tbuckley/cabot-search huggingface dataset:
IMMU-09. NIVOLUMAB THERAPY FOR A PEDIATRIC-ONSET PRIMARY INTRACRANIAL MELANOMA
Authors: Utako Oba, Yuhki Koga, Riichiro Kawaguchi, Kentaro Nakashima, Yojiro Akagi, Nobuhiro Hata, Nanae Yamamoto, Kenichi Kohashi, Satohiro Masuda, Koji Iihara, Yoshinao Oda, Shouichi Ohga
Journal: Neuro-Oncology (2020)

Abstract Primary intracranial malignant melanoma (PIMM) is an uncommon cancer in childhood, that accounts for approximately 1% of melanoma, and 0.07% of brain tumors even in all age group. Because extracranial malignant melanoma usually occurs as a cutaneous lesion, affected patients have a chance to receive the early diagnosis and curable resection of the isolated tumor. However, unresectable metastatic cases have a poor prognosis with a median overall survival of 8 months. We report a 12-year-old girl with PIMM who received nivolumab therapy after an administration of dacarbazine. The tumor harbored no BRAF mutation. After the intravenous administration of nivolumab, cerebrospinal fluid 5-S-cysteinyldopa levels declined and circulating CD8+HLA-DR+T cells increased, indicating the initial effect of nivolumab on PIMM. However, multiple lesions progressed for two month-immunotherapy, during which cerebrospinal fluid nivolumab concentrations attained to 1.2% of serum ones. The present case demonstrated the safety and modest effect of nivolumab for CNS melanoma. Nivolumab is a tolerable first-line therapy for diffuse PIMM, but pediatric patients need a more intensified CNS-specific immunotherapy.
Fludarabine/Treosulfan/Thiotepa/ATG Conditioning for Related Transplantation in b Thalassaemia Major Leads to Early and Sustained Engraftment with Low Incidence of VOD and GvHD but a High Rate of Long-Term Mixed Chimerism
Authors: Farah O'Boyle, Leena Karnik, Kirstin Lund, Richard Szydlo, Josu de la Fuente
Journal: Blood (2017)
Transparency as a Trust-Building Practice in Physician Relationships With Patients
Authors: Tara Montgomery, Jeffrey S. Berns, Clarence H. Braddock
Journal: JAMA (2020)

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マリとウガンダにおける小児死亡の状況:コミュニティに基づく機密的enir【JST・京大機械翻訳】
Authors: Willcox Merlin L, Kumbakumba Elias, Diallo Drissa, Mubangizi Vincent, Kirabira Peter, Nakaggwa Florence, Mutahunga Birungi, Diakite Chiaka, Dembele Eugene, Traore Mamadou, Daou Pierre, Bamba Drissa, Traore Amadou, Berthe Diafara, Wooding Nick, Dinwoodie Kieran, Capewell Sarah, Foster Hamish, Neville Rowena, Ngonzi Joseph, Kabakyenga Jerome, Mant David, Harnden Anthony
Journal: The Lancet Global Health (2018)
ETMR-19. SINGLE CELL ANALYSES OF ETMRs REVEAL THAT C19MC+ POPULATION DRIVES CELL CYCLE PROGRESSION AND STEM CELL MAINTENANCE
Authors: Iqra Mumal, Liming Xu, Fupan Yao, Tannu Suwal, Xiaolian Fan, Mei Lu, Annie Huang
Journal: Neuro-Oncology (2020)

Abstract Embryonal tumors with multilayered rosettes (ETMRs) are highly fatal diseases characterized by recurrent amplification of C19MC, an oncogenic miRNA cluster. While C19MC was discovered as a major driver of ETMRs, its direct role in ETMRs remains unknown. As ETMRs exhibit significant heterogeneity in C19MC expression, we employed single cell transcriptomics to investigate features of C19MC+ population. We conducted single-nuclei RNAseq of 23,269 cells from 6 primary and 2 matched recurrent ETMRs. We also conducted single-cell RNAseq of human neural stem cells (hNSC-5miR) and ETMR cell line (A664-5miR) with stable expression of 5 C19MC miRNAs. Bulk RNAseq (n=27), H3K27Ac ChiP-seq (n=5) and ATAC-seq (n=5) corroborated scRNAseq data and identified core transcription factors (TFs) of C19MC+ population. C19MC+ population (24%) mapped to neuro-epithelial cells and exhibited signatures of cell cycle and stem cell maintenance, consistent with bulk-RNAseq data. The C19MC+ population overlaps with MKI67+ cycling (57%) and PROM1+ stem cell population (56%). Interestingly, interrogation of hNSC-5mir and A664-5miR showed a larger MKI67+/PROM1+ population compared to controls. Likewise, hNSC-5miR/A664-5miR in vitro and in vivo experiments showed increased proliferation/stemness. C19MC+ population is characterized by SHH, WNT, mTOR, Hippo and IGF-signalling and driven by MEIS1, SOX11, ZNF521, RFX4 and NR2F2 TFs. Recurrent ETMRs exhibit a persistent but smaller C19MC+ population. Intriguingly, recurrent tumors were more quiescent with a smaller proliferative population. C19MC is directly involved in driving cell cycle and stemness in ETMRs. Cellular and molecular features of primary and recurrent ETMRs were remarkably different, suggesting that C19MC plays a different role upon recurrence.
IMMU-17. CAR T CELLS TARGETING THE INTEGRIN ALPHAVBETA3 EXHIBIT ROBUST ANTI-TUMOR RESPONSES AGAINST DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND GLIOBLASTOMA (GBM)
Authors: Dustin Cobb, Jacopo de Rossi, Lixia Liu, Erin An, Daniel Lee
Journal: Neuro-Oncology (2020)

Abstract Effective therapies for DIPG and GBM are lacking. CD19 chimeric antigen receptor (CAR) T cells are highly effective in patients with refractory B-cell malignancies. We aim to develop novel CARs for high-grade gliomas. The integrin complex alphavbeta3 was selected as a CAR-T cell target due to its expression on gliomas and their vasculature, yet with minimal expression throughout normal tissues, vessels and organs. Indeed, a majority of DIPG and GBM cell lines express surface α vβ 3. Second-generation CAR-T cells expressing an anti-α vβ 3 scFv and either a CD28 or 4-1BB co-stimulatory domain and CD3zeta were constructed. Transduced healthy, donor-derived T cells exhibited high level CAR expression, efficient expansion, and representative populations of memory subsets including central, effector, and stem cell-like memory CAR-T cells. α vβ 3.28z and α vβ 3.BBz CAR-T cells exhibited antigen-specific in vitro cytotoxicity and cytokine production against DIPG and GBM cell lines. Both CARs mediated rapid and robust anti-tumor responses in NSG mice bearing orthotopic DIPG or GBM tumors. 5/13 α vβ 3.28z and 0/14 α vβ 3.BBz treated animals died without detectable disease within 2 weeks of infusion suggesting different toxicity profiles and is consistent with faster CAR-T cell expansion in CD28-versus 4-1BB-containing CD19 CAR-T cells seen clinically. Our results demonstrate that α vβ 3.BBz CAR-T cell therapy may be both highly effective and safe in DIPG and GBM patients. Due to the restricted nature of α vβ 3 expression in normal tissues, the robust responses seen in tumor-bearing mice, and the slower kinetics of α vβ 3.BBz CAR-T cell expansion, a first-in-human clinical trial is being planned.
Euthanasia and Physician-Assisted Suicide in Patients With Multiple Geriatric Syndromes
Authors: Vera van den Berg, Ghislaine van Thiel, Margot Zomers, Iris Hartog, Carlo Leget, Alfred Sachs, Cuno Uiterwaal, Els van Wijngaarden
Journal: JAMA Internal Medicine (2020)

The Dutch Regional Euthanasia Review Committees (RTEs) reviewed and reported an increasing number of cases of euthanasia and physician-assisted suicide (EAS) requested by older people with multiple geriatric syndromes (MGS). Knowledge of the characteristics of cases of EAS for MGS is important to facilitate societal debate and to monitor EAS practice.To examine the accumulation of patient characteristics, geriatric syndromes, and other circumstances as reported in the case summaries of the RTEs that led to unbearable suffering associated with a request for EAS and to analyze the RTEs' assessments of these cases of EAS.A qualitative content analysis was conducted of all case summaries filed from January 1, 2013, to December 31, 2019, under the category MGS and published in a national open access database. These case summaries were selected by the RTEs from the total of 1605 reported cases of EAS in the category MGS.The RTEs published 53 cases (41 [77%] female) under the category MGS. A total of 28 patients (53%) had always perceived themselves as independent, active, and socially involved. None of the patients suffered from life-threatening conditions. Multiple geriatric syndromes, such as visual impairment (34 cases [64%]), hearing loss (28 cases [53%]), pain (25 cases [47%]), and chronic tiredness (22 cases [42%]), were common. The request for EAS was often preceded by a sequence of events, especially recurrent falls (33 cases [62%]). Although physical suffering could be determined in all cases, the case descriptions found that suffering occurred on multiple dimensions, such as the loss of mobility (44 [83%]), fears (21 [40%]), dependence (23 [43%]), and social isolation (19 [36%]).This qualitative study suggests that an accumulation of geriatric syndromes leading to a request for EAS is often intertwined with the social and existential dimension of suffering. This leads to a complex interplay of physical, psychological, and existential suffering that changes over time.
CTNI-76. PHASE 2 CLINICAL TRIAL OF VAL-083 IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM
Authors: Zhong-ping Chen, Cheng-Cheng Guo, Qun-ying Yang, Shao-xiong Wu, Jia-Wei Li, Jeffrey Bacha, Greg Johnson, John Langlands, Richard Schwartz, Claire Kwan, Sarath Kanekal, Anne Steino, Lorena Lopez, Dennis Brown
Journal: Neuro-Oncology (2020)

Abstract Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) promoter region, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated TMZ resistance in vitro and in vivo. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. The study has 2 stages: Stage 1 is a dose-escalation safety and tolerability phase to confirm the phase 2 dose of VAL-083 when administered concurrently with radiation therapy (RT). Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment (RT) (2 Gy/day, 5 days/week). The dose escalation stage is complete, and 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 comprises an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. As of June 2, 2020, all patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. Of the 29 patients enrolled, 27 have completed their prospectively planned MRI scans and had their initial assessment for tumor response. Two additional patients died prior to their post-cycle 3 MRI. Consistent with our prior experience, myelosuppression was the most common adverse event. Three patients have experienced dose-limiting toxicities - one (1/3; 33%) at the 40 mg/m2/day and two (2/25; 8%) at the 30 mg/m2/day dose. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.
PKC downregulation upon rapamycin treatment attenuates mitochondrial disease
Authors: Miguel Martin-Perez, Anthony S. Grillo, Takashi K. Ito, Anthony S. Valente, Jeehae Han, Samuel W. Entwisle, Heather Z. Huang, Dayae Kim, Masanao Yajima, Matt Kaeberlein, Judit Villén
Journal: Nature Metabolism (2020)
RARE-35. PINEOBLASTOMA IN CHILDREN SIX YEARS OF AGE OR LESS: FINAL REPORT OF THE HEAD START I, II AND III EXPERIENCE
Authors: Mohamed S AbdelBaki, Mohammad H Abu-Arja, Tom B Davidson, Jason R Fangusaro, Joseph R Stanek, Ira J Dunkel, Girish Dhall, Sharon L Gardner, Jonathan L Finlay
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND We report the outcomes of patients with pineoblastoma enrolled on the Head Start I-III trials. METHODS Twenty-three children were enrolled between 1991–2009. Treatment included maximal surgical resection followed by five cycles of intensive-chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction. RESULTS The median age was 3.12 years (range:0.44–5.72). Three patients withdrew from the protocols and two patients experienced chemotherapy-related mortality. Eight patients experienced progressive disease (PD) during induction chemotherapy. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range:18–36 Gy) with boost(s) (median dose 27 Gy, range:18–36 Gy); three received CSI as adjuvant therapy (2 post-HDCx/AuHCR) and four upon progression/recurrence. The 5-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95%,CI:2.6–36.0%) and 13% (95%,CI:4.5–37.5%), respectively. Three patients survived beyond five years. Nineteen patients relapsed in the following sites: local site (n=4), distal site (n=6), local and distal sites (n=9). Favorable OS prognostic factors were CSI (hazard ratio (HR)=0.30 (0.11–0.86), p=0.025), and HDCx/AuHCR (HR=0.40 (0.16–0.99), p=0.047). CONCLUSION CSI and HDCx/AuHCR were statistically associated with improved survival. The overall poor outcomes and high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles before consolidation and the intensification of consolidation with multiple cycles of marrow-ablative chemotherapy.
DDEL-02. DECREASED TOXICITY OF CONVENTIONAL DOSE CHEMOTHERAPY UTILIZING BODY WEIGHT INSTEAD OF BODY SURFACE AREA FOR DOSING IN YOUNG CHILDREN &amp;lt;6 YEARS OLD ENROLLED ON THE “HEAD START” 4 CLINICAL TRIAL
Authors: Girish Dhall, Ziad Khatib, Ossama Maher, Megan Blue, Myeshia Harmon, Parth Patel, Jonathan Finlay
Journal: Neuro-Oncology (2020)

Abstract Metabolism of drugs in infants and young children is significantly different from older individuals due to differences in distribution, protein-binding capacity, hepatic metabolism and renal excretion. To be consistent with Children’s Oncology Group (COG) guidelines, body surface area (BSA) was used to dose chemotherapeutics in children &amp;gt;3 years old enrolled on “Head Start” 4 clinical trial (HS 4). Four of 30 patients enrolled on HS 4 developed sinusoidal obstruction syndrome (SOS) while receiving induction chemotherapy with cisplatin, etoposide, vincristine, cyclophosphamide and high-dose methotrexate using BSA for dosing (mg/m2). Patients #1 and #2 were both 2-years old at diagnosis, received and tolerated the first two cycles with mg/kg dosing uneventfully, then turned 3-years old and received cycle #3 with mg/m2 dosing as per protocol guidelines, and developed SOS. Patient #3 was 3-years old at diagnosis, received induction chemotherapy with mg/m2 dosing, and developed SOS during the very first cycle. Patient #4 was 4-years old at diagnosis and received all 3 induction cycles with mg/m2 dosing, developed serious nephrotoxicity during cycle #1 followed by SOS during cycle #3. The HS 4 trial was amended and reopened after external, independent Data Safety Monitoring Board review to dose all chemotherapy drugs in children &amp;lt;6 years old with mg/kg dosing instead of BSA. None of 75 patients enrolled since the amendment developed SOS during induction. These data suggest using caution while dosing young children &amp;lt;6 years of age with intensive induction chemotherapy by BSA.
Reduced Intensity Vs. Non-Myeloablative Conditioning Regimens for Haploidentical Transplantation in Complete Remission Acute Myeloid Leukemia: A Study from the ALWP of the EBMT
Authors: Raynier Devillier, Jacques-Emmanuel Galimard, Myriam Labopin, Didier Blaise, Emanuele Angelucci, Luca Castagna, Jiri Pavlu, Gerard Socie, Massimo Martino, Friedrich Stoelzel, Gesine Bug, Yves Chalandon, Benedetto Bruno, Victoria Potter, Eolia Brissot, Bipin N. Savani, Arnon Nagler, Mohamad Mohty
Journal: Blood (2020)
Long Term Follow up of Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Children and Teenagers < 18 Years Old with High-Risk Acute Leukemia. Very Good Results in CR1 and CR2 Patients but Unexpected High Incidence of Severe Acute Graft Versus Host Disease in Children < 10 Years
Authors: Angela Maria Trujillo, Amado J Karduss, Gloria Suarez, Rosendo Perez, Giovanni Ruiz, Angelica Cardona, Jimenez Alejo, Monica Ramirez, Jose Betancur, Pedro Reyes, Luis R Gomez
Journal: Blood (2017)
SURG-25. EFFECT OF VENTRICULAR ENTRY DURING GLIOBLASTOMA RESECTION ON PATIENT OUTCOMES
Authors: Jacob Young, Andrew Gogos, Matheus Pereira, Ramin Morshed, Jing Li, Matthew Barkovich, Shawn Hervey-Jumper, Mitchel Berger
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Tumor proximity to the ventricle and ventricular entry (VE) during surgery have both been associated with poorer prognoses; however, the interaction between these two factors is poorly understood. METHODS The UCSF tumor registry was searched for patients with newly diagnosed and recurrent supratentorial glioblastoma who underwent surgical resection with the senior author between 2013 – 2018. Tumor location with respect to the subventricular zone (SVZ), size, VE, and extent of resection were assessed using pre and postoperative imaging. RESULTS In the 200-patient cohort of newly diagnosed and recurrent glioblastoma, 26.5% had VE. Comparing patients with VE to those without VE, there was no difference in postoperative hydrocephalus (1.9% vs. 4.8%, p = 0.36), ventriculoperitoneal shunting (0% vs. 3.4%, p = 0.17), pseudomeningoceles (7.5% vs. 5.4%, p = 0.58), or subdural hematomas (11.3% vs. 3.4%, p = 0.07). Importantly, rates of leptomeningeal disease (7.5% in VE vs. 10.2% w/o VE, p = 0.57) and distant parenchymal recurrence (17.9% in VE vs. 23.1% w/o VE, p = 0.35) were not different between the groups. There was no effect of VE on EOR when controlling for SVZ type. Newly diagnosed patients with tumors contacting the SVZ (Type 1 or 2) had worse survival than patients with tumors that did not contact the SVZ (Type 3 or 4) (1.27 vs 1.84 years, p = 0.014, HR 1.8, CI 1.08 – 3.03), but VE was not associated with worse survival in these patients with high risk SVZ Type 1 and 2 tumors (1.15 vs 1.68 years, p = 0.151, HR 0.59, CI 0.26 – 1.34). DISCUSSION VE was well tolerated with complications being rare events. There was no increase in leptomeningeal spread or distant parenchymal recurrence in patients with VE. Finally, VE did not change survival for patients with tumors contacting the ventricle.
EXTH-52. GLIOBLASTOMA-TARGETING AUTOLOGOUS INDUCED NEURAL STEM CELL THERAPY: EVALUATING SAFETY, TOXICITY, PERSISTENCE, AND TRANSPLANT METHODS IN A POST-SURGICAL CANINE MODEL
Authors: Hunter Bomba, Kevin Sheets, Alain Valdivia, Simon Khagi, Laura Ruterbories, Christopher Mariani, Luke Borst, Debra Tokarz, Shawn Hingtgen
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma patient survival statistics have remained unchanged for more than three decades. Despite tumor resection and chemoradiotherapy, recurrence is inevitable. Moreover, the invasive behavior of glioblastoma confounds treatment. To improve patient survival statistics, a targeted therapy that can home to distant tumor foci is desperately needed. Induced neural stem cells (iNSCs) armed with cytotoxic payloads have proven efficacious against human xenograft models of glioblastoma. To further propel iNSCs to human clinical trials, we investigated the safety, toxicity, and persistence of iNSCs in a canine model. METHODS Autologous iNSCs generated from the skin of four non-tumor-bearing, purpose-bred, male beagles were engineered to express TRAIL and thymidine kinase (TK). iNSCs were loaded with ferumoxytol to facilitate MRI-tracking. Canines were divided into two cohorts to denote iNSC administration route: scaffold encapsulation or intracerebroventricular (ICV). Two dose levels were investigated: 1′106 iNSCs/kg or 3′106 iNSCs/kg. The scaffold cohort received a single dose of iNSCs while the ICV cohort received three doses of iNSCs via a Rickham reservoir. To activate TK, canines were administered valganciclovir. Canine health was assessed via neurological exams, MRI, and serial blood, urine, and CSF analyses. RESULTS No acute injection reactions were observed. Three of four canines exhibited surgery-induced blindness. Urine and CSF analyses were unremarkable. Unexpectedly, blood analyses showed transient neutropenia. Hypodense signal was observed on all MRI sequences through endpoint. Post-mortem histopathology of the spleen, liver, and lung were unremarkable. As expected, brain tissues exhibited gliosis, fibrous thickening, and inflammation. Spinal cords exhibited acute hemorrhaging, attributed to perimortem CSF draws. Surprisingly, significant testicular degeneration was observed; this was confirmed to be caused by valganciclovir. In conclusion, iNSCs exhibit limited toxicity and warrant further exploration. FUTURE DIRECTIONS Prospective studies will investigate the efficacy of autologous iNSCs in a spontaneous canine glioma model in preparation for human clinical trials.
IMMU-11. LOCOREGIONAL DELIVERY OF TRANSIENT GD2 CAR T CELLS FOR SAFE AND EFFECTIVE TREATMENT OF DIPG
Authors: Jessica Foster, Crystal Griffin, Allison Stern, Cameron Brimley, Tiffany Smith, Phillip Storm, Adam Resnick
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor with a median survival of one year. Recently Mount et al (Nat Med 2018) discovered the disialoganglioside GD2 is present at high levels on the surface of DIPG and can be targeted using GD2-directed CAR T cells. However, permanently expressed CAR T cells created by lentiviral transduction resulted in a significant number of deaths from tumor swelling with uncontrolled T cell proliferation. We hypothesized that using mRNA to create transient GD2-directed CAR T cells delivered locally with repeated dosing would result in a safer yet equally effective way to treat DIPG using CAR T cell therapy. In vitro studies using mRNA GD2-directed CAR T cells resulted in robust tumor cytotoxicity and T cell degranulation across a panel of six DIPG cell lines. Using an orthotopic murine model of SU-DIPGXIIIP*, an extremely aggressive model, we delivered of a single dose of two million mRNA GD2-directed CAR T cells locoregionally to the pons via stereotactic injection. The mRNA GD2-directed CAR T cells resulted in no toxic deaths of the mice. In addition, a single dose of mRNA CAR T cells targeting GD2 prolonged survival of the mice by a median of six days (p&amp;lt;0.05). Ongoing studies using an indwelling catheter for repeated dosing of mRNA CAR T cells are currently underway and results expected at the time of presentation. This work will form of the basis of an mRNA CAR T cell trial targeting GD2 for patients with DIPG.