tbuckley/cabot-search huggingface dataset:
CTNI-57. LOW-RISK MENINGIOMA: OUTCOMES FROM NRG ONCOLOGY/RTOG 0539
Authors: Leland Rogers, Stephanie Pugh, Michael Vogelbaum, Arie Perry, Lynn Ashby, Jignesh Modi, Anthony Alleman, Emad Youssef, Steve Braunstein, Joseph Bovi, John de Groot, Anthony Whitton, Scott Lindhorst, Nicholas Taylor, Dennis Shrieve, Hui-Kuo Shu, Mitchell Machtay, Mark Mishra, Clifford Robinson, Minesh Mehta
Journal: Neuro-Oncology (2020)

Abstract PURPOSE/OBJECTIVE(S) Outcomes of low-risk meningioma from NRG/RTOG-0539. MATERIALS/METHODS Outcomes of the intermediate and high-risk cohorts from this phase II trial have been previously reported. Low-risk (Group 1: new WHO grade 1) patients were observed after gross total (GTR) or subtotal resection (STR). Progression-free (PFS) and overall (OS) were estimated using Kaplan-Meier. CTCAE v3 AE grading was employed. RESULTS Group 1 enrolled 65 patients. 56/60 (93.4%) evaluable patients had investigator-reported GTR. Sufficient imaging for central confirmation was available for 48: GTR in 35 and STR in 13. Median follow-up for living patients was 9.1 years (y). For all evaluable patients 5 and 10 y PFS and OS rates were 89.4 and 85.0%, and 98.3 and 93.8%, respectively. For patients with centrally-confirmed STR, 5/10 y PFS rates were 72.7/72.7%, with 100% 10 y OS. For patients with centrally-confirmed GTR, 5/10 y PFS and OS rates were 94.3/87.6 and 97.1/90.4%, respectively. For combined study cohorts (Groups 1–3) with central-review (n=104), the median centrally-measured largest pre-operative tumor dimension was 4.3 cm (range 0.4 - 14.4); this was significantly associated with OS (hazard ratio [HR]=1.03, p=0.021) and PFS (HR=1.03, p=0.003). No grade 4 or 5 protocol-related adverse events were reported. There were 1 grade 3 (infection), 4 grade 2 (neurologic, pulmonary, gastrointestinal, and pain), and 5 grade 1 (3 neurologic, 1 occulovisual, 1 constitutional) events from 5 patients. CONCLUSION These results prospectively validate high OS and PFS outcomes for low-risk meningioma managed with surgery followed by observation, but raise questions regarding optimal management following STR (5 y PFS 72.7%), a subcohort that could potentially benefit from adjuvant therapy. However, we identified considerable discordance between local and central assessments of resection extent. Pre-operative tumor size has a significant impact on OS and PFS. Supported by: U10CA180868 and U10CA180822 from the National Cancer Institute (NCI)
CTNI-25. PHASE IB CLINICAL TRIAL OF CHRONIC CONVECTION-ENHANCED DELIVERY OF TOPOTECAN FOR RECURRENT GLIOBLASTOMA
Authors: Jeffrey Bruce, Eleonora Spinazzi, Andrew Lassman, Fabio Iwamoto, Mary Welch, Matei Banu, Michael Argenziano, Pavan Upadhyayula, Nathalie Y R Agar, Nelson Humala, Tamara Marie, Brianna Pereira, Tejaswi Sudhakar, Aayushi Mahajan, Justin Neira, Angela Lignelli-Dipple, Jack Grinband, Peter Sims, Randy D’Amico, Peter Canoll
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVES Convection-enhanced delivery (CED) provides pharmacokinetic advantages over systemic delivery for achieving cytotoxic drug levels into targeted regions of the brain. A major shortcoming of CED has been the need to limit treatment duration because of infection risks associated with external pumps. We engineered a subcutaneously implanted catheter-pump construct for prolonged CED which was successfully tested in a large animal model and then approved by the FDA for a Phase Ib clinical trial with topotecan in patients with refractory glioblastoma (IND 131889). METHODS Five patients with recurrent glioblastoma underwent surgical implantation of a subcutaneous pump and catheter that infused intracerebral topotecan over 30 days. Gadolinium was co-infused as a surrogate tracer and advanced non-invasive radiographic imaging was used to monitor drug distribution and pharmacological effects. Tissue from multiple radiographically-localized regions of each tumor and surrounding brain was procured pre-treatment at the time of catheter implantation and then post-treatment when tumors were surgically resected. Tissue was used for drug level measurements and advanced molecular, genomic and cellular analysis of treatment effects. RESULTS Treatments were successfully completed in all five patients without significant complications. The safety and tolerability of treatment was validated by quality-of-life measures and neurological assessments. Noninvasive imaging demonstrated large and stable drug distribution volumes. Comprehensive tissue analysis demonstrated effective targeting of mitotically active tumor cells while sparing neurons. CONCLUSIONS We engineered a subcutaneously implanted catheter-pump construct for chronic CED that was successfully tested in a Phase Ib clinical trial with topotecan in recurrent glioblastoma patients. Analysis of pre- and post-treatment tissue showed significant anti-tumor activity from topotecan that was not harmful to normal brain. Chronic CED combined with non-invasive real time drug distribution monitoring provides a safe and effective glioma strategy suitable for clinical use.
RARE-06. OPTIMIZATION OF PROTON RADIATION THERAPY FOR GIANT CRANIOPHARYNGIOMAS
Authors: Valerie Cruz Flores, Stacie Stapleton, Gerald Tuite, Naren Ramakrishna
Journal: Neuro-Oncology (2020)

Abstract Craniopharyngiomas are benign intracranial tumors located in the sellar and suprasellar region. Their size and extent of invasion into surrounding structures vary considerably. While the majority of craniopharyngiomas on presentation are between 1–3 cm without hypothalamic invasion, a significant proportion of patients present with ‘giant’ craniopharyngiomas of &amp;gt;4cm in dimension with large cystic extension through the 3rd ventricle. These tumors pose a challenge both for surgical resection as well as for radiation therapy. Proton beam therapy (PBT) has become the preferred standard of care after subtotal resection of pediatric craniopharyngiomas. In the setting of giant craniopharyngioma, the use of proton therapy allows a reduction of dose to surrounding normal brain, but changes in cyst volume can result in either under-coverage of tumor or excess dose to surrounding brain, an effect further magnified by the sharp gradients associated with proton dose distributions. In this case report we describe the proton treatment planning and intra-treatment monitoring of two patients with giant craniopharyngiomas with largest pre-operative of dimension 6cm, and 9cm, respectively, and 6cm and 5.5cm, respectively, pre-radiation. Both patients had drains inserted to Ommaya reservoirs. We performed surveillance imaging during RT utilizing spiral computer tomography (CT) on a weekly basis and reconstructed the treatment dose on the surveillance CTs to ensure target coverage and normal tissue sparing. We compared the dosimetry in these cases for PBT versus intensity-modulated radiation therapy, characterized the cyst evolution during treatment in 3 dimensions, and define an optimized protocol for treatment planning and intra-treatment monitoring.
Air pollution from road traffic contributed to girl’s death from asthma, coroner concludes
Authors: Clare Dyer
Journal: BMJ (2020)

A coroner has concluded that air pollution from road traffic made a significant contribution to the death of a 9 year old girl with asthma, in a groundbreaking case.

The case of Ella Adoo Kissi-Debrah, who lived near a heavily congested road in south London, is thought to be the first in which exposure to air pollution has been recorded as a medical cause of death.

Ella, who had severe hypersecretory asthma, died in February 2013, having been taken to hospital nearly 30 times over the previous three years. On 15 February 2013, after an asthmatic episode at home, she had a cardiac arrest at University Hospital Lewisham from which she could not be resuscitated.

She lived less than …
Abstract P129: Biomarkers of Hyperglycemia With All-cause Mortality in Older Adults With and Without Diagnosed Diabetes
Authors: Mary R Rooney, Olive Tang, James S Pankow, Elizabeth Selvin
Journal: Circulation (2020)

Introduction: HbA1c is central to diagnosis and management of diabetes. However, our understanding of the associations of HbA1c with clinical outcomes is based primarily on studies of middle-aged adults. Objective: To characterize the associations between HbA1c and mortality among older adults with and without diabetes. We compared the HbA1c-mortality associations with those for alternative glycemic markers (fructosamine and glycated albumin). Methods: We conducted a prospective cohort analysis of 6370 participants (32% with diagnosed diabetes, mean age 76, 59% female, 23% black) in the Atherosclerosis Risk in Communities (ARIC) Study, baseline visit 5 (2011-13). We used Cox regression models to examine the association of each glycemic biomarker (modeled as a linear spline) with all-cause mortality through 2017, stratified by diagnosed diabetes. Model discrimination was tested using c-statistics. Results: There were 1022 deaths over 6 years of follow-up. In persons with diabetes, there was a J-shaped association between HbA1c and mortality ( Figure ). Associations were largely similar for fructosamine and glycated albumin. Among persons without diabetes, HbA1c was not strongly associated with mortality, but confidence intervals were wide for HbA1c &lt;5.0% and ≥6.5% (undiagnosed diabetes); whereas, higher levels of fructosamine and glycated albumin were associated with an elevated mortality risk. Associations were similar before and after adjustment for cardiovascular risk factors. The addition of individual glycemic markers to the models modestly improved discrimination in both persons with and without diabetes. C-statistics were similar when the glycemic markers were added individually to the diabetes-stratified models (Figure). Conclusions: Among older adults, HbA1c and other glycemic markers tend to have similar associations with mortality. HbA1c, fructosamine, and glycated albumin, including low levels, may reflect common markers of risk in older adults, particularly in those with diabetes.
Total Neoadjuvant Therapy vs Standard Therapy in Locally Advanced Rectal Cancer
Authors: Anup Kasi, Saqib Abbasi, Shivani Handa, Raed Al-Rajabi, Anwaar Saeed, Joaquina Baranda, Weijing Sun
Journal: JAMA Network Open (2020)

Standard therapy for locally advanced rectal cancer includes concurrent chemoradiotherapy followed by surgery and adjuvant chemotherapy (CRT plus A). An alternative strategy known as total neoadjuvant therapy (TNT) involves administration of CRT plus neoadjuvant chemotherapy before surgery with the goal of delivering uninterrupted systemic therapy to eradicate micrometastases. A comparison of these 2 approaches has not been systematically reviewed previously.To determine the differences in rates of pathologic complete response (PCR), disease-free and overall survival, sphincter-preserving surgery, and ileostomy between patients receiving TNT vs standard CRT plus A.MEDLINE (via PubMed) and Embase (via OVID) were searched from inception through July 1, 2020, for the following terms: anal/anorectal neoplasms OR anal/anorectal cancer AND total neoadjuvant treatment OR total neoadjuvant therapy. Only studies in English were included.Randomized clinical trials or prospective/retrospective cohort studies comparing outcomes in patients with locally advanced rectal cancer who received TNT vs CRT plus A.Data regarding the first author, publication year, location, sample size, and rates of PCR, sphincter-preserving surgery, ileostomy, and disease-free and overall survival were extracted using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and pooled using a random-effects model.Rates of PCR, sphincter-preserving surgery, ileostomy, and disease-free and overall survival.After reviewing 2165 reports, 7 unique studies including a total of 2416 unique patients, of whom 1206 received TNT, were selected. The median age for the patients receiving TNT ranged from 57 to 69 years, with 58% to 73% being male. The pooled prevalence of PCR was 29.9% (range, 17.2%-38.5%) in the TNT group and 14.9% (range, 4.2%-21.3%) in the CRT plus A group. Total neoadjuvant therapy was associated with a higher chance of achieving a PCR (odds ratio [OR], 2.44; 95% CI, 1.99-2.98). No statistically significant difference in the proportion of sphincter-preserving surgery (OR, 1.06; 95% CI, 0.73-1.54) or ileostomy (OR, 1.05; 95% CI, 0.76-1.46) between recipients of TNT and CRT plus A was observed. Only 3 studies presented data on disease-free survival, and pooled analysis showed significantly higher odds of improved disease-free survival in patients who received TNT (OR, 2.07; 95% CI, 1.20-3.56; I2 = 49%). Data on overall survival were not consistently reported.The findings of this systematic review and meta-analysis suggest that TNT is a promising strategy in locally advanced rectal cancer, with superior rates of PCR compared with standard therapy. However, the long-term effect on disease recurrence and overall survival needs to be explored in future studies.
RONC-23. NOVEL APPROACH TO REDUCE ACUTE ESOPHAGEAL TOXICITY IN CRANIO-SPINAL IRRADIATION USING INTENSITY MODULATED PROTON THERAPY
Authors: Vineet Nakra, Srinivas Chilukuri, Utpal Gaikwad, Noufal MP, Kartikeshwar Patro, Rajesh T, Dayananda Shamurailatpam, Sham Sunder, Nagarjuna Burela, Rishan T, Raees Tonse, Muthiah K, Rakesh Jalali, Manikandan A, Ganapathy Krishnan
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION We present our experience of a novel approach using intensity modulated proton therapy(IMPT) for cranio-spinal irradiation(CSI) leading to reduced acute esophageal toxicity and reduced treatment interruptions. MATERIAL AND METHODS Seven children younger than 12 years old treated consecutively with CSI using IMPT were included in this study. Three among 7 children received concurrent chemotherapy(CCT). Entire vertebral body(VB) was part of target volume in all patients. The IMPT plan was generated using 3 fields with single field optimisation technique. Last 5 patients were treated using dose gradient(DG) (98-93%) deliberately created in anterior most 3-5mm of VB. Initial 2 patients were treated with intention of covering entire VB with 98% isodose. Monte Carlo algorithm was used for dose calculations and optimisation, and robustness assessed for 3mm setup and 3.5% range uncertainty. RESULTS The CSI dose ranged from 21.6GyE to 35GyE. In patients without DG, maximum and mean dose to esophagus(36.67GyE vs. 25.45GyE, 31.53GyE vs. 20.41GyE), midline mucosa(28.95GyE vs. 25.31GyE, 21.8GyE vs. 14.61GyE) and bowel bag(32.9GyE vs. 24.27GyE, 3.59GyE vs. 3.21GyE) were higher compared to patients with DG. Both patients where DG was not created, developed grade 2 esophageal toxicities requiring supportive care and treatment interruptions(4 and 2days). All 5 patients with DG did not develop significant esophageal toxicity and had no interruptions. CONCLUSION Creating a dose gradient over anterior VB using IMPT reduces dose to esophagus and midline mucosa leading to lower acute esophageal toxicity which potentially avoids treatment interruptions during CSI.
EPCO-01. LUNG ADENOCARCINOMA BRAIN METASTASIS PREDICTION, PREVENTION, AND NON-INVASIVE DIAGNOSIS USING METHYLATION SIGNATURES WITHIN TISSUE AND CIRCULATING TUMOUR DNA
Authors: Jeffrey Zuccato, Yasin Mamatjan, Vikas Patil, Farshad Nassiri, Mathew Voisin, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND One quarter of lung adenocarcinoma (LUAD) patients develop brain metastases (BM) and experience a poorer median survival of 12 months despite treatment. Clinical variables do not robustly predict who will develop BM and targeted preventative treatments are limited. Tumour DNA methylation signatures predict outcomes in other cancers and can be detected in circulating tumour DNA (ctDNA). This work predicts BM development from LUAD using methylation data, identifies novel potential treatment targets to prevent metastases, and detects LUAD-BM ctDNA non-invasively. METHODS DNA methylation profiling was undertaken on N=124 LUAD tumours. A gradient boosted regression model built on differentially methylated CpGs (DMCs) between tumours with and without BM in 70% of samples was validated in an independent 30% testing cohort. Nine paired BM samples were profiled and DMCs between their corresponding LUAD tissue were identified along with copy number (CN) alterations. A total of 47 LUAD-BM plasma samples underwent sequencing of immunoprecipitated methylated ctDNA and differentially methylated regions (DMRs) between LUAD-BM and intrinsic brain lesions were identified. RESULTS The methylation-based model significantly predicted time to brain metastasis development within the testing cohort independently from cancer stage in a multivariate analysis (HR=4.3, 95%CI 1.1–17, p=0.038). Genes/pathways involved in the process of brain metastasis were identified through assessment of 83K DMCs (FDR&amp;lt; 0.2, mean difference &amp;gt;|0.1|) between paired samples as well as the CN losses found in chromosome 12q/19 of BM samples. A total of 5.5K DMRs were identified that distinguish BM samples from gliomas or primary CNS lymphomas (FDR&amp;lt; 0.05, logFC &amp;gt;1). CONCLUSIONS DNA methylation signatures in lung adenocarcinomas predict brain metastasis development independently from prognostic clinical factors. Genes and pathways involved in metastasis were identified as novel potential therapeutic targets. Methylated circulating tumor DNA signatures differentiate lung brain metastases from other ring-enhancing brain lesions and may have potential for non-invasive diagnosis.
QOL-06. QUALITY OF LIFE IN MEDULLOBLASTOMA SURVIVORS IN WESTERN MEXICO
Authors: Regina M Navarro-Martin del Campo, Jorge L Macias-Toscano, Erika Toral-Casillas, Fernando Sánchez-Zubieta, Ana L Orozco-Alvarado
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Treatment of children with medulloblastoma (MB) can lead survivors to lidiate with long term sequelae and affect their quality of life (QoL). This study evaluates QoL in long term MB survivors. DESIGN/ METHODS Clinical files of MB survivors from 1997 to 2016 were retrospectively analyzed. QoL was defined by Schipper Criteria in a five dimensional evaluation: clinical data, physic effects of treatment, academic develop, functional state and self welfare report. RESULTS Clinical data: Twenty eight survivors were identified, mean age at review was 18 years, median follow up was 106 months. Functional state: Last visit Karfnosky/lansky were 90 to 80% in 25% of patients. Physic effects of treatment: Cerebellar Mutism or ataxia were present in 25% of cases. Two patients required external dispositives. Audiometry detected an auditive tonal decrease in 25% of cases. An endocrine disfunction was present in 46% of cases, 32% required hormone replacement and 28% having short size. Renal damage without dialysis was detected in 7% and 10% had a transient tubulopaty. One case had bilateral amaurosis and 14% uses glasses. Three patients had a life partner. One female has offspring and two males had azoospermia. Academic development: While 90% attends to school, 35.7% complained of learning difficulties and 18% needed special education. Self welfare report: Difficulties in social environment were described in 21% and 14% still feeling sick during years. CONCLUSIONS Survivors of MB had adverse physical effects, followed by academic development, functional state and self welfare report and all this has a negative impact in their QoL.
Association of Prenatal Maternal Anxiety With Fetal Regional Brain Connectivity
Authors: Josepheen De Asis-Cruz, Dhineshvikram Krishnamurthy, Li Zhao, Kushal Kapse, Gilbert Vezina, Nickie Andescavage, Jessica Quistorff, Catherine Lopez, Catherine Limperopoulos
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Maternal psychological distress during pregnancy is associated with adverse obstetric outcomes and neuropsychiatric deficits in children. Currently unavailable in vivo interrogation of fetal brain function could provide critical insights into the onset and timing of altered neurodevelopmental trajectories. <h3>Objective</h3> To investigate the association between prenatal maternal stress, anxiety, and depression and in vivo fetal brain resting state functional connectivity. <h3>Design, Setting, and Participants</h3> This cohort study included pregnant women scanned between January 2016 and April 2019. A total of 50 pregnant women with healthy pregnancies were prospectively recruited from low-risk obstetric clinics in the Washington DC area and were scanned at Children's National in Washington DC. <h3>Exposures</h3> Maternal stress, anxiety, and depression. <h3>Main Outcomes and Measures</h3> The association of prenatal maternal stress, anxiety, and depression with whole-brain connectivity was analyzed using multivariate distance matrix regression. Prenatal maternal stress, anxiety, and depression were assessed using the Perceived Stress Scale, Spielberger State Anxiety Inventory and Spielberger Trait Anxiety Inventory, and the Edinburgh Postnatal Depression Scale, respectively. Whole-brain connectivity was measured from 100 functionally defined regions of interest. <h3>Results</h3> This study analyzed 59 resting-state functional connectivity magnetic resonance image data sets from the fetuses (mean [SD] gestational age, 33.52 [4 weeks]) of 50 healthy pregnant women (mean [SD] age, 33.77 [5.51]). Mean (SD) scores for the questionnaires were as follows: Spielberger State Anxiety Inventory, 26.66 (6.72) (range, 20-48); Spielberger Trait Anxiety Inventory, 28.09 (6.62) (range, 20-50); Perceived Stress Scale, 9.27 (5.13) (range, 1-25); and Edinburgh Postnatal Depression Scale 3.24 (2.84) (range, 0-14). Prenatal maternal anxiety scores measured using the Spielberger Trait and State Anxiety Inventories were associated with differences in fetal connectivity (Spielberger State Anxiety Inventory: pseudo-<i>R</i><sup>2</sup> = 0.019,<i>P</i> = .04; Spielberger Trait Anxiety Inventory: pseudo-<i>R</i><sup>2</sup> = 0.021,<i>P</i> = .007). Interhemispheric connections, such as those involving the parietofrontal and occipital association cortices, were associated with reduced maternal prenatal anxiety, and those between the brainstem and sensorimotor areas were associated with higher anxiety scores. <h3>Conclusions and Relevance</h3> In this cohort study, an association was found between prenatal maternal anxiety and disturbances in fetal brain functional connectivity, suggesting altered fetal programming. Early onset of functional deviations suggests the need for more widespread screening of pregnant women for symptoms of anxiety.