tbuckley/cabot-search huggingface dataset:
P11.60 Neurosurgical delivery of the poly ADP ribose polymerase-1 inhibitor olaparib from a thermo-responsive biodegradable paste potentiates radiotherapy and prolongs survival
Authors: S Smith, R Serra, J Rowlinson, N Gorelick, G Veal, K Shakesheff, H Brem, R Grundy, B Tyler, R Rahman
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND There has been considerable interest in repurposing the poly ADP ribose polymerase inhibitor and purported radiosensitiser olaparib (Lynparza), with a recent dose escalation study of olaparib plus temozolomide in recurrent GBM showing good tolerance. Due to systemic therapy-associated caveats such as dose-limiting toxicities and blood-brain-barrier penetration, here we assess localised post-surgical delivery of olaparib from our previously developed PLGA/PEG thermo-sensitive biodegradable paste. MATERIAL AND METHODS Metabolic and clonogenic assays were used to assess effects on proliferation and clonal growth upon in vitro glioma exposure to olaparib. Flow cytometry and Annexin V/Propidium iodide were used to determine apoptosis. The 9L high-grade glioma orthotopic allograft model was utilised to assess survival upon intra-cavity olaparib delivery. RESULTS Metabolic and clonogenic assays revealed impaired proliferation and clonal growth respectively, upon acute exposure of high-grade glioma cells to olaparib (3–5µM), an effect dramatically potentiated with 3Gy radiation. Flow cytometry of Annexin V+/Propidium iodide+ rodent and human high-grade glioma cells, revealed a significant cell proportion increase at late stage apoptosis when exposed to 2–3µM olaparib and 3Gy radiation (relative to untreated, olaparib alone or radiation alone). A high-grade glioma orthotopic allograft study revealed a significant overall survival benefit of locally-delivered 10% and 20% w/w (drug:polymer ratio) olaparib via PLGA/PEG paste post-surgery with adjuvant radiotherapy, compared to surgery/oral temozolomide/radiotherapy (GBM standard-of-care) and surgery/systemic olaparib (95 vs. 44 vs. 30 days respectively). A more pronounced survival benefit, as measured by number of animals surviving long-term, was observed with combined PLGA/PEG/olaparib/temozolomide/radiotherapy or PLGA/PEG/olaparib/etoposide/radiotherapy, relative to standard-of-care (95 vs. 44 days). Clinical correlation was determined using RNAseq data from 10 GBM patients, showing significantly elevated levels of apoptosis-inducing factor-1 in 5-aminolevulinic acid (5ALA)+ fluorescence-activated cell sorted populations (i.e. purified tumour cells from the invasive margin), relative to 5ALA- cells, confirming PARP-1 activity in infiltrative tumour cells. CONCLUSION Collectively our data supports a clinical rationale for localised olaparib delivery with adjuvant radiotherapy.
Frequently deleted genes in ovarian cancer as indicators of platinum response.
Authors: Scooter Willis, Victor Manuel Villalobos, Brandon Michael Young, Branimir I. Sikic, Brian Leyland-Jones
Journal: Journal of Clinical Oncology (2013)

5583 Background: Integrating chromosomal deletions/amplifications with sequencing alterations is increasingly important in the determination of key drivers of outcome in cancer (Leary 2008, Curtis 2012). We introduce a novel computational approach, Gene Set Outcome Analysis, to determine gene signatures constrained to regions with frequent deletion or amplification events in ovarian cancer identified by TCGA. Differential expressions of mRNA from these genes are used as a proxy for loss of function from deletions or amplifications. Methods: Gene signatures from each region were evaluated using log-rank test comparing high and low gene expression groups split by cohort mean. In total, 30,119,708 signatures constrained to 47 deleted and 36 amplified regions were tested for PFS for first line platinum treatment in a random 2/3 split of TCGA ovarian cohort (n=262) resulting in 26,271 gene signatures with p &lt; .001. The remaining 1/3 cohort (n=135) and full cohort (n=397) were used as a replication study where 111 signatures have a p &lt; .01 located in 2 deletion and 1 amplification region. The signature with the lowest p-value from each region that validated in the replication study, were evaluated in GSE9891 (n=179) (Tothill 2008) for PFS when treated with platinum and taxol resulting in gene signatures from 2 deletion regions with p&lt;.05. Results: Greater than mean expression in this gene signature [OXTR, SATB1, WNT7A, SH3BP5, CRBN, ATG7, CRELD1, TMEM43] located at 3p23-p26.2 predicts poor response to platinum chemotherapy in TCGA full ovarian cohort (17.9 vs 14 months p = 1.4E-7) and validates in GSE9891 (19.6 vs 13.3 months p = .014). Using a separate, compact gene signature [CAAP1, LRRC19, IFNA8] located at 9p21.2, samples with lower than mean expression demonstrate increased platinum sensitivity in TCGA full ovarian cohort (12.2 vs 18.2 months p = 1.0E-6) and in GSE9891 (15.5 vs 18.6 p = .055). Conclusions: Response to platinum therapy is an important predictor of survival in high-risk ovarian cancer patients. These signatures arising from common deletion and amplification events in ovarian cancer can anticipate platinum sensitivity and merits further study for use in choosing optimal therapies studying platinum resistance mechanisms.
P11.53 Genotype trumps phenotype: Oligodendroglioma and oligodendroglioma like tumors- A 1p19q fluorescence in situ hybridization based study at a tertiary referral centre in north India
Authors: A Dewan, L Kini, S Sharma, M Bhardwaj
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The 2016 WHO update of CNS tumours defines oligodendroglioma as a diffusely infiltrating glioma with IDH 1 or IDH 2 mutation and co-deletion of chromosomal arms 1p and 19q. We evaluated the role of 1p19q testing by Fluorescence in situ hybridization (FISH) in the diagnosis and correct classification of CNS tumours in accordance with WHO 2016 classification and exclusion of morphological mimickers of oligodendrogliomas. MATERIAL AND METHODS A retrospective analysis of CNS tumours was carried out that were tested for 1p19q co-deletion by FISH over a period of fourteen months at our institute. Correlation with tumour morphology as well as other molecular tests (IDH mutation and MGMT) where available was then done. A tumour was considered to have 1p or 19q deletion when the 1p probe to 1q probe ratio (1p/1q) or the 19q probe to 19p probe ratio (19q/19p) was &lt;0.80. RESULTS A total of 125 cases underwent FISH testing for 1p19q co-deletion over a period of last fourteen months at our institute with 74 male patients and 51 women. Thirty-eight of the 125 evaluated patients demonstrated 1p19q co-deletion on FISH. These included 25 oligodendrogliomas, 9 astrocytomas (Grade II/III) and 4 cases of oligoastrocytomas by morphology. Out of these cases, 21 cases had a co-existent IDH mutation, while two cases were IDH wild type and for 15 cases the status was unknown. Rest of the 87 patients were negative for 1p19q co-deletion and included cases of oligodendroglioma, other gliomas (pilocytic astrocytoma, oligoastrocytoma, glioblastoma) and few glioneuronal tumours (ganglioglioma, dysembryoplastic neuroepithelial tumour and central neurocytoma). CONCLUSION 1. Analysis of 1p19q co-deletion by FISH plays an important role in correctly identifying cases of oligodendroglioma as shown in our study. This is important as it is both a predictive as well as prognostic biomarker 2. In cases with co-deletion but IDH wild type status, the 1p19q status should be confirmed by other methods such as comparative genomic hybridization to confirm the presence of whole chromosome loss.3. FISH analysis also helps in excluding morphologic mimics of oligodendroglioma such as glioneuronal tumours and pilocytic astrocytomas in young patients. 4. However, in a resource limited country like ours, a good morphological diagnosis should still form the basis for FISH and other molecular tests to avoid unnecessary testing.
Sedation practices in pediatric ALL patients.
Authors: Bethany D. Nugent, Peter J. Davis, Robert Noll, Jean M. Tersak
Journal: Journal of Clinical Oncology (2019)

e21500 Background: The 5-year survival rate for pediatric acute lymphoblastic leukemia (ALL) is greater than 90%. A common late effect of pediatric ALL is neurocognitive deficits, such as lower IQ. In recent years, the use of sedation during lumbar punctures (LPs) for treatment of pediatric ALL is becoming increasingly widespread. These patients are exposed to repeated doses of sedatives. Among the most common Children’s Oncology Group (COG) ALL protocols, approximately 30 LPs are performed over a period of 2-3 years. Studies in animals (both rodents and primates) have revealed that common sedation drugs cause harm to the developing brain and can negatively affect behavior, learning, and memory. Gaps in knowledge exist regarding their use in children, particularly with repeated exposures. For children with ALL, little is known about sedation practices such as how commonly sedation is used; what medications are most common; and who administers the medications. The purpose of this study is to summarize sedation practices at COG institutions for LPs related to treatment of pediatric ALL. Methods: All Responsible Investigators (RIs) of the Cancer Control Committee (a subcommittee of COG) were invited to complete an internet-based survey about sedation practices for ALL patients at their institution. Results: Surveys were sent out to 103 RIs with a 62.1% response rate ( N = 64). A combined 2018 new patients with ALL were seen each year ( M = 31.5, range = 3-110); of these patients, 95.7% received sedation for LPs. While there was considerable variability across institutions in medications used (general anesthesia, Propofol with opioid and/or Versed, Versed and opioid, other), the most common was Propofol alone ( n = 36, 56.3%). Anesthesiologists administered sedation at the majority of institutions ( n = 36, 56.3%) while trained sedationists, oncologists, and nurses administered sedation at other institutions. Conclusions: A substantial number of pediatric patients with ALL receive sedation for LPs. However, there is much variation in the types of medications administered and who is administering these medications. Better understanding of sedation practices in children with ALL may inform future research to investigate which methods of sedation are safest, with a particular emphasis on its long-term effects.
Intra-and inter-patient variability of baseline pain intensity scores during breakthrough pain in cancer.
Authors: Allen W, Burton, Marilene Filbet, Ravi Tayi, Michael Sidney Perelman, Alastair D. Knight
Journal: Journal of Clinical Oncology (2012)

e19578 Background: Breakthrough pain in cancer (BTPc) can be assessed using a patient-reported 11-pt pain intensity (PI) scale (0=no pain; 10=worst possible pain). Little information has been reported about variation of PI between episodes and between individuals. This analysis examined intra- and inter-patient variation in baseline PI scores among patients participating in BTPc clinical trials. Methods: This was a pooled analysis of data from 2 randomized, double-blind, crossover studies that treated BTPc with fentanyl pectin nasal spray (Lazanda®, PecFent®) compared with placebo or with morphine sulfate immediate release. Patients were adults with ECOG score ≤2 who experienced BTPc despite background pain that was adequately controlled with ≥60mg morphine (or equivalent). Each study included dose titration prior to the double-blind treatment phase of 10 episodes of BTPc. Inter- and intra-patient variability of baseline pain scores for each episode were analyzed by ANCOVA using a mixed-effect model. Influence of covariables including demographics and ECOG score at study entry was assessed. Results: A total of 152 patients had 1399 BTPc episodes assessed. Mean (SD) age was 54.2 (12.0) yr; 81 patients (53%) were men. The mean ± SD episode baseline PI score was 7.3 ± 1.76 (range 2-10). Inter-patient variability of baseline PI scores was 75.9% and between-study variability, 3.5%; intra-patient variability among the 152 patients was 20.6%. Fixed terms for demographics and ECOG score were not significant factors influencing baseline PI scores at or below the 5% level. Conclusions: This analysis demonstrates that BTPc episodes have large variations in baseline PI scores between patients and that these scores are not influenced by demographics or ECOG score (0-2). However, individual patients show comparatively low variability in baseline PI scores between BTPc episodes. This supports the use of a consistent maintenance dose of an analgesic agent once it has been titrated to an effective dose.
Varenicline and Nicotine Replacement Use Associated With US Food and Drug Administration Drug Safety Communications
Authors: Ravi J. Desai, Meghan M. Good, Alvaro San-Juan-Rodriguez, Andrew Henriksen, Francesca Cunningham, Inmaculada Hernandez, Chester B. Good
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Drug safety communications released by the US Food and Drug Administration (FDA) are often based on limited evidence on safety signals after approval. Varenicline may serve as a relevant case study because it was the target of several FDA communications in 2008 and 2009; ultimately, the Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES) dismissed safety concerns on increased suicidal thoughts and aggressive and erratic behavior on December 16, 2016. <h3>Objective</h3> To examine the association between FDA drug safety communications and the use of varenicline. <h3>Design, Setting, and Participants</h3> Retrospective, longitudinal, cross-sectional study of Veterans Health Administration (VHA) outpatient data from October 1, 2001, through December 31, 2018, and Medicaid drug state use data from July 1, 2006, through September 30, 2018, on varenicline prescribing. <h3>Main Outcomes and Measures</h3> Prescribing records for varenicline and nicotine replacement therapy (NRT) in the VHA were extracted, and the number of unique varenicline and NRT users in the VHA per quarter was measured. An interrupted time series analysis was performed to describe the association between FDA safety warnings and the use of varenicline and NRT. To test the generalizability of the findings, similar analyses were conducted using the number of prescriptions reimbursed for varenicline by Medicaid every quarter in 2006-2018. <h3>Results</h3> After its addition to the VHA national drug formulary in January 2007, varenicline use presented a steady increase, reaching a peak of 32 581 quarterly unique users in the first quarter of 2008. Within 12 months of the February 1, 2008, public health advisory, quarterly varenicline use in VHA patients decreased by 68.7% (from 32 581 to 10 182 patients;<i>P</i> &lt; .001 for slope change), and NRT use increased by 32.1% (from 55 728 to 73 629 patients;<i>P</i> &lt; .001 for slope change). In Medicaid prescriptions, varenicline use decreased by 38.0% (from 109 308 to 67 761 prescriptions;<i>P</i> &lt; .001 for slope change) within 12 months of the 2008 public health advisory. Twelve months after the publication of the EAGLES trial, which showed no significant increase in psychiatric/behavioral effects with varenicline relative to NRT, use of varenicline increased by 42.7% in VHA patients (from 9251 to 13 199 patients;<i>P</i> = .01 for slope change) and by 26.0% in Medicaid prescriptions (112 063 to 141 122;<i>P</i> = .26 for slope change ). <h3>Conclusions and Relevance</h3> With use of varenicline as a case study, early communications from the FDA and VHA followed by a labeling change appeared to be associated with a considerable decrease in drug use, which may have been associated with negative public health consequences.
Abstract P241: 2013 AHA/ACC/TOS and 1998 NHLBI Clinical Guidelines for the Management of Overweight and Obesity Predict Higher Cardiovascular Disease Risk in Adults Recommended versus Not Recommended for Weight Loss Treatment: the Atherosclerosis Risk in Communities Study
Authors: June Stevens, Eva Erber-Oakkar, Zhaohui Cui, Jianwen Cai, David Wormser, Salim S Virani
Journal: Circulation (2015)

Introduction: In 2013, AHA/ACC/TOS released an algorithm to assist primary care providers in the identification of patients who should be considered for weight loss treatment to promote the prevention and treatment of cardiovascular disease (CVD). This guidance updated the recommendations released in 1998 by NHLBI. We know of no studies that have compared risk of incident CVD in adults recommended or not recommended for treatment by these two guidelines. Hypothesis: We hypothesized that adults recommended for weight loss treatment by the 1998 and 2013 algorithms have higher CVD risk than those not recommended for treatment. Additional analyses explored sources of differences in the algorithms as predictors of CVD risk. Methods: The ARIC study included 13,020 African American and White adults aged 45-64 years. Baseline data collected in 1987-1989 on BMI, waist circumference and other CVD risk factors in participants were used to form treatment groups that differed between the algorithms in regard to the choice, definition and number of risk factors. We calculated hazard ratios (HR) for first CVD event defined as ischemic stroke, fatal and non-fatal myocardial infarction (MI), silent MI and coronary revascularization procedures. Covariates included age, gender, ethnicity and study center. Results: At baseline, mean BMI was 28 kg/m2 (SD 5.3). During a median follow-up of 19.8 years, 2,698 incident CVD outcomes were recorded. The 1998 and 2013 algorithms recommended weight loss for 58% and 63% of participants, respectively, with 13% discrepant. The HR for CVD in adults recommended vs not recommended for treatment were 1.85 (95% CI: 1.69, 2.00) for the 1998 algorithm and 1.59 (95% CI: 1.47, 1.72) for the 2013 algorithm. The higher HR for the 1998 algorithm was driven in part by the inclusion of three risk factors (age, smoking and family history of premature CHD) not included in the 2013 algorithm (1998 HR reduced from 1.85 to 1.78 (95% CI: 1.65, 1.93) when those risk factors omitted). In the 2013, but not the 1998 algorithm, all overweight adults with a large waist circumference or pre-diabetes as their only risk factor were included in the treated group, but the HR’s for those subgroups were not elevated. The 2013 HR changed from 1.59 to 1.77 (95% CI: 1.63, 1.93) when those criteria were omitted. Conclusions: Both algorithms identified patients for weight loss treatment who were at elevated CVD risk, and the difference in the HR’s associated with the algorithms can be explained by differences in the specification of risk factors.
P13.08 1H-MRS metabolomics as a predictor of overall survival in glioma patients
Authors: J Solivera, A Fuentes Fayos, R M Luque, L Barrios, J M Roda, S Cerdán, M L Gandía-González
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND We assess the efficacy of the metabolomic profile from glioma biopsies, in providing estimates of postsurgical Overall Survival in glioma patients. MATERIAL AND METHODS Tumor biopsies from 46 patients bearing gliomas, obtained neurosurgically in the period 1992–1998, were analyzed by high resolution 1H magnetic resonance spectroscopy (HR- 1H MRS), following retrospectively individual postsurgical Overall Survival up to 720 weeks. RESULTS The Overall Survival profile could be resolved in three groups; Short (shorter than 52 weeks, n=19), Intermediate (between 53 and 364 weeks, n=19) or Long (longer than 365 weeks, n=8), respectively. Classical histopathological analysis assigned WHO grades II-IV to every biopsy but notably, some patients with low grade glioma depicted unexpectedly Short Overall Survival, while some patients with high grade glioma, presented unpredictably Long Overall Survival. To explore reasons underlying this behavior, we analyzed HR- 1H MRS spectra from acid extracts of these biopsies, to identify the metabolite patterns underlying OS predictions. Poor prognosis was found in biopsies with higher contents of alanine, acetate, glutamate, total choline, phosphorylcholine and glycine, while more favorable prognosis was achieved in biopsies with larger contents of total creatine, glycerol-phosphorylcholine and myo-inositol. We implemented then a multivariate analysis approach to identify hierarchically the influence of these metabolomic biomarkers on OS predictions, using Classification Regression Trees (CRTs). Metabolomic CRTs grew up to 3 branches and split into 8 nodes, predicting correctly the outcome of 94.7% of the patients in the Short Overall Survival group, 78.9 % of the patients in the Intermediate Overall Survival group, and 75% of the patients in the Long Overall Survival group, respectively. CONCLUSION Present results suggest that metabolic profiling by HR-1H MRS provides more accurate Overall Survival estimates of glioma patients than classical histopathological grading, thus allowing to implement more accurate therapeutic decisions.
P09.05 177Lu-DOTATATE therapy in progressive meningioma
Authors: M Müther, W Roll, B Zinnhardt, M Schäfers, K Rahbar, B Brokinkel, W Stummer
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Progressive meningioma is a challenging condition with a decreasing number of treatment options over the course of disease. Neurovascular involvement and multifocal disease often complicate surgical management. In addition, repeated radiotherapy carriers a risk of side effects. In somatostatin receptor expressing meningioma, peptide receptor radiotherapy (PPRT) with 177Lu-DOTATATE poses a promising alternative. However, current evidence is scarce. Hereby we present our single center experience of (PPRT) with 177Lu-DOTATATE in progressive meningioma. METHODS Eight patients (median age: 71 years; range 56–77) with progressive meningioma underwent PRRT using 177Lu-DOTATATE were included in this retrospective analysis. Response to therapy was assessed by interim and post-therapy 68Ga-DOTATATE-PET-CT and MRI. 177Lu-DOTATATE scintigraphies 48h p.i. were evaluated according to Krenning scale. Additionally, clinical outcome and follow up imaging were analyzed for progression free interval times. RESULTS Eight patients were included: Six patients with grade II and two patients with grade I meningiomas, according to the 2016 WHO classification. Six of eight patients harbored multifocal disease. One patients suffered systemic metastatic disease. Patients received a median of three cycles (range: 1 - 5) of PRRT with 177Lu-DOTATATE (mean injected dose 7.1 GBq) between 1/2015 and 1/2019. Tumor uptake in 48h p.i. 177Lu-Scintigraphies was heterogeneous (Krenning scale; median: 3; range: 1–4). Post-therapy imaging scheduled eight weeks after completion of therapy showed progressive disease in five patients, three patients had stable disease. Median follow-up post therapy response evaluation was 24 months in patients with stable disease. Median time to progression was 10 months. CONCLUSION In this cohort of eight progressive meningioma patients 177Lu-DOTATATE therapy showed heterogeneous efficacy.