The present study described for the first time stressor exposure for patients with glioblastoma at diagnosis and stress response in this population. A majority of patients did not report acute stress prior to diagnosis of glioblastoma nor a high level of stress. PFS and OS were similar in the different categories of stress response. The only factor that significantly and negatively affected PFS and OS in this study was the multifocal location.
Although stress represents an ambivalent response that can be beneficial in certain situations (concept of “fight or flight response”) , the association between stress and pathologies are numerous  and concern almost all medical specialties (depression , metabolic syndrome, coronary artery disease , psoriasis , inflammatory bowel disease  etc,). Most epidemiological studies affirm that the prolonged perception of a high level of stress remains associated with reduced physical and mental condition. [19,20] This data is consistent with our results which find the higher rate of depression in the “high stressors / high stress” category of patients.
After much fundamental and applied research, a physiological and molecular rationale has been described in the association between stress and cancer. The autonomic nervous system and the hypothalamic-pituitary-adrenal system are thought to be responsible for the majority of interactions between stress and cancer via the secretion of catecholamines and cortisol. [21–23] Inflammation and a decrease in immunoprotective functions induced by the secretion of cortisol and catecholamines could explain the mechanisms leading to tumour promotion and progression. [21,24] In several publications, stress-related psychosocial factors have been suggested to contribute to incidence of cancer, tumour progression and worst survival in cancer patients [9,25] but most studies have focused on high-incidence cancer (especially in breast cancer [26-28] ). Despite all the studies carried out, the stress-cancer association is currently not very robust. However, primary brain cancer incidence remains low (almost 20/100,000 person-years in France  ) and the risk factors for glioblastoma (brain radiation, genetic predisposition) are rarely found in medical practice. The multiple questions from patients about the origin of the disease, led us to carry out this study and, to our knowledge, this is the first study to assess the impact of stress on the emergence of glioblastomas.
To address this question, we selected patients with primary brain tumours at the time of diagnosis to break free from stress induced by cancer management. Due to the Covid-19 health crisis during 2020, several eligible patients could not be included in our study. Furthermore, the study did not include cognitive test evaluation especially for patients excluded due to advanced cognitive disorder, incompatible with filling in the questionnaire. Moreover, we choose glioblastoma with a wild-type IDH profile, an aggressive tumour recognized for its rapid growth and patient symptoms briefly preceding diagnosis. This choice made it possible to limit the risk of patients presenting symptom-induced stress directly through the slow and chronic evolution of infiltrative gliomas with IDH mutation.  The results of this study indicated a majority of men in the glioblastoma population with a median age of 66 years old and this data is almost identical to the characteristics found in the literature.  Both in our study and in the literature, MGMT promoter methylation was identified in 40% of cases.  Genetic susceptibility represents approximately 5% of glioblastomas  and a family history of brain tumours was found in 4 patients (6%) in our study but no details were available regarding the histological type. Cardiovascular risk factors or coronaropathy represented a majority (56%) of medical histories of patients and these pathologies are known for their high-prevalence in the stressed population. [6,32,33] The depression rate found in this study (30%) was a little bit higher than in the general population (20%)  and is probably explained by the cognitive impairment in the glioblastoma population. The interaction of beta-blockers with the adrenergic pathway involved in stress and depression has been the subject of many publications concerning their impact on these pathologies [35–38] and the proportion of patients treated with beta-blockers in our study seems similar to the proportion observed in the general population (20%).  Location of the tumour did not impact stress, especially frontal location that can induce hypersensitivity which can lead to organic depression and anosodiaphoria which can lead to emotional indifference. The frontal lobe is involved in several functions including emotional regulation and a large portion of the patients in this study (up to 61,5% in the high stressor / high stress category) had an extensive frontal lobe tumour. This could have made interpretation of the results more difficult, but no significant association was found between frontal location and stress level. In addition, these results are consistent because the frontal lobe represents the largest lobe of the brain and is one of the brain regions most affected by gliomas. 
Some studies have described a better quality of life in cases of minor hemisphere syndrome.  The dominant hemisphere could be defined for all patients, however in our study there did not appear to be a significant difference in stress between left and right hemisphere tumours. A large proportion of patients with recent diagnosis of glioblastoma reported no exposure to acute stress in the two years preceding the diagnosis. More than half of patients (56.3%) presented a "low stressor / low stress" profile and these results suggest an unlikely association between stress and glioblastoma incidence. It seems important to emphasize that the “low stressor / low stress” patients corresponded to the oldest patients (pensioners). The proportion of job strain found in this study is low and the publications about job strain do not find a significant increase in risk of cancer. [42,43] Among the patients who identified recent acute stress, the time between the traumatic event and the first symptom was 11 months. In this single-center study with a socioculturally homogeneous population, health problems, loss of a loved one or job strain were the main stressors and certain types of stressors may have been underestimated (financial, healthcare access, war, etc.). The results of the phase III EORTC-NCIC trial (STUPP protocol for high grade gliomas) published in 2004 found a median OS of 14.6 months and a median PFS of 6.9 months for patients treated with radiotherapy and Temodal.  In our study, tumour progression seemed to be greater (PFS at 6 months = 45.3%), probably explained by the presence of more serious patients, sometimes treated with Temodal alone or palliative care only. Tumour progression and overall survival do not seem to be influenced by the existence or intensity of the patient's stress. The multifocal nature of the tumour was the only characteristic that negatively impacted progression and survival in this study. Several biases and limitations are present in this single-center study with a small number of patients. An important limit is the absence of a control cohort and therefore the lack of possibility of calculating the hazard ratio on stress exposure. In addition, the retrospective and declarative nature of the questionnaires may overestimate the stress level in the context of recent diagnosis of cancer. On the other hand, talking about stress and cancer could tend to relativize patient stress in comparison to the diagnosis of cancer and then minimize the presence of real stress that might have been important in another context. The cognitive distortion after receiving the diagnosis and the cognitive impairment induced by the tumour are probably responsible for a significant recall bias. Despite the inter and intra individual variability of stress as well as the multiple methodological difficulties to objectively evaluate this qualitative variable , several evaluation scales have been described for stressors [45–47] and stress level  and the Cungi scale used in our study has been validated and recognized as a sensitive and reproducible scale.  The stress questionnaire completed by patients was developed in 1997 by the French psychiatrist Charly Cungi, specialist in cognitive and behavioral therapy, and author of numerous studies about stress. Thanks to the multiple dimensions explored as well as its sensitivity, reproducibility and reliability, this questionnaire constitutes a recognized and validated scale. Although some studies report a reduction in the risk of death from cancer, with no benefit in overall survival [21,49,50] the personalized and multimodal management of the stress of our patients remains essential in order to guarantee the best possible quality of life. The survival benefit of stress management as well as the stress impact on efficacy of immunotherapy are other avenues worth exploring.