bluuebunny/crossref_metadata_2025 huggingface dataset:
MDB-44. A TRANSFER LEARNING APPROACH FOR AUTOMATIC SEGMENTATION OF TUMOR SUB-COMPARTMENTS AND TUMOR HABITAT IN PEDIATRIC MEDULLOBLASTOMA
Authors: Bareja Rohan , Ismail Marwa , Martin Doug , Nayate Ameya , Yadav Ipsa , Labbad Murad , Tamrazi Benita , Salloum Ralph , Margol Ashley , Judkins Alexander , Iyer Sukanya , de Blank Peter , Tiwari Pallavi
Published: June 2023

PURPOSE

Accurate delineation of pediatric medulloblastoma (MB) tumors is required for accurate surgical resection and efficient treatment planning. However, manual delineation is time consuming and prone to errors and inter-reader variability. We present the first attempt at automatic segmentation of MB tumors via a transfer learning approach that utilizes adult brain tumor segmentations to optimize segmentation of 1) the pediatric tumor habitat, comprising enhancing tumor (ET), necrosis/non-enhancing tumor (NET), and edema sub-compartments, and 2) the individual tumor sub-compartments.

METHODS

Our cohort consisted of 300 adult tumor MRI scans (BRATS) and 78 pediatric MB scans (46 training, 32 testing) with Gd-T1w, T2w, and FLAIR protocols. Training set subjects were collected from Children’s Hospital of Los Angeles (N=18) and Cincinnati Children’s Hospital Medical Center (N=28), whereas test set subjects were collected from Children’s Hospital of Philadelphia. Preprocessing included age-specific atlas registration, skull stripping, and bias correction. Then, using nnUnet framework, we trained 3D- deep learning U-net models on BRATS dataset for the tumor sub-compartments: ET, edema, and NET + necrosis, as well as the tumor habitat. Our initial learning rate was 0.01, with stochastic gradient descent as optimizer, and an average of dice loss and cross-entropy loss as the loss function. We then performed transfer learning using Models Genesis on the pediatric subjects.

RESULTS

Our segmentation model yielded mean dice scores of 0.87± .02 for tumor habitat, .83± .04 for ET, .742±.05 for edema, and .54±.11 for NET + necrosis, across fivefold cross-validation runs. For test set, our model yielded mean dice scores of 0.80 for the tumor habitat, 0.67 for ET, 0.54 for edema, and 0.28 for NET + necrosis.

CONCLUSION

Our transfer learning model shows promise in accurate automatic delineation of the MB tumor habitat and its individual sub-compartments, towards efficient surgical and treatment planning in MB tumors.
SURG-04. INFLUENCE OF LOW-INTENSITY FOCUSED ULTRASOUND ON LOCOREGIONAL DRUG DELIVERY TO THE BRAIN
Authors: Martin Brice , Uribe Rafael , Larabee Madeline , Stavarache Mihaela , Dahmane Nadia , Kaplitt Michael , Souweidane Mark
Published: June 2023

INTRODUCTION

Efficient delivery of therapeutic drugs across the blood-brain barrier (BBB) for the treatment of central nervous system (CNS) tumors is a major challenge to the development of safe and efficacious therapies. Among the different approaches developed to circumvent these limitations to improve drug delivery to a target tissue, low-intensity focused-ultrasound (LIFU) is a particularly appealing strategy as it will transiently disrupt the blood-brain barrier. Locoregional (intrathecal [IT] and convection-enhanced delivery [CED]) are clinically relevant routes of drug delivery that bypass the BBB and avoid systemic exposure. These routes of administration are known to achieve otherwise unobtainable drug concentration in specified target tissue. However, it remains unknown how locoregional routes of delivery coupled with FUS could change the drug targeting and pharmacokinetics.

METHODS

In the present study, we quantitatively assessed how FUS coupled with IT, IV, or CED altered fluorescent dye (Dextran 2000kD) distribution and concentration in a predetermined neurotomical region in a naïve murine model. We then analyzed the pharmacokinetic effects of using FUS mediated BBB disruption coupled with CED by measuring the volume of distribution and time-dependent concentration of the dye.

RESULTS

Our results indicate that IV administration coupled with LIFU will successfully cause diffusion of dye into the pre-defined sonication targets. Alternatively, measurable dye in the sonication target was hardly detected when administered IT in comparison to IV delivery (VIT = 1.25mm3; VIV = 36.20mm3). In addition, our preliminary qualitative analysis suggests that LIFU coupled with CED shows shorter time of residence of the dye in the parenchyma when compared to CED alone. This suggests that increased BBB permeability from FUS leads to faster drug clearance.

CONCLUSION

Our results highlight the distributive and pharmacokinetic influence of FUS on various locoregional drug delivery routes.
SURG-06. ENHANCED DELIVERY OF ANTI-PD1 FOR TREATMENT OF DIFFUSE MIDLINE GLIOMA USING FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING
Authors: Kokossis Danae , Wei Hong-Jian , Gallitto Matthew , Yoh Nina , McQuillan Nicholas , Tazhibi Masih , Berg Xander , Zhang Xu , Szalontay Luca , Gartrell Robyn D , Pavisic Jovana , Zhang Zhiguo , Molotkov Andrei , Mintz Akiva , Konofagou Elisa E , Wu Cheng-Chia
Published: June 2023

Diffuse midline glioma with H3K27 mutation is a fatal central nervous system tumor, most commonly arising in the brainstem. Despite a multitude of clinical trials, prognosis remains poor with a median overall survival of 9-12 months. Immune-checkpoint inhibitors (ICIs) have transformed the treatment landscape of multiple solid tumors. Programmed cell death protein 1 (PD1) is an immune checkpoint protein expressed on the surface of activated T cells; interaction with its ligand, PDL1, is tumor-protective, dampening T cell response. Recent phase I clinical trials have shown that ICIs targeting proteins along the PD1/PDL1 axis are well tolerated in patients with DMG; however, efficacy remains low. The blood-brain barrier (BBB) poses a major challenge to the efficacious delivery of therapeutic agents with large molecular size, such as anti-PD1. Here we show that delivery of anti-PD1 can be enhanced over 3.5-fold using low intensity focused ultrasound (FUS) and concurrent microbubble administration to achieve reversible blood-brain barrier opening (BBBO) in a syngeneic mouse DMG model established with intracranial injection of cell line 4423 (PDGFB+, H3.3K27M, p53-/-). We measured this increased delivery of anti-PD1 after BBBO using Western Blot and 3D in vivo optical fluorescent imaging/CT (OI/CT) of Cy7 labeled anti-PD1. OI/CT revealed enhanced real-time antibody distribution peritumorally. Furthermore, we demonstrated that this combined treatment of FUS and anti-PD1 led to benefit in local control of tumor growth using volumetric analysis of MRI. Preliminary survival studies suggest a positive trend for overall survival. We consider these findings strong rationale for further investigation of the therapeutic effects of combinatorial treatment using FUS-mediated BBBO and ICIs for the treatment of DMG.
OTHR-04. DEVELOPMENT OF A FUNCTIONAL PLATFORM FOR REAL-TIME PERSONALIZED DRUG SENSITIVITY PROFILING OF PATIENT-DERIVED 3D FRESH TUMOR TISSUE CULTURES IN THE PEDIATRIC PRECISION ONCOLOGY PROGRAM INFORM
Authors: Peterziel Heike , Jamaladdin Nora , ElHarouni Dina , Gerloff Xenia F , Herter Sonja , Fiesel Petra , Berker Yannick , Blattner-Johnson Mirjam , Schramm Kathrin , Jones Barbara C , Reuss David , Turunen Laura , Friedenauer Aileen , Holland-Letz Tim , Sill Martin , Weiser Lena , Previti Christopher , Balasubramanian Gnanaprakash , Gerber Nicolas U , Gojo Johannes , Hutter Caroline , Øra Ingrid , Lohi Olli , Kattamis Antonis , de Wilde Bram , Westermann Frank , Tippelt Stephan , Graf Norbert , Nathrath Michaela , Sparber-Sauer Monika , Sehested Astrid , Kramm Christof M , Dirksen Uta , Kallioniemi Olli , Pfister Stefan M , van Tilburg Cornelis M , Jones David T W , Saarela Jani , Pietiäinen Vilja , Jäger Natalie , Schlesner Matthias , Kopp-Schneider Annette , Oppermann Sina , Milde Till , Witt Olaf , Oehme Ina
Published: June 2023

The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75-78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.
OTHR-05. A LIVING EX VIVO PLATFORM FOR FUNCTIONAL, PERSONALIZED PEDIATRIC BRAIN CANCER DIAGNOSIS
Authors: Mann Breanna , Zhang Xiaopei , Bell Noah , Adefolaju Adebimpe , Thang Morrent , Dasari Rajaneekar , Kanchi Krishna , Valdivia Alain , Yang Yang , Quinsey Carolyn , Rauf Yasmeen , Kram David , Cassidy Noah , Viziri Cyrus , Corcoran David L , Rego Stephan , Jiang Yuchao , Graves Lee M , Dunn Denise , Floyd Scott , Baldwin Albert , Hingtgen Shawn , Satterlee Andrew
Published: June 2023

Functional precision medicine platforms are emerging as promising strategies to improve pre-clinical drug testing and guide clinical decisions. We have developed an organotypic brain slice culture (OBSC)-based platform and multi-parametric algorithm which enable rapid engraftment, treatment, and analysis of fresh patient brain tumor tissue and patient-derived cell lines. The platform has supported engraftment of every patient tumor tested to this point: high- and low-grade adult and pediatric tumor tissue rapidly establish on OBSCs among endogenous astrocytes and microglia while maintaining the tumor’s original DNA profile. Our algorithm calculates dose-response relationships of both tumor kill and healthy tissue toxicity, generating summarized drug sensitivity scores based on therapeutic window and allowing us to normalize response profiles for a panel of FDA-approved and exploratory agents. Summarized patient tumor scores after OBSC treatment revealed positive associations to clinical outcomes, suggesting the OBSC platform can provide rapid, accurate, functional testing to ultimately guide patient care.
OTHR-06. NARRATIVE MEDICINE AND THE PRACTICE OF PEDIATRIC NEURO-ONCOLOGY: GRAPPLING WITH THE UNTHINKABLE
Authors: Riley Kathy , Toback Alison
Published: June 2023

As pediatric neuro-oncology team members work with patients, they engage in life and death struggles on behalf of children. Among patients who survive, many are left with intellectual decline, psychological difficulties, inability to take on daily life skills, and an overall decrease in health-related quality of life (Castellino et al., 2014). Absorbing the weight of these stories of illness and complex survival leads to risk of burnout and moral distress. This research sought to understand how pediatric neuro-oncology team members at a U.S. hospital interact with, interpret, and make meaning of the illnesses, complex recoveries, and deaths of patients as a result of participating in a series of narrative medicine workshops. In the workshops, team members encountered fictional stories of loss and longing for restoration as they engaged in close reading and discussion of a text. Writing about the text after participating in discussion helped members connect more deeply to their own formative stories. Further, it enlarged their capacity to connect to the stories of fellow team members and the narratives of patients and their families. Those who practice narrative medicine seek “to recognize, absorb, interpret, and be moved to action by the stories of others” (Charon et al., 2017, p. 1). Its methods harness creativity and insight to equip those in healthcare not only to diagnose and treat their patients but to bear witness to what patients undergo (Charon et al., 2017). If team members train themselves to see the beauty, pain, complexity, and ambiguity in a work of art, they may in turn see their patients and one another as works of art. The act of engaging in narrative medicine practice as a healthcare team in and of itself alleviates distress and fosters collaborative relationships among team members as they grapple with unthinkable loss in their work.
OTHR-11. THE IMPORTANCE AND INFLUENCE OF PATIENT FAMILY INVOLVEMENT IN PEDIATRIC NEURO-ONCOLOGY RESEARCH
Authors: Lyons Nicole , Resnick Adam , Waanders Angela , Nazarian Javad , Bornhorst Miriam , Minturn Jane E , Koptyra Mateusz , Monje-Deisseroth Michelle , Souweidane Mark , Greenfield Jeffery P , Smith Amy , Hegert Julia , McLean Ginny , Gustafson Patti , Gustafson Allen , Ward Lisa
Published: June 2023

The involvement of patient families in clinical research in pediatric brain cancer is an underutilized tool that benefits all those involved. These families are ultimately responsible for making decisions on treatment, as well as end-of-life decisions such as post-mortem tissue donation. As demonstrated by organizations such as Gift from a Child, listening to family input on how to best have the conversation surrounding post-mortem tissue donation has led to an increase in total donations, as well as parents stating they are overwhelmingly happy with their decision to donate. Tissue donation is just one example of a large, complex hindrance in the field that had not previously been addressed successfully. Due to the rarity and devastating impact of pediatric brain tumors, the family community is tight-knit and passionate. There is incredibly impactful communication that happens between families influencing decision-making for treatment, funding, and advocacy. Partnering with families allows care teams and researchers both the ability to understand the decision-making process as well as educate and discuss with the families. Surveys of families overwhelmingly show satisfaction with the decision to donate post-mortem and dissatisfaction when they are deprived of the option. Frustration with the lack of treatment has led families to become more proactive in both their child’s treatment and future research. Increasingly, family advocates are becoming more sophisticated in their support of research opportunities. An example of this spearheading the creation of an open access, safe, anonymized data bank with clinical data paired to the patient’s tumor tissue. Family foundations are actively partnering with researchers and industry to make it happen. It is clear that this type of partnership is a strong force for change that benefits researchers, clinicians, and most importantly, patients and their families.
XRT-01. LONG-TERM HEARING LOSS IN CHILDREN WITH MEDULLOBLASTOMA AFTER PROTON IRRADIATION AND CHEMOTHERAPY
Authors: Abu-Arja Mohammad H , Brown Austin L , Su Jack M , Okcu M Fatih , Lindsay Holly B , McGovern Susan L , McAleer Mary Frances , Grosshans David R , Chintagumpala Murali M , Paulino Arnold C
Published: June 2023

PURPOSE

To evaluate the incidence and risk factors for hearing loss (HL) among children with medulloblastoma treated with proton irradiation and cisplatin.

METHODS

We identified children with medulloblastoma ≥3 years of age treated at Texas Children’s Hospital between 2007-2022. Audiograms were graded using the International Society of Pediatric Oncology-Boston scale (SIOP-Boston). Time to grade ≥3 HL was evaluated using Kaplan-Meier and multivariable Cox models to estimate hazard ratios (HR) and 95% confidence intervals (CI).

RESULTS

Seventy-eight patients (65.4% male) were treated with craniospinal irradiation (CSI) at a median age of 7.6 years (range: 3-21). The mean cochlear irradiation dose was 31.5±9 Gy, and the cumulative cisplatin dose was 295±50 mg/m2. Fifty-six patients (72%) received amifostine. Patients completed a median of 9 audiograms (range: 4-22) with a median audiogram follow-up of 49 months (range: 3-177). Grade ≥3 HL was documented in 25 patients (32%). In adjusted Cox models, mean cochlear dose (HR=1.12, 95% CI: 1.06-1.18) and the age at CSI (HR=0.81, 95% CI: 0.68-0.98) were associated with grade ≥3 HL. Among children who received irradiation after or at 7 years of age, the estimated probability of grade ≥3 HL at three years post-CSI was 12.6% (95% CI: 4.1-34.6) in children exposed to <36 Gy cochlear irradiation and 35.6% (95% CI: 17.4-63.6) in children exposed to >36 Gy cochlear irradiation. Among children who received irradiation before 7 years of age, the estimated probability of grade ≥3 HL at three years post-CSI was 16.5% (95% CI: 5.6-43) in children exposed to <36 Gy cochlear radiation and 66.7% (95% CI: 35.4-93.7) in children exposed to >36 Gy cochlear irradiation.

CONCLUSION

Long-term follow-up shows that children who received a cochlear dose ≥36 Gy before 7 years of age are at higher risk for HL, regardless of the amifostine and the cisplatin dose.
XRT-03. EFFICACY OF RE-IRRADIATION FOR PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Cai Linbo , Lai Mingyao , Li Juan , Zhou Jiangfen , Li Shaoqun
Published: June 2023

OBJECTIVE

To analyze the efficacy and prognosticators of pediatric diffuse intrinsic pontine glioma (DPC) treated with re-irradiation.

METHODS

The clinical data and prognostic information of DIPG children younger than 18 years old who received re-irradiation in the Department of Oncology of Guangdong Sanjiu Brain Hospital from May 1, 2021, to November 1, 2022, were collected. The overall survival (OS) was calculated, and univariate analysis was performed to analyze the effect of tumor volume change and rate of change on survival.

RESULTS

Fifteen patients met the inclusion criteria. The median interval between the first and second radiotherapy was 8.8 months. The median survival after re-irradiation was 3.9 months, and the median overall survival was 16.9 months. Severe complications such as fatal radiation brain necrosis was observed after re-irradiation.

CONCLUSIONS

Re-irradiation is still the primary treatment for pediatric diffuse intrinsic pontine glioma, prolonging their survival.
TRLS-01. FDA ANALYSIS OF EXPANDED ACCESS USE IN PEDIATRIC PATIENTS WITH CNS TUMORS FROM 2015 TO 2020
Authors: Duke Elizabeth , Kormanik Natasha , Barone Amy , Chan Mitchell , Antony Ramya , Drezner Nicole , Kluetz Paul , Kim Tamy , Singh Harpreet , Pazdur Richard , Donoghue Martha
Published: June 2023

Few therapies are approved for children with central nervous system (CNS) tumors, and their prognosis is often poor. Expanded Access (EA) is a regulatory mechanism enabling patients with life-threatening or serious diseases to receive treatment with investigational drugs outside of clinical trials when no comparable or satisfactory options are available. FDA’s central database was queried for single-patient investigational new drug (spIND) applications submitted to the Office of Oncologic Diseases between January 2015-December 2020. Data collection included IND date/type/status, drug name, patient demographics. Duplicate/exempt INDs, those cancelled by physician-sponsor before initiating therapy, and those for indications occurring almost exclusively in adults or missing patient age were excluded. Of 2,901 unique spINDs granted, 534 (18%) were for patients <18 years old; of those, 229 (43%) were for patients with nervous system tumors. Demographics included: 53% male, median age 5.0 years (range 0.3-17); race/ethnicity reported in <1%. Patients were treated in 78 zip codes across 33 states; one-third of submissions were from 5 large academic hospitals. Tumor types included low-grade glioma (71), plexiform neurofibroma (35), high-grade glioma (32), DIPG/DMG (30), ATRT (27), medulloblastoma (11), ependymoma (11), other CNS tumors (12). Thirty-eight unique drugs were requested (1 to 56 spINDs per drug); 60% for kinase inhibitors, 30% for other small molecule inhibitors, and the remainder for immunotherapies/other drug types. Median time for FDA to review and deem safe to proceed was 1 day. While pediatric CNS tumors are rare, these patients made up almost half of spINDs granted for pediatric patients. Ongoing efforts are needed to assess the impact of EA on patient outcomes and ensure availability to patients, families, and institutions more widely. These data highlight interest within the pediatric neuro-oncology community in accessing innovative therapies, which supports early investigation of promising new drugs for these patients.
TRLS-03. IBRUTINIB DISRUPTS BLOOD-TUMOR BARRIER INTEGRITY TO ENHANCE CNS DRUG DELIVERY AND RODENT GLIOMA MODEL SURVIVAL
Authors: Lim Sanghee , Kwak Minhye , Tang Kayen , Cesaire Melissa , Robey Robert , Gottesman Michael , Jackson Sadhana
Published: June 2023

BACKGROUND

In the setting of malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-brain-barrier (BBB). Identifying agents that transiently increase BBB permeability would advance glioma treatment. Ibrutinib, an FDA approved lymphoma treatment, has previously impaired aortic endothelial adhesion and in combination with cytotoxic therapy, increased rodent glioma model survival. In this study, we propose ibrutinib inhibits brain endothelial cell junctional expression to disrupt BBB integrity and increase chemotherapy delivery to malignant glioma cells.

METHODS

Using rat glioma cells, S635, we evaluated treatment effects with doxil (3mg/kg), ibrutinib (25mg/kg) and combination therapy. We measured effects with serial brain MRIs, doxil plasma and brain regional concentrations, along with 3kD dextran permeability. To evaluate the effects of ibrutinib on in vitro brain endothelial cells, we measured changes in cell-cell electrical impedance and rhodamine efflux, as a surrogate of Abcb1 transporter function, over time (0 to 8h) and at varied drug concentrations (1, 5, and 10µM ibrutinib).

RESULTS

Ibrutinib in combination with doxil, prolonged median survival in rodent glioma models (18 vs. 24days, p<0.05). MRI findings demonstrated a -14 or -53% vs -75% tumor volume change with doxil or ibrutinib alone vs. combination therapy, respectively (p<0.05). Comparing combination therapy vs. doxil alone, ibrutinib increased CNS concentrations of doxil in the tumor injected brain regions with statistical significance (56ng/mL vs. 74.6ng/mL, p<0.05). In in vitro studies, ibrutinib decreased brain endothelial cell-cell impedance maximally at 2 hours, in a dose dependently without affecting cell viability. Additionally, we observed ibrutinib dose dependently inhibit Abcb1 activity in both endothelial and glioma cells.

CONCLUSION

Our results suggest ibrutinib increases brain endothelial permeability by causing junctional disruption and inhibition of Abcb1, resulting in increased CNS drug entry and prolonged survival in glioma rat models.
TRLS-13. NOVEL PAN-RAF INHIBITOR BELVARAFENIB AS A PROMISING TARGETED THERAPY FOR BRAF-ALTERED PEDIATRIC LOW-GRADE GLIOMAS
Authors: Gonzalez Maxine , Lebert Brittany , Campion Stephani , Aguilar-Bonilla Ana , Smith Amy
Published: June 2023

In recent years targeted therapy has improved the outcome of childhood cancer patients. The second most common pediatric cancers are central nervous system (CNS) tumors, particularly low-grade gliomas (LGGs). Approximately 15-20% of pediatric LGGs cases present with oncogenic mutations that alter the RAS/mitogen-activated protein kinase (MAPK) signaling pathway by the B-RAF kinase constitutive activation. Only five RAF inhibitors are FDA-approved as cancer treatments and with limited-to-no data for pediatric patients. The lack of pediatric data results from limited access to childhood clinical trials, although there has been an increase in clinical trials for RAF inhibitors and combinations for children. However, there is a pressing need for alternative therapeutic approaches for pediatric patients with BRAF-altered LGGs. Hence, this study proposes a type II pan-RAF inhibitor called Belvarafenib (BEV) as a potential therapeutic candidate. Belvarafenib has shown viability effects at 500fM to 5nM in a PRKAR2B/BRAF fusion patient-derived cell line with a calculated cytotoxic concentration 50 (CC50) of 2nM. The expression of apoptotic markers will be measured to characterize the mechanism of cell death through BEV’s direct stimulation of the MAPK signaling or via an alternative pathway. Understanding the allosteric properties of the RAF inhibitor Belvarafenib enables the opportunity to have effective and well-tolerated alternative therapies for BRAF-altered tumors in children. Thus, this preliminary study intends to profile the effectivity of Belvarafenib in cell culture and help design in vivo experiments with the potential to establish clinical trials in combination with other potential therapeutic agents.
TRLS-15. TARGETED THERAPY IN PEDIATRIC CNS TUMORS - A SINGLE INSTITUTION EXPERIENCE
Authors: Olsen Braden , Gonzalez Keishla , del Riego Angela Parra , Torres Marleni , Pabon Camila , Maher Ossama , Niazi Toba , Ragheb John , Hall Matthew , Khatib Ziad
Published: June 2023

Primary central nervous system malignancy treatment remains a difficult problem despite advancement in techniques. Personalized medicine is evolving in making treatment decisions and particular molecular characteristics allow new targeted therapies to be specific and effective. We retrospectively present patients with primary CNS tumors receiving targeted therapy from 2016 to the present date. Outcomes included length of therapy, time until progression of disease, and overall response. Our study includes 32 patients with malignancies such as Astrocytoma, Ganglioglioma, Glioblastoma, and Diffuse Intrinsic Pontine Glioma (DIPG), among others. Analysis was based on patients’ underlying malignancy and included variables such as identified mutations, targeted therapy, progression vs resolution of disease, and time to progression of disease after initiation of targeted therapy. Overall results show 23 patients with at least 1-year-survival. The most common targeted therapy was Trametinib, treating tumors of glial origin. 14 patients showed no progression after starting targeted therapy, the majority low grade Gliomas and Medulloblastomas. Multiple mutations were found with the most frequent being BRAF. Of our 11 patients with BRAF mutations, 8 had no progression of disease after starting Trametinib or Dabrafenib. Patients with Atypical Teratoid Rhabdoid Tumors (ATRT) were treated with either Alisertib or Alisertib/Tazemetostat and 2 out of 4, both treated with Alisertib maintenance therapy, had no disease progression after targeted therapy. Best outcomes with no disease progression were primarily Gliomas, treated with Trametinib, and Medulloblastomas, treated with Vismodegib. Of our patients with DIPG, treated with Ribociclib, average time to disease progression on targeted therapy was 4.7 months and survival rate was 33%. We have shown excellent use of targeted therapy and our analysis highlights the need for continued exploration of targeted therapy among patients with CNS tumors.
boston (1848–1854)
Authors: Adams Henry
Published: June 2023

Peter Chardon Brooks, the other grandfather, died January 1, 1849, bequeathing what was supposed to be the largest estate in Boston, about two million dollars, to his seven surviving children: four sons—Edward, Peter Chardon, Gorham, and Sydney; three daughters—Charlotte, married to Edward Everett; Ann,...
rome (1859–1860)
Authors: Adams Henry
Published: June 2023

The tramp in Thüringen lasted four-and-twenty hours. By the end of the first walk, his three companions—John Bancroft, James J. Higginson, and B. W. Crowninshield,* all Boston and Harvard College like himself—were satisfied with what they had seen, and when they sat...
treason (1860–1861)
Authors: Adams Henry
Published: June 2023

When, forty years afterwards, Henry Adams looked back over his adventures in search of knowledge, he asked himself whether fortune or fate had ever dealt its cards quite so wildly to any of his known antecessors as when it led him to begin the...
dilettantism (1865–1866)
Authors: Adams Henry
Published: June 2023

The campaign of 1864 and the reëlection of Mr. Lincoln in November set the American Minister on so firm a footing that he could safely regard his own anxieties as over, and the anxieties of Earl Russell and the Emperor Napoleon as begun. With...
free fight (1869–1870)
Authors: Adams Henry
Published: June 2023

The old New Englander was apt to be a solitary animal, but the young New Englander was sometimes human. Judge Hoar brought his son Sam to Washington, and Sam Hoar loved largely and well. He taught Adams the charm of Washington spring. Education for...
chicago (1893)
Authors: Adams Henry
Published: June 2023

Drifting in the dead-water of the fin-de-siècle—and during this last decade everyone talked, and seemed to feel fin-de-siècle—where not a breath stirred the idle air of education or fretted the mental torpor of self-content, one lived alone. Adams had long...
teufelsdröckh (1901)
Authors: Adams Henry
Published: June 2023

Inevitable Paris beckoned, and resistance became more and more futile as the store of years grew less; for the world contains no other spot than Paris where education can be pursued from every side. Even more vigorously than in the twelfth century, Paris taught...
Ulysses
Authors: Joyce James
Published: June 2023

‘- What is your nation if I may ask, says the citizen.

- Ireland, says Bloom. I was born here. Ireland.’

Ulysses, one of the greatest novels of the twentieth century, has had a profound influence on modern fiction. In a series of episodes covering the course of a single day, 16 June 1904, the novel traces the movements of Leopold Bloom and Stephen Dedalus through the streets of Dublin. Each episode has its own literary style, and the epic journey of Odysseus is only one of many correspondencies that add layers of meaning to the text.

Today critical interest centres on the authority of the text, and this edition, complete with an invaluable introduction, notes, and appendices, republishes without interference, the original 1922 text. Jeri Johnson’s commentary guides the reader through this highly allusive novel in an edition acclaimed by scholars and general readers alike.

This updated edition includes new explanatory notes, a revised introduction, and expanded bibliography.
I
Authors: Woolf Virginia
Published: June 2023

‘So of course,’ wrote Betty Flanders, * pressing her heels rather deeper in the sand, ‘there was nothing for it but to leave.’

Slowly welling from the point of her gold nib, pale blue ink dissolved the full stop; for there her pen stuck; her...
III
Authors: Woolf Virginia
Published: June 2023

‘This is not a smoking-carriage,’ Mrs Norman protested, nervously but very feebly, as the door swung open and a powerfully built young man jumped in. He seemed not to hear her. The train did not stop before it reached Cambridge, and here she...
XII
Authors: Woolf Virginia
Published: June 2023

The water fell off a ledge like lead — like a chain with thick white links. The train ran out into a steep green meadow, and Jacob saw striped tulips growing and heard a bird singing, in Italy.

A motor car full of Italian officers...
XIII
Authors: Woolf Virginia
Published: June 2023

‘The height of the season,’ said Bonamy.

The sun had already blistered the paint on the backs of the green chairs in Hyde Park; peeled the bark off the plane trees; and turned the earth to powder and to smooth yellow pebbles. Hyde Park...
The End of the Tether
Authors: Conrad Joseph
Published: June 2023

This selection of four tales by Conrad is about radical insecurity: lone human beings involuntarily forced into confrontation with a terrifying universe in which they can never be wholly at home. It leads with ‘The End of the Tether’ and includes also ‘The Duel’, ‘The Return’, and ‘Amy Foster’ - Sailor, Soldier, Rich Man, Immigrant. These powerful shorter works remind readers that Conrad is not just the teller of sea stories and tales of imperialist action, and not only the author of the ubiquitous ‘Heart of Darkness’. This is the Conrad who is master of the terror element - global crisis, individual test, and personal trauma - in modern literature.

For over 100 years Oxford World’s Classics has made available the widest range of literature from around the globe. Each affordable volume reflects Oxford’s commitment to scholarship, providing the most accurate text plus a wealth of other valuable features, including expert introductions by leading authorities, helpful notes to clarify the text, up-to-date bibliographies for further study, and much more.
The End of The Tether
Authors: Conrad Joseph
Published: June 2023

I

For a long time after the course of the steamer Sofala
* had been altered for the land, the low swampy coast had retained its appearance of a mere smudge of darkness beyond a belt of glitter. The sunrays fell violently upon...
XII
Authors: Wharton Edith
Published: June 2023

One afternoon towards the end of August a group of girls sat in a room at Miss Hatchard’s in a gay confusion of flags, turkey-red, blue and white paper muslin, harvest sheaves and illuminated scrolls.

North Dormer was preparing for its Old Home Week. That...
XVI
Authors: Wharton Edith
Published: June 2023

The rain held off, and an hour later, when she started, wild gleams of sunlight were blowing across the fields.

After Harney’s departure she had returned her bicycle to its owner at Creston, and she was not sure of being able to walk all the...
Swann in Love
Authors: Proust Marcel , Nelson Brian
Published: June 2023

‘Swann’s love … could not have been torn out of him without destroying him almost entirely’

Swann in Love is a brilliant, devastating novella that tells of infatuation, love, and jealousy. Set against the backdrop of Paris at the end of the nineteenth century, the story of Charles Swann illuminates the fragilities and foibles of human beings when in the grip of desire. Swann is a highly cultured man-about-town who is plunged into turmoil when he falls for a young woman called Odette de Crécy. The novel traces the progress of Swann’s emotions with penetrating exactitude as he encounters Odette at the regular gatherings in the salon of the Verdurins. His wilful self-delusion is both poignant and ridiculous, and his tormented feelings play out in scenes of high comedy amongst Odette’s socially pretentious circle.

Swann in Love is part of Proust’s monumental masterpiece In Search of Lost Time, and it is also a captivating self-contained story. This new translation encapsulates the qualities that have secured Proust’s reputation, and serves as a perfect introduction to his writing.
The League Of the Scarlet Pimpernel
Authors: Orczy Baroness
Published: June 2023

They all looked a merry, even a happy party, as they sat round the table; Sir Andrew Ffoulkes and Lord Antony Dewhurst, two typical good-looking, well-born and well-bred Englishmen of that year of grace 1792, and the aristocratic French comtesse with her two children,...
The Outrage
Authors: Orczy Baroness
Published: June 2023

A beautiful starlit night had followed on the day of incessant rain: a cool, balmy, late summer’s night, essentially English in its suggestion of moisture and scent of wet earth and dripping leaves.

The magnificent coach, drawn by four of the finest thoroughbreds in England,...
Doubt
Authors: Orczy Baroness
Published: June 2023

Marguerite Blakeney had watched the slight sable-clad figure of Chauvelin, as he worked his way through the ball-room. Then perforce she had had to wait, while her nerves tingled with excitement.

Listlessly she sat in the small, still deserted boudoir, looking out through the curtained...
Suspense
Authors: Orczy Baroness
Published: June 2023

It was late into the night when she at last reached ‘The Fisherman’s Rest.’ She had done the whole journey in less than eight hours, thanks to innumerable changes of horses at the various coaching stations, for which she always paid lavishly, thus obtaining...
On the Track
Authors: Orczy Baroness
Published: June 2023

Never for a moment did Marguerite Blakeney hesitate. The last sounds outside the ‘Chat Gris’ had died away in the night. She had heard Desgas giving orders to his men, and then starting off towards the fort, to get a reinforcement of a dozen...
Edgar Allan Poe
Authors: Poe Edgar Allan
Published: June 2023

Of course I shall not pretend to consider it any matter for wonder, that the extraordinary case of M. Valdemar has excited discussion. It would have been a miracle had it not—especially under the circumstances. Through the desire of all parties concerned, to keep...
E. M. Forster
Authors: Forster E. M.
Published: June 2023

The Air-Ship

Imagine, if you can, a small room, hexagonal in shape, like the cell of a bee. It is lighted neither by window nor by lamp, yet it is filled with a soft radiance. There are no apertures for ventilation, yet the air...
W. E. B. Du Bois
Authors: Du Bois W. E. B.
Published: June 2023

He stood a moment on the steps of the bank, watching the human river that swirled down Broadway.* Few noticed him. Few ever noticed him save in a way that stung. He was outside the world—‘nothing!’ as he said bitterly. Bits of...
7
Authors: Arnim Elizabeth Von
Published: June 2023

Their eyes followed her admiringly. They had no idea they had been snubbed. It was a disappointment, of course, to find she had forestalled them and that they were not to have the happiness of preparing for her, of watching her face when she...
22
Authors: Arnim Elizabeth Von
Published: June 2023

That evening was the evening of the full moon. The garden was an enchanted place where all the flowers seemed white. The lilies, the daphnes, the orange-blossom, the white stocks, the white pinks, the white roses — you could see these as plainly as in the...
First Conversation with the Landlady
Authors: Kafka Franz
Published: June 2023

He would have liked to speak to Frieda in private about the assistants. She laughed and joked with them now and then, but their mere intrusive presence troubled him. Not that they were demanding; they had settled down on the floor in a corner...
16
Authors: Kafka Franz
Published: June 2023

K. stayed behind, looking rather surprised; Olga laughed at him and drew him over to the bench by the stove. She seemed to be really happy to be able to sit here alone with him, but it was a peaceable happiness, certainly untroubled...
Petitioning
Authors: Kafka Franz
Published: June 2023

‘And what were we doing meanwhile? The worst thing we could have done, something for which we might more rightly have been despised than for our real offence—we betrayed Amalia, we broke with her rule of silence, we couldn’t go on living like...
21
Authors: Kafka Franz
Published: June 2023

So what could have been foreseen but not prevented had happened. Frieda had left him. That needn’t necessarily be final; it wasn’t as bad as all that, Frieda could be won back. She was easily influenced by strangers and definitely by those assistants, who...
Block, the Corn Merchant ⋅ The Dismissal of the Lawyer
Authors: Kafka Franz
Published: June 2023

K. had finally decided to take his case out of the lawyer’s hands. He couldn’t entirely rid himself of doubts as to whether this was the correct course of action, but they were outweighed by his conviction that it was necessary. On the day...
The End
Authors: Kafka Franz
Published: June 2023

On the day before his thirty-first birthday—it was towards nine o’clock in the evening, the time when the streets are quiet—two men came to K.’s apartment, pale and fat, wearing frock coats and top hats that looked as if they were stuck on. Brief...
The Metamorphosis
Authors: Kafka Franz
Published: June 2023

I

As Gregor Samsa woke one morning from uneasy dreams, he found himself transformed into some kind of monstrous vermin.* He lay on his hard, armour-like back, and if he lifted his head a little, he could see his curved brown abdomen, divided...
Lord Jim
Authors: Conrad Joseph
Published: June 2023

‘To the white men in the waterside business and to the captain of ships he was just Jim - nothing more. He had, of course, another name, but he was anxious that it should not be pronounced.’

Lord Jim tells the story of a young, idealistic Englishman - ‘as unflinching as a hero in a book’ - who is disgraced by a single act of cowardice while serving as an officer on the Patna, a merchant-ship sailing from an Eastern port. His life is blighted: an isolated scandal assumes horrifying proportions. An older man, Marlow, befriends Jim, and helps to establish him in Patusan, a remote Malay settlement. There he achieves a kind of peace, but his courage is put to the test once more.

Lord Jim is one of the most profound and rewarding psychological novels in English. Set in the context of social change and colonial expansion in late Victorian England, it embodies in Jim the values and the turmoil of a fading empire. In his introduction and notes to this new edition Jacques Berthoud explores the social and cultural dynamics that inform the novel.
Chapter II
Authors: Conrad Joseph
Published: June 2023

After two years of training he went to sea, and entering the regions so well known to his imagination, found them strangely barren of adventure. He made many voyages. He knew the magic monotony of existence between sky and water: he had to bear...
Chapter XXVII
Authors: Conrad Joseph
Published: June 2023

“Already the legend had gifted him with supernatural powers. Yes, it was said, there had been many ropes cunningly disposed, and a strange contrivance that turned by the efforts of many men, and each gun went up tearing slowly through the bushes, like...
Chapter XXVIII
Authors: Conrad Joseph
Published: June 2023

“The defeated Sherif Ali fled the country without making another stand, and when the miserable hunted villagers began to crawl out of the jungle back to their rotting houses, it was Jim who, in consultation with Dain Waris, appointed the headmen. Thus he...
Chapter XXXVI
Authors: Conrad Joseph
Published: June 2023

With these words Marlow had ended his narrative, and his audience had broken up forthwith, under his abstract, pensive gaze. Men drifted off the verandah in pairs or alone without loss of time, without offering a remark, as if the last image of that...
Chapter XXXIX
Authors: Conrad Joseph
Published: June 2023

“All the events of that night have a great importance, since they brought about a situation which remained unchanged till Jim’s return. Jim had been away in the interior for more than a week, and it was Dain Waris who had directed the...
Chapter XL
Authors: Conrad Joseph
Published: June 2023

“Brown’s object was to gain time by fooling with Kassim’s diplomacy. For doing a real stroke of business he could not help thinking the white man was the person to work with. He could not imagine such a chap (who must be confoundedly...
Chapter XLI
Authors: Conrad Joseph
Published: June 2023

“To the very last moment, till the full day came upon them with a spring, the fires on the west bank* blazed bright and clear; and then Brown saw in a knot of coloured figures motionless between the advanced houses a...
Chapter XLIV
Authors: Conrad Joseph
Published: June 2023

“I don’t think they spoke together again. The boat entered a narrow by-channel, where it was pushed by the oar-blades set into crumbling banks, and there was a gloom as if enormous black wings had been outspread above the mist that filled its...
The Great Gatsby
Authors: Fitzgerald F. Scott
Published: June 2023

“He talked a lot about the past and I gathered that he wanted to recover something, some idea of himself perhaps, that had gone into loving Daisy. His life had been confused and disordered since then, but if he could once return to a certain starting place and go over it all slowly, he could find out what that thing was …”

The Great Gatsby (1925), F. Scott Fitzgerald’s masterpiece, stands among the greatest of all American fiction. Jay Gatsby’s lavish lifestyle in a mansion on Long Island’s gold coast encapsulates the spirit, excitement, and violence of the era Fitzgerald named ‘the Jazz Age’. Impelled by his love for Daisy Buchanan, Gatsby seeks nothing less than to recapture the moment five years earlier when his best and brightest dreams - his ‘unutterable visions’ - seemed to be incarnated in her kiss.

A moving portrayal of the power of romantic imagination, as well as the pathos and courage entailed in the pusuit of an unattainable dream, The Great Gatsby is a classic fiction of hope and disillusion. This edition is fully annotated with a fine Introduction incorporating new interpretation and detailing Fitzgerald’s struggle to write the novel, its critical reception and its significance for future generations.
CHAPTER I
Authors: Fitzgerald F. Scott
Published: June 2023

In my younger and more vulnerable years my father gave me some advice that I’ve been turning over in my mind ever since.

“Whenever you feel like criticising any one,” he told me, “just remember that all the people in this world haven’t had the...
The Sisters
Authors: Joyce James
Published: June 2023

There was no hope for him this time: it was the third stroke. Night after night I had passed the house (it was vacation time) and studied the lighted square of window: and night after night I had found it lighted in the same...
An Encounter
Authors: Joyce James
Published: June 2023

It was Joe Dillon who introduced the Wild West to us. He had a little library made up of old numbers of The Union Jack, Pluck and The Halfpenny Marvel. Every evening after school we met in his back garden...
Two Gallants
Authors: Joyce James
Published: June 2023

The grey warm evening of August had descended upon the city and a mild warm air, a memory of summer, circulated in the streets. The streets, shuttered for the repose of Sunday, swarmed with a gaily coloured crowd. Like illumined pearls the lamps shone...
A Mother
Authors: Joyce James
Published: June 2023

Mr Holohan, assistant secretary of the Eire Abu Society, had been walking up and down Dublin for nearly a month, with his hands and pockets full of dirty pieces of paper, arranging about the series of concerts. He had a game leg...
I
Authors: Joyce James
Published: June 2023

Once upon a time and a very good time it was there was a moocow coming down along the road and this moocow that was coming down along the road met a nicens little boy named baby tuckoo. …

His father told him that story:...
II
Authors: Joyce James
Published: June 2023

Uncle Charles smoked such black twist that at last his nephew suggested to him to enjoy his morning smoke in a little outhouse at the end of the garden.

—Very good, Simon. All serene, Simon, said the old man tranquilly. Anywhere you like. The outhouse...
To The Lighthouse
Authors: Woolf Virginia
Published: June 2023

Inspired by the lost bliss of her childhood summers in Cornwall, Virginia Woolf produced one of the masterworks of English literature in To the Lighthouse. It concerns the Ramsay family and their summer guests on the Isle of Skye before and after the First World War. As children play and adults paint, talk, muse and explore, relationships shift and mutate. A captivating fusion of elegy, autobiography, socio-political critique and visionary thrust, it is the most accomplished of all Woolf’s novels. On completing it, she thought she had exorcised the ghosts of her imposing parents, but she had also brought form to a book every bit as vivid and intense as the work of Lily Briscoe, the indomitable artist at the centre of the novel.
8
Authors: Woolf Virginia
Published: June 2023

He said nothing. He took opium. The children said he had stained his beard yellow with it. Perhaps. What was obvious to her was that the poor man was unhappy, came to them every year as an escape; and yet every year,...
16
Authors: Woolf Virginia
Published: June 2023

Well then, Nancy had gone with them, Mrs Ramsay supposed, wondering, as she put down a brush, took up a comb, and said ‘Come in’ to a tap at the door (Jasper and Rose came in), whether the fact that Nancy was...