Central Nervous System Cancer Research Articles

T lymphocytes as dynamic regulators of glioma pathobiology.

The brain tumor microenvironment contains numerous distinct types of nonneoplastic cells, which each serve a diverse set of roles relevant to the formation, maintenance, and progression of these central nervous system cancers. While varying in frequencies, monocytes (macrophages, microglia, and myeloid-derived suppressor cells), dendritic cells, natural killer cells, and T lymphocytes represent the most common nonneoplastic cellular constituents in low- and high-grade gliomas (astrocytomas). Although T cells are conventionally thought to target and eliminate neoplastic cells, T cells also exist in other states, characterized by tolerance, ignorance, anergy, and exhaustion. In addition, T cells can function as drivers of brain cancer growth, especially in low-grade gliomas. Since T cells originate in the blood and bone marrow sinuses, their capacity to function as both positive and negative regulators of glioma growth has ignited renewed interest in their deployment as immunotherapeutic agents. In this review, we discuss the roles of T cells in low- and high-grade glioma formation and progression, as well as the potential uses of modified T lymphocytes for brain cancer therapeutics.

Polo-like kinases as potential targets and PLK2 as a novel biomarker for the prognosis of human glioblastoma.

The most prevalent malignant central nervous system (CNS) cancer is glioblastoma multiforme (GBM). PLKs (polo-like kinases) are a kind of serine-threonine kinase that modulate DNA replication, mitosis, and stress responses. PLKs in GBM need to be better studied and examined in terms of their expression, function, along with prognostic significance. Using an existing publicly available data set, we evaluated the expression level and prognostic relevance of PLKs in GBM patients at the molecular level. The biological processes along with cascades of the screened gene were predicted using the functional enrichment of Gene Set Enrichment Analysis, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathways. The data illustrated that PLK1/3/4 contents were greater in GBM tissues than in non-tumorous tissues, but PLK2/5 expression levels were lower. PLK2 expression was also linked to patient outcome in GBM. Our findings imply that PLKs might be useful molecular indicators as well as prospective treatment targets for GBM. A PLK2 inhibitor has been studied for the first time in a glioma cell in this work. In glioma cells, ON1231320 has anticancer effects. Finally, a summary of PLK inhibitors is presented, along with projections for future progress.

Advancements in Oncology with Artificial Intelligence-A Review Article.

Simple SummaryWith the advancement of artificial intelligence, including machine learning, the field of oncology has seen promising results in cancer detection and classification, epigenetics, drug discovery, and prognostication. In this review, we describe what artificial intelligence is and its function, as well as comprehensively summarize its evolution and role in breast, colorectal, and central nervous system cancers. Understanding the origin and current accomplishments might be essential to improve the quality, accuracy, generalizability, cost-effectiveness, and reliability of artificial intelligence models that can be used in worldwide clinical practice. Students and researchers in the medical field will benefit from a deeper understanding of how to use integrative AI in oncology for innovation and research.Well-trained machine learning (ML) and artificial intelligence (AI) systems can provide clinicians with therapeutic assistance, potentially increasing efficiency and improving efficacy. ML has demonstrated high accuracy in oncology-related diagnostic imaging, including screening mammography interpretation, colon polyp detection, glioma classification, and grading. By utilizing ML techniques, the manual steps of detecting and segmenting lesions are greatly reduced. ML-based tumor imaging analysis is independent of the experience level of evaluating physicians, and the results are expected to be more standardized and accurate. One of the biggest challenges is its generalizability worldwide. The current detection and screening methods for colon polyps and breast cancer have a vast amount of data, so they are ideal areas for studying the global standardization of artificial intelligence. Central nervous system cancers are rare and have poor prognoses based on current management standards. ML offers the prospect of unraveling undiscovered features from routinely acquired neuroimaging for improving treatment planning, prognostication, monitoring, and response assessment of CNS tumors such as gliomas. By studying AI in such rare cancer types, standard management methods may be improved by augmenting personalized/precision medicine. This review aims to provide clinicians and medical researchers with a basic understanding of how ML works and its role in oncology, especially in breast cancer, colorectal cancer, and primary and metastatic brain cancer. Understanding AI basics, current achievements, and future challenges are crucial in advancing the use of AI in oncology.

Incidence Trends of Cancer in Morocco: The Tale of the Oncological Center of Marrakech (Morocco) over 8 Years.

Background Determining cancer incidence and mortality is a key factor in the implementation of health policies and cancer prevention strategies. This report aims to describe the trends of cancer incidence in a single referral oncology department from the Marrakech region (Morocco). Material and Methods. All new cancer cases of age ≥ 15 years registered at the Medical Oncology department of Mohammed VI University Hospital of Marrakesh between January 1, 2012, and December 31, 2019, were included. Central nervous system (CNS) cancers, tumors of hematopoietic and lymphoid tissues, and thyroid cancers for which chemotherapy was not indicated or was managed in other cancer-specialized departments were excluded from the analysis. Manual data collection from printed archived medical records of the study population was performed. Descriptive statistics were analyzed using R software and Joinpoint Regression Program. Results A total of 15648 new cancer cases were analyzed. Missing data (n = 1822) accounted for 11.64%, and 4.1% (n = 652) were excluded. The final statistical analysis and registration included 13174 cases. The median age at diagnosis is 54 years for females and 61 years for males. Female patients outnumbered males with a ratio of 1.58 among all age groups except those aged ≥75 y. The age-standardized incidence rate (ASIR) for all sites was 68,0 per 100.000 person-years, which has increased with an annual percent change (APC) of 10.61%. The five most common malignancies among males are lung, stomach, prostate, colic, and rectal cancers. Among females, the five most frequent cancers are breast, cervix, ovary, colon, and stomach. Conclusion The higher incidence observed in our results translates into a growing burden on the center and is expected to impact our ability to deliver cancer care. Epidemiological studies to identify risk factors and effective efforts are needed to further invest in cancer control and prevention plans.

Geospatial Distribution of Age-Adjusted Incidence of the Three Major Types of Pediatric Cancers and Waterborne Agrichemicals in Nebraska.

This study was conducted to examine, at the county level, the relationship between pediatric cancer incidence rate and atrazine and nitrate mean concentrations in surface and groundwater. A negative binomial regression analysis was performed to investigate the association between central nervous system (CNS) tumors, leukemia, lymphoma, and atrazine and nitrate mean concentrations in groundwater. The age‐adjusted brain and other CNS cancer incidence was higher than the national average in 63% of the Nebraska counties. After controlling for the counties socio‐economic status and nitrate concentrations in groundwater, counties with groundwater atrazine concentrations above 0.0002 µg/L had a higher incidence rate for pediatric cancers (brain and other CNS, leukemia, and lymphoma) compared to counties with groundwater atrazine concentrations in the reference group (0.0000–0.0002 µg/L). Additionally, compared to counties with groundwater nitrate concentrations between 0 and 2 mg/L (reference group), counties with groundwater nitrate concentrations between 2.1 and 5 mg/L (group 2) had a higher incidence rate for pediatric brain and other CNS cancers (IRR = 8.39; 95% CI: 8.24–8.54), leukemia (IRR = 7.35; 95% CI: 7.22–7.48), and lymphoma (IRR = 5.59; CI: 5.48–5.69) after adjusting for atrazine groundwater concentration and the county socio‐economic status. While these findings do not indicate a causal relationship, because other contaminants or cancer risk factors have not been accounted for, they suggest that atrazine and nitrate may pose a risk relative to the genesis of pediatric brain and CNS cancers, leukemia, and lymphoma.

Abstract TMP97: The Burden Of Neurological Diseases In Asia - An Analysis For The Global Burden Of Disease Study 2019

Background: The global burden of diseases (GBD) of neurological disorders is increasing worldwide. The purpose of this study is to determine the burden of neurological disorders, including incidence, prevalence, death, disability-adjusted life-years (DALY), years lived with disability, and years of life lost between 1990 and 2019 in Asia regions. Methods: The GBD study is updated every year, and the most recent version provides the burden of diseases according to age, gender, and region from 1990 to 2019. Our study included 13 neurological diseases including stroke, Alzheimer's disease and other dementias, Parkinson's disease, brain and central nervous system cancer, idiopathic epilepsy, motor neuron disease, multiple sclerosis, migraine, tension-type headache, meningitis, encephalitis, tetanus, other neurological disorders. All rates were described as age-standardized using the GBD standard. Data were described using 95% uncertainty intervals (UIs) and changes from 1990 to 2019 as percent (95% UIs) provided by the GBD website. Results: In 2019, DALYs of neurological diseases were 64.4 million in South-East Asia (95% UI 45.2-94.2) and 85.0 million in Western pacific regions (95% UI 63.0-118.5). The three neurological diseases with the highest DALYs in WHO South-East Asia and WHO Western pacific regions in 2019 were stroke, migraine, Alzheimer's disease and other dementias. DALYs of stroke and Alzheimer's disease and other dementia, Parkinson’s disease, brain and central nervous system cancer, multiple sclerosis, migraine, and tension type headache increased in both regions in 2019 compared to 1990. Infectious diseases such as tetanus, meningitis, encephalitis decreased in both regions. The age-standardized rate of stroke incidence (-10%, 157 to 141 in South-East Asia, -12%, 211 to 186 in Western Pacific) and mortality (-30%, 135 to 95 in South-East Asia, -42%, 180 to 104 in Western Pacific) decreased markedly in both regions. Conclusion: This study demonstrated the burden of neurological diseases in Asia. To reduce the burden of neurological disease, a strategy suited to the reality of each country will be needed, and this study can serve as the cornerstone of the strategy.

Young Surgeons 4 Young Adults with Cancer (Y4Y): Understanding the surgical care & treatment strategies for patients with early-onset solid tumor cancers across the ESSO-EYSAC network

Background: Cancer morbidity and mortality among adolescents and young adults (AYA) have seen an alarming rise over the recent years. Authoritative guidelines defined AYA as patients within the age group of 15 to 39 years old. Leading cancer diagnoses differ across this bracket. Among the ages 15 to 24, highest incidence rates include hematologic, germ cell, thyroid, central nervous system, sarcoma and soft tissue cancers. Among the ages 25 to 39, breast, cervix, uterus, and colorectal were the leading diagnoses.

ADFIST: Adaptive Dynamic Fuzzy Inference System Tree Driven by Optimized Knowledge Base for Indoor Air Quality Assessment.

Air quality levels do not just affect climate change; rather, it leaves a significant impact on public health and wellbeing. Indoor air pollution is the major contributor to increased mortality and morbidity rates. This paper is focused on the assessment of indoor air quality based on several important pollutants (PM10, PM2.5, CO2, CO, tVOC, and NO2). These pollutants are responsible for potential health issues, including respiratory disease, central nervous system dysfunction, cardiovascular disease, and cancer. The pollutant concentrations were measured from a rural site in India using an Internet of Things-based sensor system. An Adaptive Dynamic Fuzzy Inference System Tree was implemented to process the field variables. The knowledge base for the proposed model was designed using a global optimization algorithm. However, the model was tuned using a local search algorithm to achieve enhanced prediction performance. The proposed model gives normalized root mean square error of 0.6679, 0.6218, 0.1077, 0.2585, 0.0667 and 0.0635 for PM10, PM2.5, CO2, CO, tVOC, and NO2, respectively. This approach was compared with the existing studies in the literature, and the approach was also validated against the online benchmark dataset.

Biomimetic nanoparticles directly remodel immunosuppressive microenvironment for boosting glioblastoma immunotherapy

Glioblastoma (GBM), as a very aggressive cancer of central nervous system, is very challenging to completely cure by the conventional combination of surgical resection with radiotherapy and chemotherapy. The success of emerging immunotherapy in hot tumors has attracted considerable interest for the treatment of GBM, but the unique tumor immunosuppressive microenvironment (TIME) of GBM leads to the failure of immunotherapy. Here, we show the significant improvement of the immunotherapy efficacy of GBM by modulating the TIME through novel all-in-one biomimetic nanoparticles (i.e. CS-I/J@CM NPs). The nanoparticles consist of utrasmall Cu2-xSe nanoparticles (NPs) with outstanding intrinsic properties (e.g., photo-responsive Fenton-like catalytic property for inducing immunogenic cell death (ICD) and alleviating the hypoxia of tumor), indoximod (IND, an inhibitor of indoleamine-2,3-dioxygenease in tumor), JQ1 (an inhibitor for reducing the expression of PD-L1 by tumor cells), and tumor cell membrane for improving the targeting capability and accumulation of nanoparticles in tumor. We reveal that these smart CS-I/J@CM NPs could drastically activate the immune responses through remodeling TIME of GBM by multiple functions. They could (1) increase M1-phenotype macrophages at tumor site by promoting the polarization of tumor-associated macrophages through the reactive oxygen species (ROS) and oxygen generated from the Fenton-like reaction between nanoparticles and H2O2 within tumor under NIR II irradiation; (2) decrease the infiltration of Tregs cells at tumor site through the release of IND; (3) decrease the expression of PD-L1 on tumor cells through JQ1. The notable increments of anti-tumor CD8+T cells in the tumor and memory T cells (TEM) in the spleen show excellent therapy efficacy and effectively prevent the recurrence of GBM after modulation of the TIME. This work demonstrates the modulation of TIME could be a significant strategy to improve the immunotherapy of GBM and other cold tumors.

Abstract PO-215: Racial disparities in proton beam therapy use for newly diagnosed cancer patients in the United States

Abstract Background: Black patients are less likely than White patients in the US to receive guideline-concordant cancer care, including radiation therapy. Proton Beam Therapy (PBT) is a potentially superior technology to photon radiotherapy for the treatment of pediatric cancers, where decreasing late effects of radiation treatment is a main concern, and in cancers where pituitary, visual, auditory, and intellectual functions might be disrupted because of radiation therapy. The aim of this study was to conduct a comprehensive evaluation of racial disparities in PBT use in the US. Methods: We identified 4,919,975 Black and White patients diagnosed between 2004 and 2018 in the National Cancer Database (NCDB) based on data collected from Commission on Cancer (CoC) accredited hospitals. Once a patient is diagnosed and/or treated at a CoC accredited facility, the patient is followed and all treatment is reported (including treatment received outside of the reporting facility). Therefore, NCDB captures PBT received both at CoC-accredited hospitals (59.5% of patients who received PBT in this study) and PBT received at hospitals not accredited by CoCs (40.5% of PBT patients in this study). American Society of Radiation Oncology (ASTRO) Model Policies were used to classify patients into Group 1, for which PBT is the recommended radiation therapy modality, and Group 2, for which evidence of PBT efficacy is still under investigation. Propensity score matching was used to ensure comparability of Black and White patients' clinical characteristics and regional availability of PBT. Results: Black cancer patients were less likely to be treated with PBT than White cancer patients with similar characteristics (Odds Ratios [OR]: 0.72; 95% Confidence Interval [CI]: 0.68, 0.76). Racial disparities were greater for Group 1 cancers (OR = 0.61; CI: 0.54, 0.69) than for Group 2 cancers (OR: 0.75; CI: 0.70, 0.81). Disparities were greatest for Group 1 cancers commonly diagnosed in children, such as central nervous system (OR: 0.54; CI: 0.46, 0.63) and rhabdomyosarcoma (OR: 0.47; CI: 0.31, 0.70). Racial disparities in PBT receipt among Group 1 cancers increased during the study period and were greatest in 2018 despite the increase in the number of facilities offering PBT from 4 to 28 during the corresponding period, Conclusion and Relevance: Racial disparities in PBT receipt are greatest for cancers for which PBT is the recommended radiation therapy modality. The racial disparities identified in our study suggest undertreatment of Black patients with the greatest need (e.g. children diagnosed with central nervous system cancers). Future studies are needed to identify modifiable factors contributing to the racial disparity in receipt of PBT as efforts other than increasing the number of facilities providing PBT will be needed to eliminate disparities. Citation Format: Leticia M. Nogueira, Ahmedin Jemal, Jason A. Efstathiou, K. Robin Yabroff. Racial disparities in proton beam therapy use for newly diagnosed cancer patients in the United States [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-215.

Metabolomics in High Grade Gliomas.

Gliomas are central nervous system (CNS) cancers that are challenging to treat due to their high proliferation and mutation rates. High grade gliomas include grade 3 and grade 4 tumors, which characteristically have a poor prognosis despite advancements in diagnostic methods and therapeutic options. Advances in metabolomics are resulting in more insight as to how cancer modifies the metabolism of the cell and surrounding tissue. Hence, this avenue of research may also emerge as a way to precisely target metabolites unique to gliomas. These biomarkers may provide opportunities for glioma diagnosis, prognosis and future therapeutic intervention. In this review, we harvest the literature that highlights notable biomolecules in high grade gliomas and promising therapeutic targets and interventions.

Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

Epidemiological study of brain cancer in Iran: A systematic review

Introduction: In recent decades, the incidence and mortality rate of brain tumours, especially in adults, has increased. In order to better plan to reduce the burden of this cancer, knowledge of the epidemiological aspects of this disease is essential. Therefore, due to the lack of a comprehensive study on brain cancer in Iran, this study aimed to investigate the epidemiological aspects of this cancer in Iran. Methods: In June 2020, keywords of 'brain tumour', 'nervous system tumours', 'nervous system neoplasm', 'nervous system cancer', 'central nervous system (CNS)' and 'Iran' were searched on Medline/PubMed and Web of Science databases Scopus, Embase, SID, IranMedex, and Google Scholar. The search results were entered Endnotes Version 8; finally, 35 full papers were reviewed and included in the study. Results: The incidence of brain cancer and CNS tumour is lower in children in central Iran. The incidence of CNS cancer was relatively high among children in Golestan province. Furthermore, the standardised incidence of primary CNS tumours in Iran is 5.69 per 100,000, which is lower than in other countries. Nervous system malignancies were more common in men than in women (age-standardized rate 3 versus 2.2 per 100,000 in men and women, respectively). Tehran had the highest incidence of CNS tumours. Meningiomas were the only most common tumour in women. Gliomas were the most common primary brain tumour, and most of the lesions in this subgroup were in low-grade astrocytoma and ependymomas. Brain cancer mortality was higher in men than in women. Age is a potential risk factor, and the incidence of CNS tumours increases with increasing age after 30 years. Conclusion: Nervous system cancers are on the rise in Iran due to lifestyle changes and increased risk factors. Planning to reduce risk factors and early detection of the disease can be helpful in reducing cases and reducing mortality.

Geriatric patient outcomes in a multidisciplinary central nervous system community hospital clinic for radiation oncology and neurosurgery (RADIANS)

IntroductionManagement of older adult patients with central nervous system (CNS) cancers requires a patient-centric, multidisciplinary approach. Assessment of neurosurgical and radiation treatment outcomes can assist in establishing guidelines for this patient population. We previously reported on the RADIANS clinic, a novel community hospital-based multidisciplinary clinic (MDC) for CNS cancer care, providing simultaneous radiation oncology and neurosurgery evaluation in a same-day, single-setting clinic. We now provide a focused analysis of our older adult patient population and recommendations for triage and standardization of care. MethodsConsecutive older adult patients (age ≥ 65) evaluated at the RADIANS clinic for CNS disease were identified and retrospectively reviewed. Observed 30-day neurosurgical outcomes were compared to predicted outcomes determined by the American College of Physicians NSQIP Surgical Risk Calculator. One-sample binomial exact tests were used to evaluate binary outcome measures. A two-sample t-test was used to evaluate the length of hospital stay. Brier Scores were calculated to assess the deviation between predicted probabilities and observed outcomes for binary outcome measures. Overall survival at 90 days was reported. ResultsFifty-six older adult patients with malignant (42/56) and benign (14/56) CNS disease were evaluated. Mean distance traveled for multidisciplinary evaluation at the RADIANS clinic was 43.4 miles. There was no incidence of radiation-induced toxicity. Mean length of hospital stay for RADIANS patients was significantly shorter by about 1.5 to 3.5 days (95% CI). There was no statistically significant difference for other outcome measures, however, Brier Scores demonstrated that NSQIP was not a good predictive tool for any or serious complications, UTI, venous thromboembolism, return to OR, readmission, or death in our cohort. Local tumor control rate and progression-free survival at 90 days were 97.4% and 76.9%, respectively. ConclusionsThis is the first report of CNS disease outcomes in older adult patients evaluated by radiation oncology and neurosurgery at a community hospital-based MDC. We observed minimal adverse radiation outcomes and high tumor control in our cohort. Findings show significantly shorter postoperative hospital stay for patients evaluated and managed at the RADIANS clinic.

High-dose drug heat map analysis for drug safety and efficacy in multi-spheroid brain normal cells and GBM patient-derived cells.

To test the safety and efficacy of drugs via a high does drug heat map, a multi-spheroids array chip was developed by adopting a micropillar and microwell structure. In the chip, patient-derived cells were encapsulated in alginate and grown to maturity for more than 7 days to form cancer multi-spheroids. Multi-spheroids grown in conventional well plates require many cells and are easily damaged as a result of multiple pipetting during maintenance culture or experimental procedures. To address these issues, we applied a micropillar and microwell structure to the multi-spheroids array. Patient-derived cells from patients with Glioblastoma (GBM), the most common and lethal form of central nervous system cancer, were used to validate the array chip performance. After forming multi-spheroids with a diameter greater than 100μm in a 12×36 pillar array chip (25mm × 75mm), we tested 70 drug compounds (6 replicates) using a high-dose to determine safety and efficacy for drug candidates. Comparing the drug response of multi-spheroids derived from normal cells and cancer cells, we found that four compounds (Dacomitinib, Cediranib, LY2835219, BGJ398) did not show toxicity to astrocyte cell and were efficacious to patient-derived GBM cells.

Abstract P082: Distinct and significant anti-cancer efficacy of plinabulin in patient derived small cell lung cancer (SCLC) 3D soft agar clonogenic assays

Abstract Plinabulin (Plin) is a new chemical entity and a selective immunomodulating microtubule-targeting agent (SIMBA), which exerts immune-enhancing effects through increasing dendritic cell (DC) maturation and DC-dependent antigen presentation to CD4+ and CD8+ T-Cells. Here we evaluated whether Plin also exerts direct anti-cancer effects against approximately 80 patient derived (PDX) models. Plin was characterized for its ability to inhibit anchorage independent growth and ex vivo colony formation of PDX tumor cells in semi-solid medium. The compound was investigated in PDX models of various cancer types, using a 3D clonogenic assay in a 96-well format. Briefly, tumor cell suspensions were prepared from subcutaneous xenografts in NMRI nu/nu mice and seeded into 96 well ultra-low attachment plates within a layer of semi-solid medium. Plin was added to the assay plate at either day 2 or day 7 and tested at 9 concentrations in half-log increments up to a concentration of 3 µM. Supernatant was exchanged 24 h after dosing and cells were further incubated at 37°C and 7.5 % CO2 up to a total assay time of 8 or 13 days. Colony counts based on image analysis were utilized to evaluate efficacy. Plin inhibited tumor colony formation in a concentration-dependent manner. With Plin treatment beginning 2 days after PDX cell seeding, the most sensitive cancer types were small cell lung cancer (mean absolute IC70 = 0.035 μM; n = 7), bladder cancer (mean absolute IC70 = 0.038 μM; n = 9), and soft tissue sarcoma (mean absolute IC70 = 0.057 μM; n = 10). Melanoma models were observed to be the least sensitive to Plin monotherapy, with a mean absolute IC70 of 1.105 μM (n = 19). With Plin treatment beginning 7 days after PDX cell seeding, based on absolute IC70 values, 9 out of 68 tumor models were sensitive towards plinabulin. The most sensitive histotypes were gastric cancer (Asian, mean abs. IC70 = 0.319 µM, n = 3), small cell lung cancer (mean abs. IC70 = 0.385 µM, n = 7; 3 below 50 nM), osteosarcoma (mean abs. IC70 = 0.624 µM, n = 3), and central nervous system cancer (mean abs. IC70 = 1.521 µM, n = 6). Overall, the most responsive models based on IC70 were the small cell lung cancer models 2156 (abs. IC70 = 0.015 µM), 1129 (abs. IC70 = 0.032 µM) and 650 (abs. IC70 = 0.032 µM), and the osteosarcoma model 1186 (abs. IC70 = 0.027 µM). Soft tissue sarcoma models (n = 8), Her2-enriched breast cancer models (n = 6), melanoma models (n = 9), bladder cancer models (n = 6), and gastric cancer models (Caucasian, n = 3) were observed to be the least sensitive cancer types with a mean IC70 value > 3 µM. In conclusion, using patient-derived tumor models in a 3D clonogenic assay, SCLC tumor types were the most sensitive to Plin. These results provide mechanistic support for the preliminary positive results recently reported with Plin in combination with Nivolumab and Ipilimumab in SCLC patients (Malhotra ASCO 2021). Citation Format: George K. Lloyd, James Tonra, Claudia Goettlich, Tobias Deigner, Ramon Mohanlal, Lan Huang. Distinct and significant anti-cancer efficacy of plinabulin in patient derived small cell lung cancer (SCLC) 3D soft agar clonogenic assays [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P082.

Nanoparticle designs for delivery of nucleic acid therapeutics as brain cancer therapies.

Glioblastoma (GBM) is an aggressive central nervous system cancer with a dismal prognosis. The standard of care involves surgical resection followed by radiotherapy and chemotherapy, but five-year survival is only 5.6% despite these measures. Novel therapeutic approaches, such as immunotherapies, targeted therapies, and gene therapies, have been explored to attempt to extend survival for patients. Nanoparticles have been receiving increasing attention as promising vehicles for non-viral nucleic acid delivery in the context of GBM, though delivery is often limited by low blood-brain barrier permeability, particle instability, and low trafficking to target brain structures and cells. In this review, nanoparticle design considerations and new advances to overcome nucleic acid delivery challenges to treat brain cancer are summarized and discussed.

The Effect of Statins in Cancer Risk Reduction in Patients on Dialysis: A Population-Based Case-Control Study.

Simple SummaryThe lifetime risk of several cancers is elevated in patients receiving dialysis following kidney failure compared with the general population. Using a large dataset available in Taiwan, we conducted a nationwide population-based cohort study to delineate the relationship between statin use and cancer risk in patients on dialysis. Our study provides an association that statins reduce the risk of malignancy in patients on dialysis, especially with a longer treatment duration, and irrespective of the type of statin prescription. The use of statins in patients on dialysis was associated with significantly lower incidences in developing respiratory, soft tissue and connective tissue, breast, gynecological, prostate, central nervous system, and lymphatic and hematopoietic cancer.Background: To realize whether statins reduce the risk of cancer in susceptible dialysis populations, this study analyzed the relationship between statin use and cancer risk in patients on dialysis. Methods: Patients having a history of chronic kidney disease with hemodialysis or peritoneal dialysis and receiving statin prescriptions or not were enrolled. The main outcome was cancer diagnosis. This study used univariate and multivariate Cox regression analyses. Results: In total, 4236 individuals in the statin group and 8472 individuals in the statin nonuser group were included in the study. Multivariate Cox regression analysis revealed that statin users are significantly less likely to develop cancer than statin nonusers (adjusted hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.78–0.90). Subgroup analyses revealed that statin cumulative defined daily doses >365 were associated with a significantly decreased risk of cancer incidence (adjusted HR 0.59, 95% CI 0.45–0.87), and statin users have a reduced risk of respiratory, soft tissue and connective tissue, breast, gynecological, prostate, central nervous system, and lymphatic and hematopoietic cancer than nonusers. Conclusions: Our population-based cohort study provides an association that statins reduce the risk of malignancy in patients on dialysis, especially with a longer treatment duration, and certain types of cancer.

Metallothionein 1: A New Spotlight on Inflammatory Diseases.

MT1 has been demonstrated to be an essential stress protein in maintaining physiological balance and regulating immune homeostasis. While the immunological involvement of MT1 in central nervous system disorders and cancer has been extensively investigated, mounting evidence suggests that MT1 has a broader role in inflammatory diseases and can shape innate and adaptive immunity. In this review, we will first summarize the biological features of MT1 and the regulators that influence MT1 expression, emphasizing metal, inflammation, and immunosuppressive factors. We will then focus on the immunoregulatory function of MT1 on diverse immune cells and the signaling pathways regulated by MT1. Finally, we will discuss recent advances in our knowledge of the biological role of MT1 in several inflammatory diseases to develop novel therapeutic strategies.

Utilizing preclinical models to develop targeted therapies for rare central nervous system cancers.

Patients with rare central nervous system (CNS) tumors typically have a poor prognosis and limited therapeutic options. Historically, these cancers have been difficult to study due to small number of patients. Recent technological advances have identified molecular drivers of some of these rare cancers which we can now use to generate representative preclinical models of these diseases. In this review, we outline the advantages and disadvantages of different models, emphasizing the utility of various in vitro and ex vivo models for target discovery and mechanistic inquiry and multiple in vivo models for therapeutic validation. We also highlight recent literature on preclinical model generation and screening approaches for ependymomas, histone mutated high-grade gliomas, and atypical teratoid rhabdoid tumors, all of which are rare CNS cancers that have recently established genetic or epigenetic drivers. These preclinical models are critical to advancing targeted therapeutics for these rare CNS cancers that currently rely on conventional treatments.