Central Nervous System Cancer Research Articles

Abstract LB084: High cardiovascular disease mortality after central nervous system tumor diagnosis: Evidence from UK and USA population-based study

Abstract Background Accumulating data show cardiovascular disease (CVD) is a major cause of death in many cancer patients supporting cardio-oncology epidemiology and clinical studies. Although rare, patients diagnosed with brain and central nervous system (CNS) tumours have significant morbidity and mortality. Whether CVD is a major cause of death and if this differs by malignancy has not been comprehensively assessed. Methods We aimed to examine the risk of CVD mortality in patients diagnosed with malignant and non-malignant CNS tumours using cancer registry data in the UK and US. Analyses were conducted using Wales Cancer Registry, UK (Secure Anonymised Information Linkage, SAIL) for 8,743 patients diagnosed from 2000-2015 (54.9% of which died); and the US National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) for 188,526 patients diagnosed from 2005-2015 (40.0% of which died). Standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were calculated for CVD cause of death (heart disease, cerebrovascular disease, hypertension, atherosclerosis, and aortic aneurysm/dissection) and adjusted for age, sex and calendar year compared to all Welsh and US residents. SMRs were stratified by tumour types (malignant and non-malignant tumours) and main histologic types (glioma and meningioma). Results CVD is the second major cause of death for CNS tumour patients in SAIL and SEER (9.5% & 12.1%, respectively). Patients with malignant and non-malignant CNS tumours had excess CVD mortality compared with the general population (SAIL SMR=2.64, 95% CI=2.39-2.90, SEER SMR=1.38, 95% CI=1.35-1.42). Patients were more likely to die of CVD compared to the general population regardless of whether they were diagnosed with non-malignant meningiomas subtypes (SAIL SMR=3.13, 95%CI=2.73-3.57; SEER SMR=1.36, 95%CI=1.32-1.40) or malignant gliomas (SAIL SMR=2.08, 95%CI=1.46-2.88; SEER SMR=2.21, 95%CI=2.05-2.38). Patients diagnosed younger than 50 years of age had excess risk from CVD mortality compared to general population than those diagnosed at older ages (SAIL SMR=4.58, 95%CI=2.38-7.84, SEER SMR 2.03-95%CI=1.79-2.03). Patients had greater risk of CVD mortality within the first year after CNS tumour diagnosis in both SAIL and SEER (SMR=2.98, 95% CI=2.39-3.66 & SMR=2.14 95%CI=2.03-2.25, respectively). Conclusion CVD mortality is high among patients diagnosed with CNS tumours compared to general population. Cross national datasets for different histologic types of CNS tumours could help define high risk groups that may be targeted for future prevention and clinical studies to clarify the aetiology of CVD among CNS cancer patients. Citation Format: KAI JIN, Paul Brennan, Michael Poon, Cathie Sudlow, Jonine FIGUEROA. High cardiovascular disease mortality after central nervous system tumor diagnosis: Evidence from UK and USA population-based study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB084.

Income and Education Inequalities in Brain and Central Nervous System Cancer Incidence in Canada: Trends over Two Decades.

The socioeconomic gradient of brain and central nervous system (CNS) cancer incidence in Canada is poorly understood. This study aimed to measure socioeconomic inequalities in brain and CNS cancer incidence in Canada from 1992 to 2010. Using a unique census division level dataset (n = 280) pooled from the Canadian Cancer Registry (CCR), the Canadian Census of Population and the National Household Survey, we measured brain and CNS cancer incidence in Canada. The age-adjusted concentration index (C) was used to measure income- and education-related inequalities in brain and CNS cancers in Canada, and for men and women, separately. Time trend analyses were conducted to examine the changes in socioeconomic inequalities in brain and CNS cancers in Canada over time. The results indicated that the crude brain and CNS cancer incidence increased from 7.29 to 8.17 per 100,000 (annual percentage change: 0.70) over the study period. The age-adjusted C results suggested that the brain and CNS cancer incidence was not generally significantly different for census division of different income and educational levels. There was insufficient evidence to support changes in income and education-related inequalities over time. Since the incidence of brain and CNS cancers in Canada showed no significant association with socioeconomic status, future cancer control programs should focus on other risk factors for this cancer subset.

Parenthood among men diagnosed with cancer in childhood and early adulthood: trends over time in a Danish national cohort

Abstract STUDY QUESTION Is the rate of fatherhood among men diagnosed with cancer in childhood and early adulthood different from men without cancer, and, if so, have the differences changed over time? SUMMARY ANSWER Men diagnosed with cancer have had significantly reduced rates of fatherhood compared with undiagnosed men; however, the rates of fatherhood among the cancer survivors have increased markedly over time. WHAT IS KNOWN ALREADY The number of children and young adolescents who survive cancer has steadily increased over recent decades, with a current 5-year survival rate of approximately 80%. Consequently, life circumstances after cancer have gained increasing importance, including the desire among survivors to have children and a family. ARTs to aid reproduction among cancer survivors have been developed, and fertility preservation is increasingly a topic being discussed before undergoing cancer treatment. But the potential for fertility preservation differs dependent on age at diagnosis and type of cancer. Earlier studies have shown a decreased fertility rate among survivors of child and adolescent cancer compared to those diagnosed in early adulthood. STUDY DESIGN, SIZE, DURATION This study is a national, register-based cohort study. Men diagnosed with cancer in childhood and early adulthood (<30 years of age) were registered in the Danish Cancer Register in 1978–2016 (n = 9353). According to the time of diagnosis, each cancer-diagnosed man was randomly matched with 150 undiagnosed men from the background population within the same birth year. The men were followed until having their first child, death, migration or the end of the study (31 December 2017) in medical registers and socio-demographic population registers. PARTICIPANTS/MATERIALS, SETTING, METHODS Fatherhood among the boys and young men diagnosed with cancer were compared with the age-matched comparison group in all statistical analyses. Cancer diagnoses were categorised as central nervous system (CNS) cancers, haematological cancers or solid cancers. Analyses were stratified by age at diagnosis (0–9, 10–19, 20–29 years) and time of diagnosis (1978–1989, 1990–1999, 2000–2009, 2010–2016). Death was incorporated as a competing risk in all analyses. MAIN RESULTS AND THE ROLE OF CHANCE The study population consisted of 9353 boys and young men diagnosed with cancer between 1978 and 2016 and 1 386 493 men in the age-matched comparison group. Those surviving CNS cancer as young men had the lowest hazard ratio (HR) of fatherhood compared with the age-matched comparison group (HR 0.67, 95% CI 0.57–0.79), followed by survivors of haematological cancers (HR 0.90, 95% CI 0.81–1.01), while the highest chance of fatherhood was among survivors of solid cancers (HR 1.16, 95% CI 1.12–1.20) with a slightly increased HR compared with undiagnosed males. The HR of becoming a father increased over time. From the first decade to the last decade 30 years later, the HR of becoming a father increased for solid tumours (HR 0.78, 95% CI 0.73–0.83 to HR 1.08, 95% CI 0.95–1.22), haematological cancers (HR 0.64, 95% CI 0.53–0.79 to HR 0.97, 95% CI 0.73–1.30) and CNS cancers (HR 0.44, 95% CI 0.34–0.57 to HR 0.98, 95% CI 0.49–1.95) compared to the age-matched comparison group. Also, when compared with the age-matched comparison group, men diagnosed with cancer when aged 20–29 years were more likely became fathers over the time of the study (HR 0.80, 95% CI 0.74–0.86 to HR 1.08, 95% CI 0.96–1.22). LIMITATIONS, REASONS FOR CAUTION The study was based on register data, and information was not available about the men’s fertility potential, whether they had a desire to have children and whether it was possible for them to find a partner. Information about fertility preservation, e.g. sperm freezing, could also have provided additional insights. Furthermore, information about diagnosis and ART treatment would have been beneficial. WIDER IMPLICATIONS OF THE FINDINGS Information and education of male patients diagnosed with cancer about fertility preservation options and their chances to create their own family is crucial. Reassuringly, time trends showed more men with a previous cancer diagnosis becoming fathers in recent years than in earlier years, reflecting that survival and fertility preservation have improved over time. STUDY FUNDING/COMPETING INTEREST(S) R.S. received a PhD grant from the Rosa Ebba Hansen Foundation and from the Health Foundation (J.nr. 15-B-0095). The funding for the establishment of the DANAC II Cohort was obtained from the Rosa Ebba Hansen Foundation. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A.

Cryopreservation of sperm before gonadotoxic treatment at the University Hospital Brno in the years 1995-2020

Sperm cryopreservation before gonadotoxic treatment is the basic and mos teffective method of preserving reproduction, which can be used during adolescence. The communication summarizes 26 years of experience in the operation of an oncological sperm bank, analyzes spermiograms of oncological patients, assesses the relationship between sperm pathology and diagnosis, and determines the number of deaths and the use of frozen sperm. During the existence of CAR 01 (assisted reproduction center), more than 50,000 spermiograms were performed. From January 1995 to December 2020, a total of 24,729 men were examined within the sperm bank, of which 1,448 (5.9%) had an oncological diagnosis. The spermiograms were evaluated according to current WHO (World Health Organization) manuals. Cryopreservation of sperm has undergone a major development. The rules for the storage of frozen cells have been laid down by Act No. 296/2008 Coll. since 2008. In 2019, the methodology „Cryopreservation of reproductive cells and tissues in patients before cancer treatment“ was updated. In all cases, the standard thawing technique was used. The sperms were processed by the swim-up method. As part of the treatment with assisted reproduction methods, oocytes were fertilized by the ICSI (intracytoplasmatic sperm injection) micromanipulation technique. Out of 1,448 examined spermiograms in men with oncological diagnoses, testicular cancer was present in 43.7% of patients and malignant diseases of lymphatic and hematopoietic tissue were found in 24.1%, of which 70,1% included Hodgkin‘s lymphomas and 29,9% were non-Hodgkin‘s lymphomas. Leukemia was found in 7.9%, bone and cartilage cancers in 6.8%. The age of the clients of the whole group ranged from 13 to 64 years (27.2 ± 6.8 years). A total of 38.3% of men had normozoospermia, 54.2% of spermiograms showed pathological findings in 1 to 3 evaluated parameters and 7.5% of patients had azoospermia. Severe asthenozoospermia (mobility ≤ 10%) was detected in 57.2% of men and severe oligozoospermia (concentration ≤ 1 × 106 mm3) in 22.3% of patients. The lowest values of the spermiogram were found in men with testicular cancer; the best values were seen in CNS (central nervous system) cancers. The cryopreservation of sperm was performed in 1,340 cases (92.5%). So far, a total of 160 men (11.9%) have used frozen sperm, of which 6.2% in our center. In these 83 cases, the ICSI technique was always used, 38 clinical pregnancies (45.8%) and 32 births were achieved. We have registered 424 completed storages of semen (31.6%), of which 148 (11.0% of all oncology patients) were made due to death and the others at patients’ request. Using the sperm of the dead is a specific issue. In cancer patients, sperm pathologies occur in high percentage. The lowest spermiogram values were found in men with testicular cancer. It is necessary to take into account long-term storage and fertilization by micromanipulation methods. The number of men who die is significantly higher than the number of those who use sperm to treat infertility. Cryopreservation of sperm should be offered to each patient prior to the therapy leading to the destruction of spermatogenesis.

SMARCB1 deletion in atypical teratoid rhabdoid tumors results in human endogenous retrovirus K (HML-2) expression

Atypical Teratoid Rhabdoid Tumor (AT/RT) is a rare pediatric central nervous system cancer often characterized by deletion or mutation of SMARCB1, a tumor suppressor gene. In this study, we found that SMARCB1 regulates Human Endogenous Retrovirus K (HERV-K, subtype HML-2) expression. HML-2 is a repetitive element scattered throughout the human genome, encoding several intact viral proteins that have been associated with stem cell maintenance and tumorigenesis. We found HML-2 env expression in both the intracellular and extracellular compartments in all AT/RT cell lines (n = 4) and in 95% of AT/RT patient tissues (n = 37) evaluated. SMARCB1 knock-down in neural stem cells (NSCs) led to an upregulation of HML-2 transcription. We found that SMARCB1 binds adjacent to the HML-2 promoter, repressing its transcription via chromatin immunoprecipitation; restoration of SMARCB1 expression in AT/RT cell lines significantly downregulated HML-2 expression. Further, targeted downregulation of HML-2 transcription via CRISPR-dCas9 coupled with suppressor proteins led to cellular dispersion, decreased proliferation, and cell death in vitro. HML-2 knock-down with shRNA, siRNA, and CRISPR-dCas9 significantly decreased Ras expression as measured by qRT-PCR, suggesting that HML-2 modulates MAPK/ERK signaling in AT/RT cells. Overexpression of NRAS was sufficient to restore cellular proliferation, and MYC, a transcription factor downstream of NRAS, was bound to the HERV-K LTR significantly more in the absence of SMARCB1 expression in AT/RT cells. We show a mechanism by which these undifferentiated tumors remain pluripotent, and we demonstrate that their formation is aided by aberrant HML-2 activation, which is dependent on SMARCB1 and its interaction with MYC.

Impact of Ecklonia maxima Seaweed Extract and Mo Foliar Treatments on Biofortification, Spinach Yield, Quality and NUE.

Seaweed extract (SE) application is a contemporary and sustainable agricultural practice used to improve yield and quality of vegetable crops. Plant biofortification with trace element is recognized as a major tool to prevent mineral malnourishment in humans. Mo deficiency causes numerous dysfunctions, mostly connected to central nervous system and esophageal cancer. The current research was accomplished to appraise the combined effect of Ecklonia maxima brown seaweed extract (SE) and Mo dose (0, 0.5, 2, 4 or 8 µmol L−1) on yield, biometric traits, minerals, nutritional and functional parameters, as well as nitrogen indices of spinach plants grown in a protected environment (tunnel). Head fresh weight (FW), ascorbic acid, polyphenols, N, P, K, Mg and nitrogen use efficiency (NUE) were positively associated with SE treatment. Moreover, head FW, head height (H), stem diameter (SD), ascorbic acid, polyphenols, carotenoids as well as NUE indices were enhanced by Mo-biofortification. A noticeable improvement in number of leaves (N. leaves), head dry matter (DM) and Mo concentration in leaf tissues was observed when SE application was combined with a Mo dosage of 4 or 8 µmol L−1. Overall, our study highlighted that E. maxima SE treatment and Mo supply can improve both spinach production and quality via the key enzyme activity involved in the phytochemical homeostasis of SE and the plant nutritional status modification resulting in an enhanced spinach Mo tolerance.

EMBR-29. PEDIATRIC MEDULLOBLASTOMA PATIENT WITH MULTIPLE MIDLINE DEFECTS, A CASE REPORT

Abstract Medulloblastoma (MB) is the most common malignant central nervous system (CNS) cancer diagnosed in childhood and is divided into four subtypes: WNT-activated, SHH-activated, Group 3 (Non-WNT, Non-SHH), and Group 4 (Non-WNT, Non-SHH). Non-WNT/Non-SHH make up roughly two-thirds of MB and have the least understood pathogenesis with substantial intratumoral heterogeneity. Therapeutic targets and treatment strategies for Group 3 and 4 patients therefore remain unclear. In this report we present a 16-year-old patient with standard risk Group 4 medulloblastoma and multiple midline defects. The patient’s medical history was remarkable for a cleft lip (which healed in utero), a notable heart murmur, an inguinal hernia repair at 3 months of age, and significant pectus excavatum. This patient was diagnosed at age 12 with a MB. Tumor cells were negative for GAB-1, p53 stain was positive for approximately 1–2% of tumor cells, no evidence on monosomy 6, MYC or MYCN amplification. The family history is significant for paternal biliary cancer. The patient was treated as per ACNS0331 and is approximately 36 months off-therapy. This case presents an interesting instance of a CNS tumor arising within the microenvironment of wide-spread dysregulated development. Single cases do not provide any substantiative evidence. However, they do give insight on factors which may drive oncogenesis and may provide an indication as to whether we should continue to pursue targeted therapy for Group 3/4 uniformly or move towards personalized therapy strategies in this group patients.

ATRT-07. DEFINING LOST AND GAINED TRANSCRIPTIONAL REGULATORY NETWORKS IN ATYPICAL TERATOID RHABDOID TUMOR

Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system cancer of infancy and early childhood that may occur anywhere along the neuraxis and is associated with a high rate of mortality. While contemporary multimodal therapeutic approaches have significantly improved overall survival, targeted therapy remains elusive, and treatment is often associated with significant morbidity. ATRT is unique in its genomic stability, with the only recurrent genetic abnormality being bi-allelic loss of the SMARCB1 gene, which encodes a core subunit of the BAF chromatin remodeling complex. The epigenetic mechanisms by which SMARCB1 loss leads to tumorigenesis are not yet well-defined and addressing this gap in understanding is necessary for creating efficacious, targeted therapeutics. To better understand the epigenetic features gained and lost in ATRT, we re-expressed SMARCB1 in a library of patient-derived and established ATRT cell lines of multiple molecular subtypes. SMARCB1 restoration significantly reduced or eliminated the proliferative and clonogenic capacity of each cell line. We performed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) and RNA sequencing (RNA-Seq) to define putative transcriptional regulatory networks that are gained and lost in ATRT. SMARCB1 restoration was associated with global changes in chromatin openness consistent with the creation of new regulatory elements throughout the genome, and these were associated with induction of a diverse developmental transcriptional signature. Motif enrichment analysis of regions with increased accessibility defined a small but consistent number of centrally enriched transcription factor motifs across cell lines indicative of putative pioneer factors whose functions may be lost in ATRT. Pertinent chromatin immunoprecipitation with sequencing (ChIP-Seq) data will be discussed in the context of lost and gained transcriptional regulatory networks in ATRT and normal cellular development.

Drug Delivery Nanosystems in Glioblastoma Multiforme Treatment: Current State of the Art.

Glioblastoma multiforme (GBM) is the most common primary malignant Central Nervous System cancer, responsible for about 4% of all deaths associated with neoplasia, characterized as one of the fatal human cancers. Tumor resection does not possess curative character, thereby radio and/or chemotherapy are often necessary for the treatment of GBM. However, drugs used in GBM chemotherapy present some limitations, such as side effects associated with non-specific drug biodistribution as well as limited bioavailability, which limits their clinical use. To attenuate the systemic toxicity and overcome the poor bioavailability, a very attractive approach is drug encapsulation in drug delivery nanosystems. The main focus of this review is to explore the actual cancer global problem, enunciate barriers to overcome in the pharmacological treatment of GBM, as well as the most updated drug delivery nanosystems for GBM treatment and how they influence biopharmaceutical properties of anti-GBM drugs. The discussion will approach lipid-based and polymeric nanosystems, as well as inorganic nanoparticles, regarding their technical aspects as well as biological effects in GBM treatment. Furthermore, the current state of the art, challenges to overcome and future perspectives in GBM treatment will be discussed.

AMOTL2‑knockdown promotes the proliferation, migration and invasion of glioma by regulating β‑catenin nuclear localization.

Glioblastoma multiforme (GBM) is the most prevalent type of malignant cancer in the adult central nervous system; however, its mechanism remains unclear. Angiomotin-like 2 (AMOTL2) is a member of the motin family of angiostatin-binding proteins. It has been reported as an oncogene in cervical and breast cancer, but its association with glioma remains unknown. The aim of the present study was to investigate AMOTL2-regulated processes in glioma cell lines using extensive in vitro assays and certain bioinformatics tools. These results revealed that AMOTL2 was downregulated in high-grade glioma cells and tissues, with patients with glioma exhibiting a high AMOTL2 expression having a higher survival rate. The results of the glioma cell phenotype experiment showed that AMOTL2 suppressed GBM proliferation, migration and invasion. In addition, immunoblotting, co-immunoprecipitation and immunofluorescence assays demonstrated that AMOTL2 could directly bind to β-catenin protein, the key molecule of the Wnt signaling pathway, and regulate its downstream genes by regulating β-catenin nuclear translocation. In conclusion, the present study demonstrated that AMOTL2 inhibited glioma proliferation, migration and invasion by regulating β-catenin nuclear localization. Thus, AMOTL2 may serve as a therapeutic target to further improve the prognosis and prolong survival time of patients with glioma.

Profiling 523 cancer associated genes in circulating tumor DNA of children with CNS tumors.

3023 Background: Pediatric central nervous system (CNS) cancers often pose unique challenges including tumor ‘invisibility’, where surgical resection is restricted due to the sensitive tumor location and tissue biopsy is not always feasible. Detecting cancer associated mutations and copy number variations (CNV) at diagnosis is increasingly important, as the WHO classification of pediatric CNS cancers has incorporated molecular signatures with tumor grade. To achieve CNS tumor molecular ‘visibility’, we previously established a liquid biopsy platform for detecting single nucleotide variants in circulating tumor DNA (ctDNA). However, our method was limited by the restricted number of genes that can be monitored and the inability to detect genomic events including CNVs. To address this, we developed a deep sequencing liquid biopsy approach to profile alterations across selected genes. Our platform provides an opportunity for multi-gene monitoring, to assess tumor subclonal evolution and response to treatment in the absence of repeat tissue biopsies. Methods: We tested the performance of our platform using paired tissue, CSF, and plasma/serum from 10 children with diffuse midline glioma (DMG). ctDNA was analyzed using the TruSight Oncology 500 (TSO500) ctDNA targeted panel covering 523 genes. Matched tumor, CSF, and blood were assessed for concordance and sequencing results were compared to digital droplet PCR (ddPCR) detection of H3K27M mutation. Results: The median exons with ³500X coverage was 96% for 7 CSF samples with optimal input (³60ng), 0.01% for 3 CSF samples with < 5ng input, and 74.5% for plasma/serum samples. ctDNA was more readily detectable in CSF, yet concordance between paired tumor, CSF and plasma/serum was observed. DMG associated mutations in genes including H3F3A, HIST1H3B, TP53, and ACVR1 were detected in ctDNA. Of 9 H3K27M mutations identified in tumor, 8 were present in CSF and 3 in plasma/serum, for a positive percent agreement of 89% and 33%, respectively, with the tumor results. Among CSF samples, H3.3K27M was detected in 6/6 cases, and H3.1K27M in 2/3 cases, with variant allele frequencies comparable to ddPCR results. CNVs including PDGFRA/B and MDM4 amplifications were present in CSF and confirmed by analysis of paired tumor. Additional events, including PIK3CA p.E545Q, PPM1D truncation, and KRAS amplification, were detected in CSF but absent from paired tumor, indicating tissue heterogeneity. Strategies to optimize ctDNA detection, including optimization of ctDNA isolation and adjustment of library QC metrics, were identified. Conclusions: This proof-of-concept study demonstrates the feasibility of our high depth, targeted sequencing approach for detecting clinically relevant mutations in ctDNA from children with CNS tumors. This approach may aid in diagnosis of CNS tumor molecular subtype, and monitoring of tumor evolution and response to therapy in serially collected ctDNA.

Mental health needs among parents of children with cancer: A commercial claims data analysis.

e18722 Background: Caring for a child diagnosed with cancer may adversely affect mental health (MH) of parents. However, little is known about MH care needs among parents of pediatric cancer patients. This study examined the patterns of MH care for parents of children diagnosed with cancer, as compared to parents of children without cancer. Methods: We used MarketScan® Commercial Database to identify continuously-insured parents of children receiving therapy for leukemia, lymphoma, central nervous system, bone, or gonadal cancers (aged ≤21 years at diagnosis) in 2009-2017. We also identified parents who matched eligibility criteria but had no child with cancer (with a randomly-assigned, fictitious date of cancer diagnosis) as controls. Outcomes included parents’ visits related to a MH disorder (anxiety, depression, substance use disorder [SUD], post-traumatic stress disorder [PTSD]) during six months before to 12 months after their child’s cancer diagnosis. Multivariable regressions were estimated to compare MH visits between 9,870 parents of pediatric cancer patients and 3,396,097 parents in the control group, adjusting for sociodemographic factors (parents’ age and sex, rurality, region, number of children in household) and presence of MH history. Among parents of pediatric cancer patients, we explored sociodemographic factors, MH history, and clinical factors (children’s cancer types, age at diagnosis, therapeutic modalities) associated with MH-related visits in multivariable regression analyses. Results: While the likelihood of MH history was similar between the two groups, a higher proportion of parents caring for cancer patients than controls had any visits related to anxiety (13.1%% vs. 9.5%), depression (9.6% vs. 7.5%), PTSD (0.5% vs. 0.4%), or any MH disorders (22.0% vs. 17.6%). These differences persisted in adjusted analyses. For example, parents of cancer patients were 24%, 37%, and 27% ( p-values < 0.001) more likely than controls to have any MH visits, anxiety-related visits, and depression-related visits, respectively. No difference was observed in SUD-related visits. Among MH care utilizers, no significant difference was observed in the number of MH visits. Among parents of cancer patients, those with MH history, mothers (vs. fathers), and parents of children with bone cancer (vs. leukemia) were more likely to have any MH visits ( p-values < 0.05). Parents whose children received surgery only and those with ≥3 children in household were less likely to have any MH visits ( p-values < 0.05). Conclusions: Parents of pediatric cancer patients have significantly higher needs for MH care as compared to the general parent population. Our finding underlines the importance of future interventions toward targeted MH counseling and supportive strategies for vulnerable parent groups, such as mothers and those caring for children undergoing more complex treatment plans.

Anti-PD-L1 treatment to enhance the response of glioblastoma to radiation and produce long-term survival in mice.

e14048 Background: Glioblastoma (GBM) is the most aggressive and most common primary central nervous system cancer in adults. Blocking the interaction between Programmed Cell Death Protein-1 (PD-1) and its ligand (PD-L1) has shown remarkable success in the treatment of several cancers. However, many challenges remain in improving the efficacy of using monoclonal antibodies (Ab) against the receptor PD-1 in GBM, mainly due to the “non-immunogenic” tumor characteristics of GBM. PD-L1 has been found to be overexpressed on the surface of human GBM tumor cells and tumor-associated macrophages (TAM). Radiotherapy (RT), as one of the standard therapy of GBM, could alter the tumor microenvironment and promote an antitumor immune response. We hypothesize that anti-PD-L1 therapy can enhance the RT effects and improve the outcome of treatment when combined. Methods: Using a preclinical orthotropic syngeneic CT-2A mouse GBM tumor model, we studied the efficacy of combined therapy with anti-PD-L1 and RT. Mice were stratified into four treatment groups: control, RT, anti-PD-L1 Ab, and anti-PD-L1 Ab plus RT. RT(8 Gy) was given one time simultaneously with the first dose of anti-PD-L1, followed by systemic anti-PD-L1 maintenance treatment to the mice. Overall survival and tumor growth were monitored. Immunohistochemistry on resected tumors during treatment was performed to characterize the immune response. Single-cell RNA sequencing (scRNA-seq) was also performed to further study the immunologic parameters in the mouse brain. Results: Our results showed that anti-PD-L1 Ab in combination with RT provided a remarkable antitumor immune response and improved overall survival, with 25.5, 34, and 30 days of median survival in control (no-treatment), RT, and anti-PD-L1 groups, respectively, and achieving long-term survival and complete tumor response in 80% of the mice in the anti-PD-L1+RT treatment group (median survival not reached) in GBM tumor-bearing mice. The combined therapy promoted the recruitment of tumor-infiltrating immune cells, reversed the hostile tumor immune environment with a higher M1/TAM ratio, CD8+ /CD4+ T cell ratio, and CD8+ T cell /Treg cell ratio in the tumor area comparing with those parameters in single modality treatment groups. Furthermore, scRNA-seq data demonstrated that anti-PD-L1 combined with RT resulted in robust higher CD8 effector T cells, while lower CD4 and CD8 exhausted T cells in the tumor region compared to other groups. Increased CD4 central memory T cells and CD8 central memory T cells were seen only in tumors treated with anti-PD-L1+RT providing immunologic explanations on the durable control of GBM achieved only by the combined therapy. Conclusions: The anti-PD-L1 therapy synergizes with RT by reversing the hostile tumor immune environment resulting in improved tumor control and long-term survival in the syngeneic mouse GBM model.

Exposure to nitrate from drinking water and the risk of childhood cancer in Denmark

BackgroundThere is limited evidence that nitrate, a common contaminant in drinking water, increases the risk of childhood cancers. Our objective was to examine this association in Denmark. MethodsWe conducted a nationwide case-control study based on all singletons liveborn to Danish-born parents from 1991 to 2015 (N = 1,219,140) that included 596 leukemias, 180 lymphomas, and 310 central nervous system cancers (CNC) who were ≤15 years of age at diagnosis and were identified from the Danish Cancer Registry. Approximately 100 controls were randomly selected and matched to each case on date of birth and sex. Nitrate measurements in public water systems were linked with an address registry to estimate individual average nitrate concentrations during preconception, prenatal, and postnatal periods. Odd ratios (OR) and 95% confidence intervals (95%CI) were estimated using conditional logistic regression controlling for the matching variables, and birth order, birthweight, urbanicity, maternal education, employment, income and smoking, and parental age. ResultsThere was no evidence of an association of nitrate with leukemia or lymphoma. An association between CNC and the highest category of nitrate exposure (>25 mg/L nitrate) was observed for preconception (OR = 1.82, 95%CI:1.09 to 3.04), prenatal (OR = 1.65, 95%CI:0.97 to 2.81), and postnatal exposure (OR = 1.48, 95%CI:0.82 to 2.68) in fully adjusted models. There was also some evidence of an exposure–response in models of continuous nitrate exposure and CNC. ConclusionsOur findings provide some evidence that exposure to nitrate from drinking water may increase the risk of childhood CNC cancer, but not leukemia or lymphoma.

Antipsychotic drugs elicit cytotoxicity in glioblastoma multiforme in a calcium-dependent, non-D2 receptor-dependent, manner.

Dopamine D2‐like receptor antagonists have been suggested as being potential anticancer therapeutics with specific utility for central nervous system cancers due to their ability to cross the blood‐brain barrier. Despite a plethora of data reporting anticancer effects for D2R antagonists in cell or animal studies, the ligand concentrations or doses required to achieve such effects greatly exceed the levels known to cause high degrees of occupancy of the D2 receptor. To resolve this conundrum, we interrogated a panel of glioblastoma multiforme (GBM) cell lines using D2 antagonists of varying chemotype. We studied the cytotoxic effects of these compounds, and also ascertained the expression of D2 receptors (D2R) on these cells. Although several chemotypes of D2R antagonists, including phenothiazines and phenylbutylpiperidines, were effective against GBM cell line cultures, the highly selective antagonist remoxipride had no anticancer activity at biologically relevant concentrations. Moreover the D2R antagonist‐induced cytotoxicity in monolayer cultures was independent of whether the cells expressed D2R. Instead, cytotoxicity was associated with a rapid, high‐magnitude calcium flux into the cytoplasm and mitochondria, which then induced depolarization and apoptosis. Blocking this flux protected the GBM cell lines U87MG, U251MG, and A172. Together, these data suggest that the cytotoxicity of these D2R antagonists involves calcium signaling mechanisms, not D2R antagonism. Repurposing of existing drugs should focus on the former, not latter, mechanism.

CtDNA-Based Liquid Biopsy of Cerebrospinal Fluid in Brain Cancer.

Simple SummaryThe optimal treatment and management of patients with brain cancer depend on the molecular characteristics of their tumour. Since the tumour changes with time, it is, therefore, essential to characterise the tumour of each patient at the exact time of selecting the most suitable therapeutic strategy. However, obtaining a tumour biopsy for its characterisation is a risky and invasive procedure and, sometimes, not even feasible, leading to a lack of information about the tumour. These challenges can be overcome by using a liquid biopsy of cerebrospinal fluid. Brain cancer cells release DNA into the cerebrospinal fluid, and the analysis of the cell-free circulating tumour DNA can reveal the genetic profile of brain cancer in a relatively noninvasive manner. In this review, we revise the recent results in this field that show how circulating tumour DNA in cerebrospinal fluid can provide diagnostic and prognostic information, identify potential therapeutic targets, monitor the tumour response or resistance to treatment, and help to identify tumour relapse.The correct characterisation of central nervous system (CNS) malignancies is crucial for accurate diagnosis and prognosis and also the identification of actionable genomic alterations that can guide the therapeutic strategy. Surgical biopsies are performed to characterise the tumour; however, these procedures are invasive and are not always feasible for all patients. Moreover, they only provide a static snapshot and can miss tumour heterogeneity. Currently, monitoring of CNS cancer is performed by conventional imaging techniques and, in some cases, cytology analysis of the cerebrospinal fluid (CSF); however, these techniques have limited sensitivity. To overcome these limitations, a liquid biopsy of the CSF can be used to obtain information about the tumour in a less invasive manner. The CSF is a source of cell-free circulating tumour DNA (ctDNA), and the analysis of this biomarker can characterise and monitor brain cancer. Recent studies have shown that ctDNA is more abundant in the CSF than plasma for CNS malignancies and that it can be sequenced to reveal tumour heterogeneity and provide diagnostic and prognostic information. Furthermore, analysis of longitudinal samples can aid patient monitoring by detecting residual disease or even tracking tumour evolution at relapse and, therefore, tailoring the therapeutic strategy. In this review, we provide an overview of the potential clinical applications of the analysis of CSF ctDNA and the challenges that need to be overcome in order to translate research findings into a tool for clinical practice.

A New Era of Neuro-Oncology Research Pioneered by Multi-Omics Analysis and Machine Learning

Although the incidence of central nervous system (CNS) cancers is not high, it significantly reduces a patient’s quality of life and results in high mortality rates. A low incidence also means a low number of cases, which in turn means a low amount of information. To compensate, researchers have tried to increase the amount of information available from a single test using high-throughput technologies. This approach, referred to as single-omics analysis, has only been partially successful as one type of data may not be able to appropriately describe all the characteristics of a tumor. It is presently unclear what type of data can describe a particular clinical situation. One way to solve this problem is to use multi-omics data. When using many types of data, a selected data type or a combination of them may effectively resolve a clinical question. Hence, we conducted a comprehensive survey of papers in the field of neuro-oncology that used multi-omics data for analysis and found that most of the papers utilized machine learning techniques. This fact shows that it is useful to utilize machine learning techniques in multi-omics analysis. In this review, we discuss the current status of multi-omics analysis in the field of neuro-oncology and the importance of using machine learning techniques.

Synthesis and Biological Screening of New Cyano-Substituted Pyrrole Fused (Iso)Quinoline Derivatives.

Several new cyano-substituted derivatives with pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinoline scaffolds were synthesized by the [3 + 2] cycloaddition of (iso)quinolinium ylides to fumaronitrile. The cycloimmonium ylides reacted in situ as 1,3-dipoles with fumaronitrile to selectively form distinct final compounds, depending on the structure of the (iso)quinolinium salt. Eleven compounds were evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compound 9a showed a broad spectrum of antiproliferative activity against cancer cell lines representing leukemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast and prostate cancer. In vitro assays and molecular docking revealed tubulin interaction properties of compound 9a.

MTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2',4'-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications.

BackgroundThe application of computational and multi-omics approaches has aided our understanding of carcinogenesis and the development of therapeutic strategies. NSC765598 is a novel small molecule derivative of salicylanilide. This study aims to investigate the ligand-protein interactions of NSC765598 with its potential targets and to evaluate its anticancer activities in vitro. MethodsWe used multi-computational tools and clinical databases, respectively, to identify the potential drug target for NSC765598 and analyze the genetic profile and prognostic relevance of the targets in multiple cancers. We evaluated the in vitro anticancer activities against the National Cancer Institute 60 (NCI60) human tumor cell lines and used molecular docking to study the ligand-protein interactions. Finally, we used the DTP-COMPARE algorithm to compare the NSC765598 anticancer fingerprints with NCI standard agents.ResultsWe identified mammalian target of rapamycin (mTOR)/epidermal growth factor receptor (EGFR)/inducible nitric oxide synthase (iNOS)/mitogen-activated protein 2 kinase 1 (MAP2K1)/fibroblast growth factor receptor (FGFR)/transforming growth factor-β1 (TGFB1) as potential targets for NSC765598. The targets were enriched in cancer-associated pathways, were overexpressed and were of prognostic relevance in multiple cancers. Among the identified targets, genetic alterations occurred most frequently in EGFR (7%), particularly in glioblastoma, esophageal squamous cell cancer, head and neck squamous cell cancer, and non–small-cell lung cancer, and were associated with poor prognoses and survival of patients, while other targets were less frequently altered. NSC765598 displayed selective antiproliferative and cytotoxic preferences for NSCLC (50% growth inhibition (GI50) = 1.12–3.95 µM; total growth inhibition (TGI) = 3.72–16.60 μM), leukemia (GI50 = 1.20–3.10 µM; TGI = 3.90–12.70 μM), melanoma (GI50 = 1.45–3.59 µM), and renal cancer (GI50 = 1.38–3.40 µM; TGI = 4.84–13.70 μM) cell lines, while panels of colon, breast, ovarian, prostate, and central nervous system (CNS) cancer cell lines were less sensitive to NSC765598. Interestingly, NSC765598 docked well into the binding cavity of the targets by conventional H-bonds, van der Waal forces, and a variety of π-interactions, with higher preferences for EGFR (ΔG = −11.0 kcal/mol), NOS2 (ΔG = −11.0 kcal/mol), and mTOR (ΔG = −8.8 kcal/mol). NSC765598 shares similar anti-cancer fingerprints with NCI standard agents displayed acceptable physicochemical values and met the criteria of drug-likeness.ConclusionNSC765598 displayed significant anticancer and potential multi-target properties, thus serve as a novel candidate worthy of further preclinical studies.

Medication-related harm and the newspapers - what has been communicated to the public in Ireland: A systematic content analysis

Abstract Introduction Reducing the global prevalence of severe, avoidable medication-related harm (MRH) by 50% by the end of 2022 is the WHO’s third global patient safety challenge [1]. MRH is reported frequently in the academic literature, with increasing age being a key risk factor. The WHO have highlighted the need to improve public health literacy and knowledge about medications. Little is known about the frequency and nature of Irish newspaper reports about MRH. This study sought to address this gap and to examine reporting during the calendar years 2019 and 2009. Methods In this mixed-methods study, LexisNexis® [2], an online newspaper archive database, was searched for newspaper articles reporting on MRH, published in the Republic of Ireland during the calendar years 2019 and 2009. The search strategy focussed on “medication” AND “harm” AND “patient”. Quantitative data extraction aimed to describe the frequency (by count of articles) of reporting of MRH and the nature by describing the publishing newspaper titles and the reported details of: drug class(es), demographics (age or life stage, gender) of those experiencing harm and the severity of harm. Qualitatively, a systematic content analysis, using inductive coding is ongoing and will be reported separately. Research ethics committee approval for this study is not required because this is an analysis of material in the public domain. Results In total, 7098 newspaper articles were identified through database searching for 2019 (n=3217) and 2009 (n=3881). To date, 54% (3867: n=3217, 45% 2019, n=650, 9% 2009) of these were screened, of which 63 newspaper articles (n=44 2019, n=19 2009) were included and quantitative data were extracted. Within these 63 articles, 71 cases of individual people experiencing MRH were reported (52 in 2019 and 19 in 2009). The newspapers most commonly reporting MRH were Irish Daily Mail (31/63: 27 in 2019 and 4 in 2009) and Irish Times (17/63:9 in 2019 and 8 in 2009). Drug classes most frequently reported as causing MRH were central nervous system drugs (antiepileptics n=10, opioid analgesics n=5, antidepressants n=9, and anxiolytics n=1), cancer chemotherapy (23 cases) and non-steroidal anti-inflammatories (n=3). MRH was reported as being fatal (13 /71:8 in 2019 and 5 in 2009) and non-fatal (58/71), with seven cases (5 in 2019 and 2 in 2009) of permanent harm. Among the 71 individual cases of MRH, the majority were adults aged 18–64 years (n=36), children (n=7), older adults (n=8), foetus (n=3) and newborn (n=1), while the remainder did not report the person’s age. Conclusion MRH is frequently reported to the public through Irish newspapers. The study is limited by focus on newsprint media with the exclusion of other forms of digital or social media and restriction to two calendar years in a single country, which likely stifles the generalisability of findings to other contexts. Future work could explore this issue across a wider range of media platforms and examine changes in reporting over time. The study findings may support an agenda to improve the general public's exposure to information and knowledge of MRH and medication safety.