Model For Translational Research Research Articles

Establishment of Patient-derived Preclinical Models for Invasive Papillary Cholangiocarcinoma.

Invasive papillary cholangio-carcinoma (IPC) is a minor subtype of extrahepatic cholangiocarcinoma. However, its etiology and characteristics remain unknown because of the unavailability of in vitro and in vivo models. We aimed to establish a novel preclinical model for translational research of IPC. A patient-derived xenograft (PDX) was engrafted in NOG mice and the cell line National Cancer Center human IPC (NCChIPC) was subsequently established from the PDX tumors. Immunohistochemistry and RNA-sequencing were used to determine the retention of original characteristics of patient tissues. PDX tumors showed successful amplification, and the NCChIPC-derived xenograft largely retained the histopathological features of the original tumor with CK19, MUC1 and MUC5AC expression. Transcriptome analysis showed a high correlation between patient and preclinical models. Additionally, anticancer drugs response was analyzed in the NCChIPC PDX. These novel preclinical models here will help elucidate IPC etiology and facilitate translational research.

RETRACTED: Toxicity of spike fragments SARS-CoV-2 S protein for zebrafish: A tool to study its hazardous for human health?

Despite the significant increase in the generation of SARS-CoV-2 contaminated domestic and hospital wastewater, little is known about the ecotoxicological effects of the virus or its structural components in freshwater vertebrates. In this context, this study evaluated the deleterious effects caused by SARS-CoV-2 Spike protein on the health of Danio rerio, zebrafish. We demonstrated, for the first time, that zebrafish injected with fragment 16 to 165 (rSpike), which corresponds to the N-terminal portion of the protein, presented mortalities and adverse effects on liver, kidney, ovary and brain tissues. The conserved genetic homology between zebrafish and humans might be one of the reasons for the intense toxic effects followed inflammatory reaction from the immune system of zebrafish to rSpike which provoked damage to organs in a similar pattern as happen in severe cases of COVID-19 in humans, and, resulted in 78,6% of survival rate in female adults during the first seven days. The application of spike protein in zebrafish was highly toxic that is suitable for future studies to gather valuable information about ecotoxicological impacts, as well as vaccine responses and therapeutic approaches in human medicine. Therefore, besides representing an important tool to assess the harmful effects of SARS-CoV-2 in the aquatic environment, we present the zebrafish as an animal model for translational COVID-19 research.

Translating Embodied Cognition for Embodied Learning in the Classroom

In this perspective piece, we briefly review embodied cognition and embodied learning. We then present a translational research model based on this research to inform teachers, educational psychologists, and practitioners on the benefits of embodied cognition and embodied learning for classroom applications. While many teachers already employ the body in teaching, especially in early schooling, many teachers’ understandings of the science and benefits of sensorimotor engagement or embodied cognition across grades levels and the content areas is little understood. Here, we outline seven goals in our model and four major “action” steps. To address steps 1 and 2, we recap previously published reviews of the experimental evidence of embodied cognition (and embodied learning) research across multiple learning fields, with a focus on how both simple embodied learning activities—as well as those based on more sophisticated technologies of AR, VR, and mixed reality—are being vetted in the classroom. Step 3 of our model outlines how researchers, teachers, policy makers, and designers can work together to help translate this knowledge in support of these goals. In the final step (step 4), we extract generalized, practical embodied learning principles, which can be easily adopted by teachers in the classroom without extensive training. We end with a call for educators and policy makers to use these principles to identify learning objectives and outcomes, as well as track outcomes to assess whether program objectives and competency requirements are met.

MRI longitudinal and cross‐sectional monitoring of amyloid pathology in non‐human primates

AbstractBackgroundThe potential for using MRI technologies to visualize amyloid deposits has been increasingly recognized. The present study utilized a New World non‐human primate (NHP) model of amyloid pathology, squirrel monkey (SQM), which unlike other NHPs, develops age‐dependent abundant cerebral amyloid angiopathy (CAA). The transverse relaxation rate (R2*) has a linear correlation with iron content, a component of amyloid deposits and microhemorrhages. Here we assessed whether the region of interest (ROI)‐based quantitative R2* assessment is able to detect differences in SQM neuropathology between varying age cohorts as well as longitudinally. An additional focus was to examine the presence of naturally occurring ARIA‐E like pathologies in geriatric SQMs.MethodMulti‐gradient echo (MGE) MRI datasets were acquired in three different SQM age cohorts at various stages of Aβ pathology development. The R2* maps were generated (Firevoxel parametric map tool) from each subject to enable ROI‐based quantitative R2* analyses. DAB‐enhanced histochemical iron stain (Meguro method), along with 6E10/4G8 immunohistochemistry, was used to identify iron‐positive Aβ deposits. Histological examination of neuroinflammation and microhemorrhages (Perls’ iron stain) was performed. T2‐w FLAIR images were acquired to assess the presence of ARIA‐E.ResultMGE imaging was capable of depicting brain pathology differences between three SQM age cohorts (ages 5, 16, 21). Absolute quantitation of R2* values, defined by ROI circumventing the cortex, revealed significant age‐related differences in selected brain regions, with the highest R2* counts detected in 21yr old monkeys. The ability to longitudinally track pathology‐related increase in R2* values was further validated by MRIs performed at specific intervals post‐initial scans in our geriatric monkeys. Iron‐positive Aβ deposits and microhemorrhages detected by MRI were confirmed via matched histological sections. Subsequent histological evaluation demonstrated disease‐stage differences in microgliosis and astrocytosis. Moreover, ARIA‐E like T2‐w signal hyperintensities were detected in our oldest cohort. Neuropathological correlates of ARIA‐E‐related changes were characterized histologically.ConclusionThe current study highlights the utility of MRI methodologies to monitor age‐dependent progression of Aβ‐related pathology, as well as the importance of the SQM model for future translational research on advancing therapeutic interventions targeting amyloid depositions.

The Spiny Mouse-A Menstruating Rodent to Build a Bridge From Bench to Bedside.

Menstruation, the cyclical breakdown of the uterine lining, is arguably one of evolution's most mysterious reproductive strategies. The complexity and rarity of menstruation within the animal kingdom is undoubtedly a leading contributor to our current lack of understanding about menstrual function and disorders. In particular, the molecular and environmental mechanisms that drive menstrual and fertility dysregulation remain ambiguous, owing to the restricted opportunities to study menstruation and model menstrual disorders in species outside the primates. The recent discovery of naturally occurring menstruation in the Egyptian spiny mouse (Acomys cahirinus) offers a new laboratory model with significant benefits for prospective research in women's health. This review summarises current knowledge of spiny mouse menstruation, with an emphasis on spiral artery formation, inflammation and endocrinology. We offer a new perspective on cycle variation in menstrual bleeding between individual animals, and propose that this is indicative of fertility success. We discuss how we can harness our knowledge of the unique physiology of the spiny mouse to better understand vascular remodelling and its implications for successful implantation, placentation, and foetal development. Our research suggests that the spiny mouse has the potential as a translational research model to bridge the gap between bench to bedside and provide improved reproductive health outcomes for women.

Temporal exposure to chronic unpredictable stress induces precocious neurobehavioral deficits by distorting neuromorphology and glutathione biosynthesis in zebrafish brain

Modelling of chronic stress conditions in experimental animals and its neuropsychiatric outcomes has been well documented in literature. Zebrafish (Danio rerio) by exhibiting significant genetic and epidemiological similarities with human beings, has now emerged as a promising animal model of translational research. In this line, risk assessment following exposure to chronic unpredictable stress (CUS) towards neurobehavioral response and neuromorphology of sensitive brain region in zebrafish is the prime objective of the present study. With the existing knowledge on CUS in affecting diverse neurobehavioral aspects, we were primarily interested in whether this neurobehavioral transformation is an outcome of altered glutathione biosynthesis in zebrafish. We were also concerned about whether the precocious neurobehavioral transformation has been linked to altered neuromorphology in the periventricular grey zone (PGZ) of the zebrafish brain. Our basic findings showed that CUS itself represented as a universal factor in altering native bottom-dwelling and scototaxis behaviour of zebrafish. Our findings also backing the argument that CUS itself represented a collective stress regimen by altering the brain glutathione biosynthesis in zebrafish. Correspondingly, a temporal transformation in CUS instigated augmentation in neuronal pyknosis and chromatin condensation were observed in PGZ of the zebrafish brain. Collectively, these findings designate that CUS induced temporal neurobehavioral transformation is an outcome of augmented oxidative stress and neuromorphological alteration in the zebrafish brain. However, the underlying mechanism of such neuropathological manifestation associated with CUS might provide novel insight towards the development of prophylactic/therapeutic intervention to counter such co-morbid behavioral alteration.

Validation of baboon pluripotent cells as a model for translational stem cell research

Translation of stem cell therapies to the clinic will be most successful following optimization of efficacy and safety in appropriate preclinical model systems. Among available models, nonhuman primates (NHPs) provide the most accurate recapitulation of human anatomy, physiology, genetics and epigenetics. Here, we show that baboon pluripotent cells (PSCs) recapitulate key molecular features of human PSCs with greater accuracy than that found in PSCs from non-primate species such as mice. Specifically, baboon and human PSCs exhibit greater conservation of gene expression patterns, higher sequence and structural homology among pluripotency factors, more equivalent genome-wide patterns of histone and DNA methylation modifications, and similar maintenance of bivalent programming of developmental genes than that found between human and non-primate PSCs.

Developing a social prescribing research school using translational research: Learning from Wales

Abstract The Wales School for Social Prescribing Research (WSSPR) was launched in April 2020. Central to its functioning, WSSPR uses a translational research model (Cooksey, 2007; Weeks et al 2013) to describe, order and organise a multi-phase programme of applied research, development and evaluation. It promotes an equal and mutually supporting relationship between theory-building, knowledge acquisition and practice, without privileging any one activity. Within WSSPR sits the Wales Social Prescribing Research Network. The network has a membership of over 300 individuals interested in social prescribing research across Wales, this includes academics, social prescribers, policy makers, health and social care professionals and commissioners. The school is also linked to three communities of practice in the North, West & Mid, and South East of Wales, which collectively reach over 1000 social prescribing practitioners. Through the translational research model, issues and questions are raised by practice or members of the public through the network to WSSPR. These inform thinking and development of research projects and proposals. The network is then used to disseminate findings, receive feedback on findings and implement evidence-based changes in practice. This presentation will discuss the development of WSSPR and our networks & communities of practice using a translational model of research to develop programmes of research for Wales. It will discuss the challenges and provide step by step developmental guidance about setting up a research organisation for SP. It will demonstrate the impact of the social prescribing research and its contribution to the evidence base to date.

Validation of in vitro models for smoke exposure of primary human bronchial epithelial cells.

The bronchial epithelium is constantly challenged by inhalative insults including cigarette smoke (CS), a key risk factor for lung disease. In vitro exposure of bronchial epithelial cells using CS extract (CSE) is a widespread alternative to whole CS (wCS) exposure. However, CSE exposure protocols vary considerably between studies, precluding direct comparison of applied doses. Moreover, they are rarely validated in terms of physiological response in vivo and the relevance of the findings is often unclear. We tested six different exposure settings in primary human bronchial epithelial cells (phBECs), including five CSE protocols compared with wCS exposure. We quantified cell-delivered dose and directly compared all exposures using expression analysis of 10 well-established smoke-induced genes in bronchial epithelial cells. CSE exposure of phBECs was varied in terms of differentiation state, exposure route, duration of exposure, and dose. Gene expression was assessed by quantitative real-time PCR (qPCR) and Western Blot analysis. Cell type-specific expression of smoke-induced genes was analyzed by immunofluorescent analysis. Three surprisingly dissimilar exposure types, namely, chronic CSE treatment of differentiating phBECs, acute CSE treatment of submerged basal phBECs, and wCS exposure of differentiated phBECs performed best, resulting in significant upregulation of seven (chronic CSE) and six (acute wCS, acute submerged CSE exposure) out of 10 genes. Acute apical or basolateral exposure of differentiated phBECs with CSE was much less effective despite similar doses used. Our findings provide guidance for the design of human in vitro CS exposure models in experimental and translational lung research.

A systematic review of porcine models in translational pain research.

Translating basic pain research from rodents to humans has proven to be a challenging task. Efforts have been made to develop preclinical large animal models of pain, such as the pig. However, no consistent overview and comparison of pig models of pain are currently available. Therefore, in this review, our primary aim was to identify the available pig models in pain research and compare these models in terms of intensity and duration. First, we systematically searched Proquest, Scopus and Web of Science and compared the duration for which the pigs were significantly sensitized as well as the intensity of mechanical sensitization. We searched models within the specific field of pain and adjacent fields in which pain induction or assessment is relevant, such as pig production. Second, we compared assessment methodologies in surrogate pain models in humans and pigs to identify areas of overlap and possible improvement. Based on the literature search, 23 types of porcine pain models were identified; 13 of which could be compared quantitatively. The induced sensitization lasted from hours to months and intensities ranged from insignificant to the maximum attainable. We also found a near to complete overlap of assessment methodologies between human and pig models within the area of peripheral neurophysiology, which allows for direct comparison of results obtained in the two species. In spite of this overlap, further development of pain assessment methodologies is still needed. We suggest that central nervous system electrophysiology, such as electroencephalography, electrocorticography or intracortical recordings, may pave the way for future objective pain assessment.

Systemic treatment of penile squamous cell carcinoma-hurdles and hopes of preclinical models and clinical regimens: a narrative review.

Despite contemporary research efforts, the prognosis of penile squamous cell carcinoma (PeSCC) has not significantly improved over the past decade. Despite frequently encountered patient-related delayed medical consultations impairing outcomes, several other aspects contribute to the lack of advancement in the treatment of this condition. One essential reason is that translational research, a prerequisite for the clinically successful disease management, is still at an early stage in PeSCC as compared to many other malignancies. Preclinical experimental models are indispensable for the evaluation of tumor biology and identification of genomic alterations. However, since neither commercial PeSCC cell lines are available nor xenograft models sustainably established, such analyses are challenging in this field of research. In addition, systemic therapies are less effective and toxic without decisive breakthroughs over recent years. Current systemic management of PeSCC is based on protocols that have been investigated in small series of only up to 30 patients. Thus, there is an unmet medical need for new approaches necessitating research efforts to develop more efficacious systemic strategies. This review aims to highlight the current state of knowledge in the molecular alterations involved in the etiology and ensuing steps for cancer progression, existing preclinical models of translational research, clinically relevant systemic protocols, and ongoing clinical trials.

Obesity Animal Models for Acupuncture and Related Therapy Research Studies.

Obesity and related diseases are considered as pandemic representing a worldwide threat for health. Animal models are critical to validate the effects and understand the mechanisms related to classical or innovative preventive and therapeutic strategies. It is, therefore, important to identify the best animal models for translational research, using different evaluation criteria such as the face, construct, and predictive validity. Because the pharmacological treatments and surgical interventions currently used for treating obesity often present many undesirable side effects, relatively high relapse probabilities, acupuncture, electroacupuncture (EA), and related therapies have gained more popularity and attention. Many kinds of experimental animal models have been used for obesity research studies, but in the context of acupuncture, most of the studies were performed in rodent obesity models. Though, are these obesity rodent models really the best for acupuncture or related therapies research studies? In this study, we review different obesity animal models that have been used over the past 10 years for acupuncture and EA research studies. We present their respective advantages, disadvantages, and specific constraints. With the development of research on acupuncture and EA and the increasing interest regarding these approaches, proper animal models are critical for preclinical studies aiming at developing future clinical trials in the human. The aim of the present study is to provide researchers with information and guidance related to the preclinical models that are currently available to investigate the outcomes of acupuncture and related therapies.

The roles of epigenetics in cancer progression and metastasis.

Cancer metastasis remains a major clinical challenge for cancer treatment. It is therefore crucial to understand how cancer cells establish and maintain their metastatic traits. However, metastasis-specific genetic mutations have not been identified in most exome or genome sequencing studies. Emerging evidence suggests that key steps of metastasis are controlled by reversible epigenetic mechanisms, which can be targeted to prevent and treat the metastatic disease. A variety of epigenetic mechanisms were identified to regulate metastasis, including the well-studied DNA methylation and histone modifications. In the past few years, large scale chromatin structure alterations including reprogramming of the enhancers and chromatin accessibility to the transcription factors were shown to be potential driving force of cancer metastasis. To dissect the molecular mechanisms and functional output of these epigenetic changes, it is critical to use advanced techniques and alternative animal models for interdisciplinary and translational research on this topic. Here we summarize our current understanding of epigenetic aberrations in cancer progression and metastasis, and their implications in developing new effective metastasis-specific therapies.

Sex-Related Motor Deficits in the Tau-P301L Mouse Model.

The contribution of mouse models for basic and translational research at different levels is important to understand neurodegenerative diseases, including tauopathies, by studying the alterations in the corresponding mouse models in detail. Moreover, several studies demonstrated that pathological as well as behavioral changes are influenced by the sex. For this purpose, we performed an in-depth characterization of the behavioral alterations in the transgenic Tau-P301L mouse model. Sex-matched wild type and homozygous Tau-P301L mice were tested in a battery of behavioral tests at different ages. Tau-P301L male mice showed olfactory and motor deficits as well as increased Tau pathology, which was not observed in Tau-P301L female mice. Both Tau-P301L male and female mice had phenotypic alterations in the SHIRPA test battery and cognitive deficits in the novel object recognition test. This study demonstrated that Tau-P301L mice have phenotypic alterations, which are in line with the histological changes and with a sex-dependent performance in those tests. Summarized, the Tau-P301L mouse model shows phenotypic alterations due to the presence of neurofibrillary tangles in the brain.

Swine models for translational oncological research: an evolving landscape and regulatory considerations.

Swine biomedical models have been gaining in popularity over the last decade, particularly for applications in oncology research. Swine models for cancer research include pigs that have severe combined immunodeficiency for xenotransplantation studies, genetically modified swine models which are capable of developing tumors in vivo, as well as normal immunocompetent pigs. In recent years, there has been a low success rate for the approval of new oncological therapeutics in clinical trials. The two leading reasons for these failures are either due to toxicity and safety issues or lack of efficacy. As all therapeutics must be tested within animal models prior to clinical testing, there are opportunities to expand the ability to assess efficacy and toxicity profiles within the preclinical testing phases of new therapeutics. Most preclinical in vivo testing is performed in mice, canines, and non-human primates. However, swine models are an alternative large animal model for cancer research with similarity to human size, genetics, and physiology. Additionally, tumorigenesis pathways are similar between human and pigs in that similar driver mutations are required for transformation. Due to their larger size, the development of orthotopic tumors is easier than in smaller rodent models; additionally, porcine models can be harnessed for testing of new interventional devices and radiological/surgical approaches as well. Taken together, swine are a feasible option for preclinical therapeutic and device testing. The goals of this resource are to provide a broad overview on regulatory processes required for new therapeutics and devices for use in the clinic, cross-species differences in oncological therapeutic responses, as well as to provide an overview of swine oncology models that have been developed that could be used for preclinical testing to fulfill regulatory requirements.

Endometrial Cancer Molecular Characterization: The Key to Identifying High-Risk Patients and Defining Guidelines for Clinical Decision-Making?

Simple SummaryEndometrial carcinomas (EC) have been traditionally classified based on histopathology (types I and II). Determining the risk of a patient to experience disease recurrence is important to decide which patients need adjuvant treatment. The current endometrial carcinoma risk assessment approaches fail to accurately classify patients into low-and high-risk groups. Several studies suggest that combining molecular characteristics with the current risk classification in EC may improve patients’ stratification and treatment decision-making. In this review, we describe how evolving molecular trends can be used as prognostic factors to identify high-risk EC subpopulations. We also look at how the most recent patient-derived models can help researchers find new possible targets and treatments for EC patients.Endometrial carcinomas (EC) are the sixth most common cancer in women worldwide and the most prevalent in the developed world. ECs have been historically sub-classified in two major groups, type I and type II, based primarily on histopathological characteristics. Notwithstanding the usefulness of such classification in the clinics, until now it failed to adequately stratify patients preoperatively into low- or high-risk groups. Pieces of evidence point to the fact that molecular features could also serve as a base for better patients’ risk stratification and treatment decision-making. The Cancer Genome Atlas (TCGA), back in 2013, redefined EC into four main molecular subgroups. Despite the high hopes that welcomed the possibility to incorporate molecular features into practice, currently they have not been systematically applied in the clinics. Here, we outline how the emerging molecular patterns can be used as prognostic factors together with tumor histopathology and grade, and how they can help to identify high-risk EC subpopulations for better risk stratification and treatment strategy improvement. Considering the importance of the use of preclinical models in translational research, we also discuss how the new patient-derived models can help in identifying novel potential targets and help in treatment decisions.

Embedded versus translational research: science-based innovation in biomedical product development

This article examines models of science-based innovation, embedded research and translational research in development of biomedical devices. While the applicability of linear of models of innovation in product develop have been widely questioned, studies have yet to explain how science-based biomedical knowledge production is reduced to practice in development of new devices. To understand how this occurs I investigated concepts of science-based innovation, embedded research and translational research in the context of commercial product development in the powered prosthetic arm industry from 1945 to 2020. I found that development of commercial powered prosthetic arms was strongly influenced by scientific research, with a majority of cases involving the originating researcher contributing to first reduction to practice in new commercial products. Instead of integrated knowledge translation practices, embedded research followed university research in many of the cases. The focus on a biomedical engineering industry limits the generalizability of the findings. Future research directions include examination of other historical and contemporary case studies, and identification of effective practices in embedding knowledge production projects in locations-of-use.

Advances on colorectal cancer 3D models: The needed translational technology for nanomedicine screening.

Colorectal cancer (CRC) is a heterogeneous and molecularly complex disease, associated with high mortality worldwide, exposing the urgent need for novel therapeutic approaches. Their development and translation to the clinic have been hampered, partially due to the absence of reliable cellular models that resemble key features of the human disease. While traditional 2D models are not able to provide consistent and predictive responses about the in vivo efficiency of the formulation, animal models frequently fail to recapitulate cancer progression and to reproduce adverse effects. On its turn, multicellular 3D systems, by mimicking key genetic, physical and mechanical cues of the tumor microenvironment, constitute a promising tool in cancer research. In addition, they constitute more physiological and relevant environment for anticancer drugs screening and for predicting patient's response towards personalized approaches, bridging the gap between simplified 2D models and unrepresentative animal models. In this review, we provide an overview of CRC 3D models for translational research, with focus on their potential for nanomedicines screening.

Abstract 2713: Preclinical models for translational immuno-oncology research: patient-derived xenografts on humanized mice

Abstract Background: The preclinical evaluation of novel immune checkpoint modulators is dependent on models with functional human immune cells. In previous experiments, we have demonstrated, that we can use either peripheral blood mononuclear cells (PBMC) or hematopoietic stem cells (HSC) to establish a humanized immune system on highly immunodeficient mice with functional T, B or NK cells. Furthermore, we determined PD-L1 expression as a predictive marker and target for immunotherapy on different patient-derived xenografts (PDX). By co-transplantation of PDX, we successfully generated a fully human tumor-immune-cell model in mice. Finally, we evaluated the functionality of the model by the treatment with checkpoint inhibitors and for combination therapies i.e. with chemotherapy or radiation. Methods: HSC-humanized mice (HIS) were generated by i.v. transplantation of HSC. Engraftment of immune cells was monitored by FACS analysis. For PBMC-humanized mice, immune cells were implanted i.v. PD-L1 expression on PDX was determined by FACS and immunohistochemistry (IHC). PDX from 13 different entities (i.e. melanoma, lymphoma) were transplanted on HIS mice and treated with Ipilimumab (Ipi) and Nivolumab (Nivo) alone or in combination with radiation. Results: 14 weeks after HSC transplantation up to 20% of the human immune cells in the blood were T-cells. We have transplanted more than 40 different PDX from 13 different tumor entities on HIS mice. Most of the investigated PDX (>70%) successfully engrafted and showed no significant difference in tumor growth compared non-humanized mice. However, for some PDX we observed a delayed tumor growth or a complete rejection. Engraftment delay seems to correlate with the PD-L1 expression of PDX (the higher PD-L1, then the higher growth delay). Treatment with Ipi or Nivo alone or in combination led to a minor tumor growth delay and an increased percentage of T-cells in the blood and the tumor. Response showed a correlation to innate immune response and PD-L1 expression of PDX and could further be increased by combination with radiotherapy. Conclusions: Our humanized immune-PDX models enable appropriate preclinical translational research on tumor immune biology and the evaluation of new therapies and combinations, as well as the identification and validation of biomarkers for immune therapy. Citation Format: Maria Stecklum, Annika Wulf-Goldenberg, Bernadette Brzezicha, Konrad Klinghammer, Korinna Jöhrens, Wolfgang Walther, Jens Hoffmann. Preclinical models for translational immuno-oncology research: patient-derived xenografts on humanized mice [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 2713.

Primary central nervous system lymphoma: clinicopathological and genomic insights for therapeutic development.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive, extra-nodal non-Hodgkin lymphoma that is confined to the central nervous system (CNS) and the eyes. Most PCNSLs arise in immunocompetent older patients and less frequently in immunocompromised patients with Epstein-Barr virus infection. Although a patient's initial response to chemotherapy and radiation therapy is favorable, the clinical outcome of PCNSL remains poor compared to that of systemic lymphoma. Radiation-induced neurotoxicity is also a critical problem for patients with PCNSL. Therefore, a novel therapeutic strategy is required to overcome these challenges. Recent studies have largely uncovered the genomic landscape and associated histopathological features of PCNSL. Based on this background, novel therapeutic agents, such as Bruton's tyrosine kinase inhibitors and immune checkpoint inhibitors, have been introduced for patients with PCNSL. Here, we provide an overview of the updated histopathological and genomic characterization of PCNSL and summarize the current therapeutic strategies. We also review current preclinical PCNSL models for translational research.