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.

Tumors associated with Von Hippel-Lindau disease

Tumors associated with Von Hippel-Lindau disease

see Cerebellar hemangioblastoma associated with Von Hippel-Lindau disease.

see Spinal cord hemangioblastoma.

see Brainstem hemangioblastoma.

see Pheochromocytoma

see Endolymphatic sac tumor.

see Retinal hemangioblastoma.

see Renal cell carcinoma associated with Von Hippel-Lindau disease.

a) 50–70% of Von Hippel-Lindau disease patients have bilateral and multiple renal cysts

b) rarely cause profound renal impairment

c) chronic renal failure or renal hypertension not as common as with polycystic kidney disease

a) benign lesions that arise from the epididymal duct

b) found in 10–60% of male VHL patients

c) typically appear in the teenage years

d) may cause infertility if bilateral

e) may be multiple

Broad ligament cystadenomas

a) arise from the embryonic mesonephric duct

b) true incidence unknown

c) rarely reported and usually not recognized in women with VHL

Pancreatic neuroendocrine tumors and cysts

a) 35 to 70% of patients with VHL develop an endocrine tumor or cyst

b) pancreatic cysts are generally asymptomatic and often multiple

c) pancreatic neuroendocrine tumors are usually non-functional and 8% of them are malignant

d) differential diagnosis: pancreatic islet cell tumors, MEN2

Sinonasal renal cell-like adenocarcinoma is an emerging tumor associated with VHL syndrome and it is hoped that future studies shed light on the underlying biology of this unique tumor 1).


1)

Maharaj S, Seegobin K, Wakeman K, Chang S, Potts K, Williams B, Redman R. Sinonasal renal cell-like adenocarcinoma arising in von Hippel Lindau (VHL) syndrome. Oral Oncol. 2022 Jan 5;125:105705. doi: 10.1016/j.oraloncology.2021.105705. Epub ahead of print. PMID: 34998175

Cigarette smoking

Cigarette smoking

95 % of small-cell lung cancer arise in proximal airways, usually in mainstem or lobar brochii. Tipically younger (27-66 years) than other lung cancer. Strongly associated with cigarrete smoking

Cigarette smoke (CS) contains several carcinogens known to initiate and promote tumorigenesis and metastasis. Because various genes that mediate carcinogenesis and tumorigenesis are regulated by nuclear factor kappa-B (NF-kappaB), Anto et al., postulated that the effects of CS must be mediated through activation of this transcription factor 1).


Kamal et al. conducted a meta-analysis to address the outcomes in cancer patients after oncologic surgery during the COVID-19 pandemic. The primary endpoint was the COVID-19-related mortality rate. Higher body mass index was significantly and negatively associated with higher all-cause mortality and in-hospital COVID-19 infection rates. Male sex, preoperative respiratory disease, and smoking history were positively and significantly associated with increased all-cause mortality rates. Furthermore, male sex was positively and significantly associated with the COVID-19 infection rate 2).

Tobacco smoking is one of the most important risk factors for the formation of intracranial aneurysms and for aneurysmal subarachnoid hemorrhage3) 4) 5).

The prevalence of smoking in patients who have suffered from SAH is higher than that in general adult population 6) 7).

Smoking has also been suggested to contribute to the recurrence of aneurysms after endovascular coiling.

To improve the understanding of the impact of smoking on long-term outcomes after coil embolization of intracranial aneurysms, Brinjikji et al. studied a consecutive contemporary series of patients treated at their institution. The aims of this study were to determine whether smoking is an independent risk factor for aneurysm recurrence and retreatment after endovascular coiling.

All patients who had received an intrasaccular coil embolization of an intracranial aneurysm, who had undergone a follow-up imaging exam at least 6 months later, and whose smoking history had been recorded from January 2005 through December 2012 were included in this study. Patients were stratified according to smoking status into 3 groups: 1) never a smoker, 2) current smoker (smoked at the time of treatment), and 3) former smoker (quit smoking before treatment). The 2 primary outcomes studied were aneurysm recurrence and aneurysm retreatment after treatment for endovascular aneurysms. Kruskal-Wallis and chi-square tests were used to test statistical significance of differences in the rates of aneurysm recurrence, retreatment, or of both among the 3 groups. A multivariate logistic regression analysis controlling for smoking status and for several characteristics of the aneurysm was also performed.

In total, 384 patients with a combined total of 411 aneurysms were included in this study. The aneurysm recurrence rate was not significantly associated with smoking: both former smokers (OR 1.00, 95% CI 0.61-1.65; p = 0.99) and current smokers (OR 0.58, 95% CI 0.31-1.09; p = 0.09) had odds of recurrence that were similar to those who were never smokers. Former smokers (OR 0.78, 95% CI 0.46-1.35; p = 0.38) had odds of retreatment similar to those of never smokers, and current smokers had a lower odds of undergoing retreatment (OR 0.44, 95% CI 0.21-0.91; p = 0.03) than never smokers. Moreover, an analysis adjusting for aneurysm rupture, diameter, and initial occlusion showed that former smokers (OR 0.65, 95% CI 0.33-1.28; p = 0.21) and current smokers (OR 1.04, 95% CI 0.60-1.81; p = 0.88) had odds of aneurysm recurrence similar to those who were never smokers. Adjusting the analysis for aneurysm rupture, diameter, and occlusion showed that both former smokers (OR 0.49, 95% CI 0.23-1.05; p = 0.07) and current smokers (OR 0.82, 95% CI 0.46-1.46; p = 0.50) had odds of retreatment similar to those of patients who were never smokers.

The results show that smoking was not an independent risk factor for aneurysm recurrence and aneurysm retreatment among patients receiving endovascular treatment for intracranial aneurysms at the authors’ institution. Nonetheless, patients with intracranial aneurysms should continue to be counseled about the risks of tobacco smoking 8).

Tobacco use were not significantly associated with poor outcome after aneurysmal subarachnoid hemorrhage 9).

Previously established risk factors such as hypertension and smoking were identified as the most prevalent comorbidities, with disparity between subgroups, particularly women and African Americans 10).

The duration and timing of tobacco use, rather than the dose of tobacco per se, seem to be risk factors for delayed neurological deterioration after aneurysmal subarachnoid hemorrhage (aSAH). Although Krishnamurthy et al. did not find an association between tobacco use and overall clinical outcome after aneurysmal SAH, these results suggest that the distribution of various patterns of tobacco use within a given data set may influence the overall result 11).

Only 8 studies have investigated the incidence and epidemiology of aneurysmal subarachnoid hemorrhage (aSAH) in the United States. This is the first investigation in Indiana, which has some of the highest rates of tobacco smoking and obesity in the nation. The authors prospectively identified 441 consecutive patients with aSAH from 2005 to 2010 at 2 hospitals where the majority of cases are treated. Incidence calculations were based on US Census populations. Epidemiologic variables included demography; risk factors; Hunt and Hess scale; Fisher grade; number, location, and size of aneurysms; treatment type; and complications. Overall incidence was 21.8 per 100,000 population. Incidence was higher in women, increased with age, and did not vary by race. One third to half of patients were hypertensive and/or smoked cigarettes at the time of ictus. Variations by count were partially explained by Health Factor and Morbidity Rankings. Complications varied by treatment. These findings deviate from estimates that 6-16 per 100,000 people in the United States will develop aSAH and are double the incidence in a Minnesota population between 1945 and 1974. The results also deviate from the worldwide estimate of 9.0 aSAHs per 100,000 person-years. The predictive value of variations in Health Factor and Morbidity Rankings implicates the importance of future research on multivariate biopsychosocial causation of aSAH 12).

Very low birth weight (VLBW) infants (< 1500 gm), cocaine-exposed infants were at increased risk of intraventricular hemorrhage, were more likely to be placed outside maternal care, and had higher incidences of cognitive and motor delays at follow-up. Cocaine-using women were also more likely to use other drugs, especially alcohol, marijuana, and tobacco 13).

In a analysis, intraventricular hemorrhage and tobacco use were associated with symptomatic vasospasm 14).

Tobacco use and a history of diabetes mellitus were associated with vasospasm 15).

CT-evident SAH, left ventricular hypertrophy (LVH), cigarette smoking, and hypertension are associated with vasospasm. In smokers or hypertensive patients, premorbid LVH appears to predict much more severe vasospasm 16).

Cocaine users were younger than control, and were more likely to smoke tobacco, drink alcohol, and have renal dysfunction 17).

Smoking is a modest risk factor for lumbar radicular pain and clinically verified sciatica. Smoking cessation appears to reduce, but not entirely eliminate, the excess risk 18)

Microdecompression for lumbar spinal stenosis

There are limited scientific data on the impact of smoking on patient-reported outcomes following minimally invasive spine surgery.

Nonsmokers experienced a significantly larger improvement at 1 year following microdecompression for LSS compared to smokers. Smokers were less likely to achieve a minimal clinically important difference. However, it should be emphasized that considerable improvement also was found among smokers 19).

Lumbar disc herniation

Considering sex, smoking and heavy works as predictors of recurrent lumbar disc herniation (LDH), surgeons should advice their patients to limit hard work and put away smoking especially in tall and male ones to prevent LDH recurrence 20).

Smoking was the strongest predictor of reoperation in patients who had undergone single level laminectomy, multilevel laminectomy, or reoperation for progression of spinal degeneration. These findings suggest that smokers have worse outcomes of lumbar decompression than nonsmokers 21).

In postlaminectomy pseudomeningocele a retrospective analyses of six cases was made including: clinical signs and symptoms, radiological findings, and possible therapeutic modalities.

In every case, there was a palpable fluctuating mass under the surgical scarsensory loss in both low extremity, and limited leg raising; moreover, heel tapping produced pain. Also, every patient had a history of long standing cigarette smoking and multiple spinal surgeries. Radiologically dural saccular or tubular structures were noted at myelograms, magnetic resonance imaging, or computed axial tomography scan, usually at the site of the surgery. In one patient with metallic devices, diagnosis was made by ultrasound 22).

Compensation claims and smoking had very significant adverse impacts on both employment and pain results despite high fusion rates, particularly in patients under the age of 55 years 23).

Cotinine, a main metabolite of nicotine, has harmful effects on SCI via GFAP and CNP expression. The findings of the present study support the hypothesis that tobacco causes neuronal degeneration via cotinine 24).

Exposure of nonsmoking pregnant women to environmental tobacco smoke (ETS) is associated with a number of adverse perinatal outcomes including lower birthweight, smaller head circumference and stillbirth, as well as shorter birth length. This information is important for women, their families and healthcare providers, and reinforces the continued need for increased public policy and education on prevention of exposure to ETS 25).

Effects of cigarette smoking on clopidogrel


1)

Anto RJ, Mukhopadhyay A, Shishodia S, Gairola CG, Aggarwal BB. Cigarette smoke condensate activates nuclear transcription factor-kappaB through phosphorylation and degradation of IkappaB(alpha): correlation with induction of cyclooxygenase-2. Carcinogenesis. 2002 Sep;23(9):1511-8. PubMed PMID: 12189195.
2)

Kamal M, Baudo M, Shmushkevich S, Geng Y, Hanna E, Goepfert RP, Lewis CM, Rahouma M. COVID-19 infection and its consequences among surgical oncology patients: A systematic analysis, meta-analysis and meta-regression. J Surg Oncol. 2022 Jan 11. doi: 10.1002/jso.26787. Epub ahead of print. PMID: 35014703.
3) , 6)

Juvela S, Porras M, Poussa K: Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. J Neurosurg 93:379-387,2000
4)

Juvela S, Poussa K ,Porras M: Factors affecting formation and growth of intracranial aneurysms: A long term follow-up study. Stroke 32:485-491,2001
5) , 7)

Ruigrok YM, Buskens E, Rinkel GJE: Attributable risk of common and rare determinants of subarachnoid hemorrhage. Stroke 32: 1173-1175,2001
8)

Brinjikji W, Lingineni RK, Gu CN, Lanzino G, Cloft HJ, Ulsh L, Koeller K, Kallmes DF. Smoking is not associated with recurrence and retreatment of intracranial aneurysms after endovascular coiling. J Neurosurg. 2015 Jan;122(1):95-100. doi: 10.3171/2014.10.JNS141035. PubMed PMID: 25380112.
9)

Moon K, Albuquerque FC, Mitkov M, Ducruet AF, Wilson DA, Crowley RW, Nakaji P, McDougall CG. Methamphetamine use is an independent predictor of poor outcome after aneurysmal subarachnoid hemorrhage. J Neurointerv Surg. 2014 Apr 29. doi: 10.1136/neurintsurg-2014-011161. [Epub ahead of print] PubMed PMID: 24780822.
10)

Larrew T, Pryor W 3rd, Weinberg J, Webb S, Battenhouse H, Turk AS, Chaudry I, Spiotta A, Turner R. Aneurysmal subarachnoid hemorrhage: a statewide assessment of outcome based on risk factors, aneurysm characteristics, and geo-demography. J Neurointerv Surg. 2014 Sep 8. pii: neurintsurg-2014-011359. doi: 10.1136/neurintsurg-2014-011359. [Epub ahead of print] PubMed PMID: 25200246.
11)

Krishnamurthy S, Kelleher JP, Lehman EB, Cockroft KM. Effects of tobacco dose and length of exposure on delayed neurological deterioration and overall clinical outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2007 Sep;61(3):475-80; discussion 480-1. PubMed PMID: 17881958.
12)

Ziemba-Davis M, Bohnstedt BN, Payner TD, Leipzig TJ, Palmer E, Cohen-Gadol AA. Incidence, epidemiology, and treatment of aneurysmal subarachnoid hemorrhage in 12 midwest communities. J Stroke Cerebrovasc Dis. 2014 May-Jun;23(5):1073-82. doi: 10.1016/j.jstrokecerebrovasdis.2013.09.010. Epub 2013 Oct 19. PubMed PMID: 24144595.
13)

Singer LT, Yamashita TS, Hawkins S, Cairns D, Baley J, Kliegman R. Increased incidence of intraventricular hemorrhage and developmental delay in cocaine-exposed, very low birth weight infants. J Pediatr. 1994 May;124(5 Pt 1):765-71. PubMed PMID: 7513757; PubMed Central PMCID: PMC4181569.
14)

Wilson TJ, Stetler WR Jr, Davis MC, Giles DA, Khan A, Chaudhary N, Gemmete JJ, Xi G, Thompson BG, Pandey AS. Intraventricular Hemorrhage Is Associated with Early Hydrocephalus, Symptomatic Vasospasm, and Poor Outcome in Aneurysmal Subarachnoid Hemorrhage. J Neurol Surg A Cent Eur Neurosurg. 2014 Dec 29. [Epub ahlow birth weight (VLBW) infants (< 1500 gm), cocaine-exposed infants were at increased risk of intraventricular hemorrhage, were more likely to be placed outside maternal care, and had higher incidences of cognitive and motor delays at follow-up. Cocaine-using women were also more likely to use other drugs, especially alcohol, marijuana, and tobacco ((Singer LT, Yamashita TS, Hawkins S, Cairns D, Baley J, Kliegman R. Increased incidence of intraventricular hemorrhage and developmental delay in cocaine-exposed, very low birth weight infants. J Pediatr. 1994 May;124(5 Pt 1):765-71. PubMed PMID: 7513757; PubMed Central PMCID: PMC4181569.
15)

Kilbourn KJ, Levy S, Staff I, Kureshi I, McCullough L. Clinical characteristics and outcomes of neurogenic stress cadiomyopathy in aneurysmal subarachnoid hemorrhage. Clin Neurol Neurosurg. 2013 Jul;115(7):909-14. doi: 10.1016/j.clineuro.2012.09.006. Epub 2012 Sep 26. PubMed PMID: 23021080.
16)

Inagawa T, Yahara K, Ohbayashi N. Risk factors associated with cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Neurol Med Chir (Tokyo). 2014 Jun 17;54(6):465-73. Epub 2014 Mar 27. PubMed PMID: 24670311.
17)

Alaraj A, Wallace A, Mander N, Aletich V, Charbel FT, Amin-Hanjani S. Effect of acute cocaine use on vasospasm and outcome in aneurysmal subarachnoid hemorrhage. World Neurosurg. 2010 Apr;73(4):357-60. doi: 10.1016/j.wneu.2010.01.011. PubMed PMID: 20849793.
18)

Shiri R, Falah-Hassani K. The Effect of Smoking on the Risk of Sciatica: A Meta-analysis. Am J Med. 2016 Jan;129(1):64-73.e20. doi: 10.1016/j.amjmed.2015.07.041. Epub 2015 Sep 25. PubMed PMID: 26403480.
19)

Gulati S, Nordseth T, Nerland US, Gulati M, Weber C, Giannadakis C, Nygaard ØP, Solberg TK, Solheim O, Jakola AS. Does daily tobacco smoking affect outcomes after microdecompression for degenerative central lumbar spinal stenosis? – A multicenter observational registry-based study. Acta Neurochir (Wien). 2015 May 6. [Epub ahead of print] PubMed PMID: 25943982.
20)

Shimia M, Babaei-Ghazani A, Sadat BE, Habibi B, Habibzadeh A. Risk factors of recurrent lumbar disk herniation. Asian J Neurosurg. 2013 Apr;8(2):93-6. doi: 10.4103/1793-5482.116384. PubMed PMID: 24049552; PubMed Central PMCID: PMC3775189.
21)

Bydon M, Macki M, De la Garza-Ramos R, Sciubba DM, Wolinsky JP, Gokaslan ZL, Witham TF, Bydon A. Smoking as an independent predictor of reoperation after lumbar laminectomy: a study of 500 cases. J Neurosurg Spine. 2015 Jan 2:1-6. [Epub ahead of print] PubMed PMID: 25555058.
22)

Aldrete JA, Ghaly R. Postlaminectomy pseudomeningocele. An unsuspected cause of low back pain. Reg Anesth. 1995 Jan-Feb;20(1):75-9. PubMed PMID: 7727333.
23)

Schnee CL, Freese A, Ansell LV. Outcome analysis for adults with spondylolisthesis treated with posterolateral fusion and transpedicular screw fixation. J Neurosurg. 1997 Jan;86(1):56-63. PubMed PMID: 8988082.
24)

Dalgic A, Okay O, Helvacioglu F, Daglioglu E, Akdag R, Take G, Belen D. Tobacco-induced neuronal degeneration via cotinine in rats subjected to experimental spinal cord injury. J Neurol Surg A Cent Eur Neurosurg. 2013 May;74(3):136-45. doi: 10.1055/s-0033-1337607. Epub 2013 Mar 19. PubMed PMID: 23512588.
25)

Crane JM, Keough M, Murphy P, Burrage L, Hutchens D. Effects of environmental tobacco smoke on perinatal outcomes: a retrospective cohort study. BJOG. 2011 Jun;118(7):865-71. doi: 10.1111/j.1471-0528.2011.02941.x. Epub 2011 Mar 23. PubMed PMID: 21426481.
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