J.R.R. Tolkien and his Influence on Modern Fantasy Writer Tamora Pierce

Tolkien’s writing of female and racial minority characters has been criticized as misogynistic and racist by many critics of Tolkien. However, these critics come to these conclusions due to the limited quantity of these characters overall, especially those of the female sex, and their involvement in the overall story’s plot. Tolkien uses women sparingly and because of this, each one has important characteristics and roles that they play. Therefore, if not invalidating the critics position on his supposed misogynistic views, then, at least, dissolving some of their support platforms. However, the roles that the women play are important in understanding Tolkien’s true moral and world view points. We are able to more clearly see these subtle aspects in Tolkien’s writing when we separate it from the moral overarching story of the One Ring. However, in order to do that, it helps to analyze these characters along with a mirror character that modern fantasy authors have created. Tamora Pierce is such a writer, and her characters in her first series align very succinctly with the characters in Tolkien’s series. Through a close character analysis, we are able to see that the criticisms lobbed at Tolkien for his treatment of Arwen and Éowyn are not as substantiated as some would believe

Abstract 27: Early dynamics in peripheral blood immune cell subsets and ctDNA are predictive of outcome to immunotherapy

Abstract Background: Treatment-induced anti-tumor immune response may be reflected in peripheral blood leukocyte composition and shifts. The relative abundance of immune cell subsets captured by neutrophil-to-lymphocyte ratio (NLR) is a promising biomarker of response to immune checkpoint inhibition (ICI). However early dynamics and integration with circulating tumor DNA (ctDNA) kinetics during ICI have not been comprehensively studied. Methods: We evaluated the predictive role of early dynamic changes of peripheral immune cell subsets in 239 ICI treated metastatic non-small cell lung cancers (mNSCLC) and combined those with ctDNA dynamics in 18 early stage NSCLCs (esNSCLC) treated with neoadjuvant ICI. Blood cell counts were analyzed at baseline, 4 weeks on treatment, and at first radiographic follow up (mNSCLC) or preoperatively (esNSCLC). mNSCLC patients without progression at 6 months were considered to have durable clinical benefit (DCB). We employed eXtreme Gradient Boosting, a decision-tree based machine learning algorithm, to integrate baseline values and early changes in immune cell subsets. To reduce modeling overfitting, we trained an ensemble of models, incorporating 10-fold cross-validation that included feature selection (training n=171) and tested the model in an unseen independent set (n=68). For esNSCLCs, major pathologic response (MPR; ≤10% residual tumor; RT) was determined. We performed Targeted Error Correction next generation sequencing on 60 serial plasma and matched leukocyte DNA samples to assess ctDNA clonal dynamics. Changes in immune cell subsets were correlated with RT, MPR, progression-free (PFS) and overall survival (OS). Results: Our machine learning integrative model predicted DCB with an area under the ROC curve (AUC) of 0.96 for training, 0.72 for cross-validation testing and 0.74 for unseen testing datasets. Feature importance analysis revealed that NLR at 4 weeks, first radiographic follow up, and relative change in NLR from baseline were the strongest predictors of outcome together with relative eosinophil and lymphocyte count. Our model's performance was superior to TMB (AUC=0.52) or PD-L1 (AUC=0.54). For esNSCLCs, change in NLR at 4 weeks after ICI initiation was predictive of tumor regression (p=0.02), such that those with MPR showed significant decrease in NLR. This was also predictive of PFS (log rank p=0.004) and OS (log rank p=0.02). Furthermore, higher eosinophil count at 4 weeks was correlated with MPR (p=0.006) and decreased RT (p=0.006). Immune cell subset kinetics were concordant with ctDNA clearance in all but two patients and importantly NLR dynamics at 4 weeks were predictive of MPR even when ctDNA was undetectable. Conclusions: Early changes in peripheral immune cell subsets together with ctDNA are reflective of anti-tumor immune response during ICI and may more accurately predict ICI response than currently used biomarkers. Citation Format: Michael Hwang, Jenna Canzoniero, Samuel Rosner, Guangfan Zhang, Mara Lanis, Lamia Rhymee, Alexandria Curry, Gavin Pereira, Kristen Marrone, Joshua Reuss, Jarushka Naidoo, Christine Hann, Vincent Lam, Benjamin Levy, David Ettinger, Patrick Forde, Julie Brahmer, Victor Velculescu, Tanguy Seiwert, Valsamo Anagnostou. Early dynamics in peripheral blood immune cell subsets and ctDNA are predictive of outcome to immunotherapy [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 27.</jats:p

A Clinical Rule for Preoperative Prediction of BRAF Mutation Status in Craniopharyngiomas

Papillary craniopharyngiomas are characterized by BRAFV600E mutations. Targeted therapy can elicit a dramatic radiographic regression of these tumors. Therefore, prediction of BRAF mutation status before definitive surgery could enable neoadjuvant treatment strategies. To establish preoperative prediction criteria to identify patients with a BRAF mutant craniopharyngioma. Sixty-four patients with craniopharyngioma were included in this study. We determined BRAF mutation status by targeted sequencing. After scoring interobserver variability between presurgical clinical data and radiographic features, we established a diagnostic rule for BRAF mutation in our discovery cohort. We then validated the rule in an independent cohort. The BRAFV600E mutation was detected in 12 of 42 patients in the discovery cohort. There were no patients under age 18 with BRAF mutation. Calcification was rare in tumors with BRAF mutation (P < .001), and 92% of them were supradiaphragmatic in location. Combining these 3 features-older than 18 years, absence of calcification, and supradiaphragmatic tumor location-we established a rule for predicting BRAF mutation. In cases where all 3 criteria were fulfilled, the sensitivity and specificity for the presence of BRAF mutation were 83% and 93%, respectively. In the validation cohort (n = 22), the sensitivity was 100% and specificity was 89%. We propose predictive criteria for a BRAF mutation in craniopharyngioma using preoperative clinical and radiographic data. This rule may be useful in identifying patients who could potentially benefit from neoadjuvant BRAFV600E-targeted systemic therapies

Peripheral blood immune cell dynamics reflect antitumor immune responses and predict clinical response to immunotherapy

BackgroundDespite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor–immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade.MethodsUsing machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance.ResultsIntegrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts.ConclusionsOur findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade.</jats:sec

PI3K/AKT/mTOR Pathway Alterations Promote Malignant Progression and Xenograft Formation in Oligodendroglial Tumors

Abstract Purpose: Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression. Experimental Design: Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models in vitro and in vivo. Results: A specimen from the tumor site that subsequently manifested rapid clinical progression contained a PIK3CA mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations (IDH1R132H and 1p/19q codeletion) and PIK3CAE542K, and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type PIK3CA. In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, P &amp;lt; 0.0001). Importantly, mutant PIK3CA oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors in vitro and in vivo—evidence that mutant PIK3CA is a tumorigenic driver in oligodendroglioma. Conclusions: Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas. </jats:sec

PI3K/AKT/mTOR Pathway Alterations Promote Malignant Progression and Xenograft Formation in Oligodendroglial Tumors

Oligodendroglioma has a relatively favorable prognosis, however, often undergoes malignant progression. We hypothesized that preclinical models of oligodendroglioma could facilitate identification of therapeutic targets in progressive oligodendroglioma. We established multiple oligodendroglioma xenografts to determine if the PI3K/AKT/mTOR signaling pathway drives tumor progression. Two anatomically distinct tumor samples from a patient who developed progressive anaplastic oligodendroglioma (AOD) were collected for orthotopic transplantation in mice. We additionally implanted 13 tumors to investigate the relationship between PI3K/AKT/mTOR pathway alterations and oligodendroglioma xenograft formation. Pharmacologic vulnerabilities were tested in newly developed AOD models and . A specimen from the tumor site that subsequently manifested rapid clinical progression contained a mutation E542K, and yielded propagating xenografts that retained the OD/AOD-defining genomic alterations ( and 1p/19q codeletion) and , and displayed characteristic sensitivity to alkylating chemotherapeutic agents. In contrast, a xenograft did not engraft from the region that was clinically stable and had wild-type . In our panel of OD/AOD xenografts, the presence of activating mutations in the PI3K/AKT/mTOR pathway was consistently associated with xenograft establishment (6/6, 100%). OD/AOD that failed to generate xenografts did not have activating PI3K/AKT/mTOR alterations (0/9, < 0.0001). Importantly, mutant oligodendroglioma xenografts were vulnerable to PI3K/AKT/mTOR pathway inhibitors and -evidence that mutant is a tumorigenic driver in oligodendroglioma. Activation of the PI3K/AKT/mTOR pathway is an oncogenic driver and is associated with xenograft formation in oligodendrogliomas. These findings have implications for therapeutic targeting of PI3K/AKT/mTOR pathway activation in progressive oligodendrogliomas

Genotype-targeted local therapy of glioma

Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations, which sensitize to metabolism-altering agents. To improve local control of IDH mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting