-old child with biliary atresia. The donor was a 3-year-old patient who had suffered from brain death following neurosurgery. 9).

1)

Lazaridis C. Defining Death: Reasonableness and Legitimacy. J Clin Ethics. 2021 Summer;32(2):109-113. PMID: 34129526.
2)

Truog RD, Miller FG, Halpern SD. The dead-donor rule and the future of organ donation. N Engl J Med 2013;369:1287-1289
3)

A definition of irreversible coma: report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337-340
4)

President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Defining death: a report on the medical, legal and ethical issues in the determination of death. Washington, DC: Government Printing Office, 1981.
5)

National Conference of Commissioners on Uniform State Laws. Uniform Determination of Death Act, 1981 (http://www.uniformlaws.org/shared/docs/determination%20of%20death/udda80.pdf).
6)

Shakeri M, Mahdkhah A, Panahi F. S100B Protein as a Post-traumatic Biomarker for Prediction of Brain Death in Association With Patient Outcomes. Arch Trauma Res. 2013 Aug;2(2):76-80. doi: 10.5812/atr.8549. Epub 2013 Aug 1. PubMed PMID:24396798.
7)

Luchtmann M, Beuing O, Skalej M, Kohl J, Serowy S, Bernarding J, Firsching R. Gadolinium-enhanced magnetic resonance angiography in brain death. Sci Rep. 2014 Jan 13;4:3659. doi: 10.1038/srep03659. PubMed PMID: 24413880.
8)

Reis FP, Gomes BH, Pimenta LL, Etzel A. Brain death and tissue and organ transplantation: the understanding of medical students. Rev Bras Ter Intensiva. 2013 Oct-Dec;25(4):279-283. Portuguese, English. PubMed PMID: 24553508.
9)

Hibi T, Eguchi S, Egawa H. Evolution of living donor liver transplantation: A global perspective. J Hepatobiliary Pancreat Sci. 2018 Jun 28. doi: 10.1002/jhbp.571. [Epub ahead of print] PubMed PMID: 29953731.

Book:Do No Harm: Stories of Life, Death, and Brain Surgery By Henry Marsh

Do No Harm: Stories of Life, Death, and Brain Surgery
By Henry Marsh

Do No Harm: Stories of Life, Death, and Brain Surgery
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What is it like to be a brain surgeon? How does it feel to hold someone’s life in your hands, to cut into the stuff that creates thought, feeling, and reason? How do you live with the consequences of performing a potentially lifesaving operation when it all goes wrong?
In neurosurgery, more than in any other branch of medicine, the doctor’s oath to “do no harm” holds a bitter irony. Operations on the brain carry grave risks. Every day, leading neurosurgeon Henry Marsh must make agonizing decisions, often in the face of great urgency and uncertainty.
If you believe that brain surgery is a precise and exquisite craft, practiced by calm and detached doctors, this gripping, brutally honest account will make you think again. With astonishing compassion and candor, Marsh reveals the fierce joy of operating, the profoundly moving triumphs, the harrowing disasters, the haunting regrets, and the moments of black humor that characterize a brain surgeon’s life.
Do No Harm provides unforgettable insight into the countless human dramas that take place in a busy modern hospital. Above all, it is a lesson in the need for hope when faced with life’s most difficult decisions.

Product Details

  • Original language: English
  • Number of items: 1
  • Dimensions: 8.46″ h x 1.09″ w x 5.77″ l, 1.00 pounds
  • Binding: Hardcover
  • 288 pages

Editorial Reviews

Review
Neurosurgery has met its Boswell in Henry Marsh. Painfully honest about the mistakes that can ‘wreck’ a brain, exquisitely attuned to the tense and transient bond between doctor and patient, and hilariously impatient of hospital management, Marsh draws us deep into medicine’s most difficult art and lifts our spirits. It’s a superb achievement. (Ian McEwan)
His love for brain surgery and his patients shines through, but the specialty–shrouded in secrecy and mystique when he entered it–has now firmly had the rug pulled out from under it. We should thank Henry Marsh for that. (The Times)
When a book opens like this: ‘I often have to cut into the brain and it is something I hate doing’ – you can’t let it go, you have to read on, don’t you? Brain surgery, that’s the most remote thing for me, I don’t know anything about it, and as it is with everything I’m ignorant of, I trust completely the skills of those who practice it, and tend to forget the human element, which is failures, misunderstandings, mistakes, luck and bad luck, but also the non-professional, everyday life that they have. Do No Harm: Stories of Life, Death and Brain Surgery by Henry Marsh reveals all of this, in the midst of life-threatening situations, and that’s one reason to read it; true honesty in an unexpected place. But there are plenty of others – for instance, the mechanical, material side of being, that we also are wire and strings that can be fixed, not unlike cars and washing machines, really. (Karl Ove Knausgaard, Financial Times)
Marsh, one of our leading neurosurgeons, is an eloquent and poetic writer. Do No Harm offers a rare behind-the-scenes look at the most mysterious part of human life. His descriptions of neurosurgery are at once fascinating and illuminating; a gripping memoir of an extraordinary career. (Daniel J. Levitin, PhD, author of The Organized Mind and This Is Your Brain On Music)
Do No Harm is a penetrating, in-the-trenches look at the life of a modern day neurosurgeon. With rare and unflinching honesty, Henry Marsh describes not only the soaring triumphs but the shattering tragedies that are so much a part of every surgeon’s life. A remarkable achievement. (Michael J. Collins, author of Hot Lights, Cold Steel)
A soul-baring account of a practical-minded neurosurgeon who does not suffer fools or believe in souls, who favors ‘statistical outlier’ over ‘miracle,’ and who admits that a surgeon’s ultimate achievement is marked by patients who ‘recover completely and forget us completely.’ Readers, however, will not soon forget Dr. Marsh. (Katrina Firlik, author of Another Day in the Frontal Lobe: A Brain Surgeon Exposes Life on the Inside)
Do No Harm is a fascinating look into the reality of life as a neurosurgeon. The personal patient stories are gripping, providing the public with an incredibly candid look into the imperfections and perfections of a dedicated neurosurgeon. In Do No Harm, Dr. Marsh takes the reader into deep into a world of life, death, and everything in between. Despite it all, Dr. Marsh’s commitment to his patients and his profession never wavers. You will not be able to put this book down. (Paul Ruggieri M.D., surgeon and author of Confessions of a Surgeon and The Cost of Cutting)
Do No Harm dares to reveal the raw and tender humanity behind brain surgery. Each story invites readers into the private thoughts of a neurosurgeon and astonishes them with the counterintuitive compassion required in the operating room. (Michael Paul Mason, author of Head Cases)
The outstanding feature of Do No Harm is the author’s completely candid description of the highs and lows of a neurosurgical career. … For its unusual and admirable candor, wisdom and humor, Do No Harm is a smashing good read from which the most experienced and the most junior neurosurgeons have much to learn. (AANS Neurosurgeon)
This thoughtful doctor provides a highly personal and fascinating look inside the elite world of neurosurgery, appraising both its amazing successes as well as its sobering failures. (Publishers Weekly (Starred Review))
One of the best books ever about a life in medicine, Do No Harm boldly and gracefully exposes the vulnerability and painful privilege of being a physician. (Booklist (starred review))
Henry Marsh peels back the meninges to reveal the glistening, harrowing, and utterly compelling world of neurosurgery. Top-notch medical writing. (Danielle Ofri, MD, PhD, author of What Doctors Feel: How Emotions Affect the Practice of Medicine)
The Knausgaard of neurosurgery. … Marsh writes like a novelist. (The New Yorker)
Riveting. … [Marsh] gives us an extraordinarily intimate, compassionate and sometimes frightening understanding of his vocation. (The New York Times)
About the Author
Henry Marsh studied medicine at the Royal Free Hospital in London, became a Fellow of the Royal College of Surgeons in 1984, and was appointed Consultant Neurosurgeon at Atkinson Morley’s/St George’s Hospital in London in 1987. He has been the subject of two major documentary films, Your Life in Their Hands,which won the Royal Television Society Gold Medal, and The English Surgeon, which won an Emmy. He is married to the anthropologist and writer Kate Fox.