Immune cell profiles of tumor and regional lymph nodes in surgically treated non-small cell lung cancer

In recent years, improved understanding of the interaction between cancer and the immune system has led to the introduction of various immunotherapy approaches, all harnessing the power of the immune system to impede tumor development, growth and spread. The immune system is a vastly complex network and response to a foreign antigen must be launched in a coordinated fashion both locally as well as systemically. In the case of NSCLC, this requires a response in the lung tissue surrounding the tumor as well as the regional lymph nodes. Most previous studies that attempted to characterize this response were limited by investigating only tumor or lymph nodes, and those who investigated both did not include tumor-free lymph nodes. To tackle these caveats, I have composed a diverse cohort of surgically-treated NSCLC patients containing both long- and short-term survivors. I investigated morphological features in tumor and matched tumor-bearing and non-tumor bearing lymph nodes and analyzed their association with survival. I then used these results to inform transcriptomic analyses of these tissues to determine how morphological changes were reflected on a molecular level. In this thesis, I showed that tumor-infiltrating lymphocytes and macrophages are key components of the immune response in the primary tumor and non-tumor bearing lymph nodes. The importance of lymphocytes in immune mediated tumor control is further corroborated by an association between CD4 expression in non-tumor bearing lymph nodes and survival. Based on these results, immune transcriptomics showed a negative impact of immune dysfunction measured by Tumor Immune Dysfunction and Exclusion (TIDE) score on patient survival. When comparing patients with high levels to patients with low levels of immune dysfunction, CD8 expression was significantly higher in patients with lower levels of immune dysfunction. A more in depth analysis explored the relation of the expression of multiple immune cell exhaustion markers and survival. Among these, TIM-3 and PD-L1 were identified as the only markers to be associated with survival in more than one tissue. Overall, this work presented an integrative approach to assessing immune composition and dysfunction. Levels of immune cell exhaustion markers may indicate a dysfunctional immune status and can predict survival after curative surgery in NSCLC. This work provides the basis for further investigation of the clinical relevance of immune cell exhaustion in early-stage NSCLC

Systemic inflammation and pro-inflammatory cytokine profile predict response to checkpoint inhibitor treatment in NSCLC: a prospective study

Treatment with single agent immune checkpoint inhibitors (ICIs) has tremendously changed second line therapy in NSCLC. However, there are still no reliable biomarkers predicting response and survival in this group of patients. PD-L1 revealed to be a correlating, but no perfect marker. Therefore, we sought to investigate in this prospective study, whether inflammation status and cytokine profile could serve as additional biomarkers guiding treatment decision for single agent ICIs in NSCLC. 29 stage IV NSCLC patients receiving single agent PD-1 checkpoint-inhibitor in second line were prospectively enrolled. Inflammatory scores and cytokine profiles (IL-6, IL-8, IL-10, IFN-γ and TNFα) have been obtained before treatment and at the time of the first staging. Cytokine profiles were correlated with response and survival. Patients with signs of pre-therapeutic inflammation (elevated, NLR, SII, IL-6, IL-8) showed significantly lower response to ICI treatment and reduced PFS. Contrary, elevated levels of IFN-γ revealed to characterize a subgroup of patients, who significantly benefits from ICI treatment. Furthermore, low systemic inflammation and high levels of IFN-γ characterized patients with long term-response to ICI treatment. Pre-therapeutic assessment of inflammation and cytokine profiles has the ability to predict response and survival in NSCLC patients treated with single agent ICIs

Intracranial manifestations in neurofibromatosis 1

Introduction: Gliomas in the brain and the optic pathway affect up to 20% of all children with neurofibromatosis 1 (NF1); however, their frequency and natural history in adults is poorly described. Our objectives were to characterize the frequency and natural history of gliomas seen in NF1 patients by serial head magnetic resonance imaging (MRI) and to investigate associations between combined annotation-dependent depletion (CADD) scores and the presence of MRI features of NF1. Methods: 1775 head and whole-body MRI scans of 562 unselected NF1 patients were collected at the University Hospital Hamburg-Eppendorf in Hamburg, Germany. All scans were analyzed, and the frequency and natural history of gliomas was determined. In addition, the constitutional disease-causing variants of the NF1 gene in 283 patients were annotated with CADD scores, and genotype-phenotype correlations were performed. Results: Between 1 and 12 MRI scans were collected for each patient; the median length of follow-up was 3.7 years. We found the prevalence of non-optic gliomas to be 4.3%, with a median age at glioma diagnosis at 21.2 years. The prevalence of optic pathway gliomas (OPGs) was 9.3%, with a median age at diagnosis at 12.1 years. We determined the rates of appearance, progression and regression of both of these tumour types. We found that individual CADD scores were associated with the presence of plexiform neurofibromas (but not with the presence of UBOs or optic gliomas) in NF1 patients in whom the pathogenic mutation had been identified. Conclusion: The frequencies of gliomas in the brain and optic pathway is higher in adults with NF1 than previously reported. NF1 patients with constitutional mutations associated with high CADD scores appear to be at higher risk to develop plexiform neurofibromas than other NF1 patients.Medicine, Faculty ofMedical Genetics, Department ofGraduat

Consequences of the COVID-19 pandemic on lung cancer care and patient health in a German lung cancer center: results from a cross-sectional questionnaire

Background The novel coronavirus SARS-CoV-2 has caused a global COVID-19 pandemic, leading to worldwide changes in public health measures. In addition to changes in the public sector (lockdowns, contact restrictions), hospitals modified care to minimize risk of infection and to mobilize resources for COVID-19 patients. Our study aimed to assess the impact of these measures on access to care and behaviour of patients with thoracic malignancies. Methods Thoracic oncology patients were surveyed in October 2020 using paper-based questionnaires to assess access to ambulatory care services and tumor-directed therapy during the COVID-19 pandemic. Additionally, behaviour regarding social distancing and wearing of face masks were assessed, as well as COVID-19 exposure, testing and vaccination. Results are presented as absolute and relative frequencies for categorical variables and means with standard deviation for numerical variables. We used t-test, and ANOVA to compare differences in metric variables and Chi 2 -test to compare proportions between groups. Results 93 of 245 (38%) patients surveyed completed the questionnaire. Respiration therapy and physical therapy were unavailable for 57% to 70% of patients during March/April. Appointments for tumor-directed therapy, tumor imaging, and follow-up care were postponed or cancelled for 18.9%, 13.6%, and 14.8% of patients, respectively. Patients reported their general health as mostly unaffected. The majority of patients surveyed did not report reducing their contacts with family. The majority reduced contact with friends. Most patients wore community masks, although a significant proportion reported respiratory difficulties during prolonged mask-wearing. 74 patients (80%) reported willingness to be vaccinated against SARS-CoV-2. Conclusions This survey provides insights into the patient experience during the second wave of the COVID-19 pandemic in Munich, Germany. Most patients reported no negative changes to cancer treatments or general health; however, allied health services were greatly impacted. Patients reported gaps in social distancing, but were prepared to wear community masks. The willingness to get vaccinated against SARS-CoV-2 was high. This information is not only of high relevance to policy makers, but also to health care providers

Markers of Immune Cell Exhaustion as Predictor of Survival in Surgically-Treated Early-Stage NSCLC

Background: Tumor tissue as well as regional lymph nodes are removed during curative surgery for early-stage non-small cell lung cancer (NSCLC). These tissues provide a unique snapshot of the immune cell composition at the time of surgery. We investigated the immune landscape in matched tumor tissue, tumor bearing (tb) and non-tumor bearing (ntb) N1 as well as N2 lymph nodes (LNs) in patients with NSCLC and its relation to survival. Methods: Internal hospital databases were screened for surgically treated NSCLC patients for whom tumor tissue, tbLNs as well as N1 and N2 ntbLNs were available. Clinical as well as demographic data were extracted from hospital records. Expression profiling of 770 immune-related genes was performed using the PanCancer IO 360 panel by NanoString Technologies. Results: We identified 190 surgically treated patients of whom 16 fulfilled inclusion criteria and had sufficient archived tissue. The Tumor Immune Dysfunction and Exclusion (TIDE) score in N1 tumor-free lymph nodes was associated with OS. TIM-3 expression was inversely correlated with TIDE scores in affected LNs, N1 and N2 ntbLNs. Levels of CD8 expression were significantly higher in TIDE High compared to TIDE Low patients. TIM-3 and PD-L1 were selected for the final model for OS in multivariate regression in more than one tissue. Conclusion: Levels of immune cell exhaustion markers may indicate a dysfunctional immune status and are associated with survival after curative surgery in NSCLC

Changes in Behavior After Vaccination and Opinions Toward Mask Wearing: Thoracic Oncology Patient-Reported Experiences During the COVID-19 Pandemic

BACKGROUND: The COVID-19 vaccines, face masks, and social distancing are effective interventions to prevent SARS-CoV-2 infections. In this study, we aimed to determine lung cancer patients' attitudes toward vaccination, changes in behavior after vaccination, and willingness to continue mask wearing after the pandemic. METHODS: We sent out questionnaires to 220 thoracic oncology patients treated at our lung cancer center in May 2021. The questionnaire focused on patients' vaccination status, self-reported experiences surrounding vaccination, and assessed changes in behaviors before and after vaccination as well as opinions toward mask wearing after the pandemic. Results are presented as absolute and relative frequencies and means with standard deviation and compared using t test. paired t test, and analysis of variance test as well as chit test. and Fisher exact text. RESULTS: About 91.0% of patients reported having received at least 1 vaccination. About 73.3% of patients reported having at least 1 reaction to the vaccination. The most common reactions were pain at the injection site, fatigue, and headache. After vaccination, patients increased contact with family and friends, use of public transport. and grocery shopping. Overall, the level of willingness to wear masks beyond the end of the pandemic differed according to vaccination status. CONCLUSIONS: Acceptance of the COVID-19 vaccination among thoracic oncology patients in Germany was high. Overall. patients with thoracic malignancies tolerated the COVID-19 vaccination well. Rate of adverse reaction was not higher compared with the general population. After the vaccination, patients increased social contacts and usage of public transport. These changes suggest positive psychological effects on quality of life. While reducing social distancing can increase the risk of infection, our results indicate that an extension of mask mandates after the pandemic would likely be accepted by a majority of thoracic oncology patients, suggesting that our cohort was still aware and in support of other measure of protection

Serial MRIs provide novel insight into natural history of optic pathway gliomas in patients with neurofibromatosis 1

Background: Optic pathway gliomas (OPGs) are present in 20% of children with neurofibromatosis 1 (NF1) but are less frequently observed in adults. Our goal was to determine the natural history of OPGs in children and adults with NF1. Results: We analyzed the features of OPGs and other intracranial lesions on 1775 head MRI scans of 562 unselected adults and children with NF1 collected between 2003 and 2015. 52 (9.3%) of 562 patients in this study had an OPG diagnosed on their MRI. The median age at first scan with an OPG present was 12.7 years. Of the 52 OPG patients, the intraorbital optic nerves were affected in 29 patients (56%), the prechiasmatic optic nerves were affected in 32 patients (62%), the optic chiasm was affected in 17 patients (33%) and the optic radiations were affected in 19 patients (37%). 29 patients had two or more areas affected. One patient had a newly-appearing OPG, and 1 patient showed progression. The rate of progression over 5 years was 2.4% (95% CI: 0.4% to 16%). Four patients showed partial regression of their OPGs, but we observed no case of complete regression during this study. The rate of regression over 5 years was 8.9% (95% confidence intervals: 2.8% to 26%). We found the presence of UBOs and the presence of OPGs in individual patients to be highly associated (p = 0.0061). Conclusion: OPGs are more common in older adults with NF1 than previously thought. The occurrences of unidentified bright objects (UBOs) and asymptomatic OPGs are associated with each other. This suggests the possibility that OPGs that remain asymptomatic may differ pathogenically from those that become symptomatic.Medicine, Faculty ofOther UBCNon UBCMedical Genetics, Department ofRadiology, Department ofReviewedFacult

Non-optic glioma in adults and children with neurofibromatosis 1

Background: Non-optic gliomas occur in 5% of children with NF1, but little is known about these tumours in adults. We aimed to investigate progression, spontaneous regression and the natural history of non-optic gliomas in adults and compare these findings to the results found in children. Results One thousand seven hundred twenty-two brain MRI scans of 562 unselected individuals with NF1 were collected at the NF outpatient department of the University Hospital Hamburg-Eppendorf between 2003 and 2015. The number of scans per patient ranged from one to 12; patients were followed for a median of 3.7 years. We identified 24 patients (4.3%) with non-optic gliomas. Median age at first scan with glioma was 21.2 years, much higher than in previous publications. Only seven of the 24 non-optic glioma patients were symptomatic. Five of 24 patients had multiple non-optic gliomas. Four individuals developed a new tumour, and 4 cases showed progression. The risk of new tumour development was 0.19% (95% confidence interval 0.06% to 0.52%) per patient year of follow-up for patients over 10 years. The rate of progressing non-optic gliomas per patient year of follow-up in the first 5 years after tumour diagnosis was 4.7% (95% confidence interval 1.5% to 12%). Conclusions Non-optic gliomas are twice as common in an unselected cohort of NF1 patients as previously reported. This is likely due to increased frequency of diagnosis of asymptomatic tumours when routine MRIs are performed and a higher prevalence in older individuals.Medicine, Faculty ofOther UBCNon UBCMedical Genetics, Department ofReviewedFacult

Additional file 1: of Serial MRIs provide novel insight into natural history of optic pathway gliomas in patients with neurofibromatosis 1

Table S1. Overview of all 35 asymptomatic OPG patients. OPG location indicates extent after shrinkage in patients with regression or extent after growth in patients with progression of the tumour. None of the asymptomatic patients received any treatment for their OPGs. (DOCX 16 kb

Additional file 3: of Serial MRIs provide novel insight into natural history of optic pathway gliomas in patients with neurofibromatosis 1

Table S3. Published cases of spontaneous regression of symptomatic and asymptomatic OPG in NF1 patients. (XLSX 9 kb