tbuckley/cabot-search huggingface dataset:
Population pharmacokinetics of low dose suramin as a chemosensitizer in pet dogs with naturally occurring tumors
Authors: Xiao S. Hu, Carrie E. Koserek, C. Guillermo Couto, Danny Chen, William C. Kisseberth, M. Guill Wientjes, Jessie L.-S. Au
Journal: Cancer Research (2004)

2003  Suramin is an inhibitor of multiple growth factors including fibroblast growth factors. Our preclinical in vitro and in vivo studies showed that suramin reversed FGF-induced chemoresistance in a narrow therapeutic range from ∼ 10-50 μM, with antagonism at higher concentrations. Suramin is currently under investigation in a Phase II trial as a chemosensitizer in human non-small cell lung cancer patients treated with standard chemotherapy (paclitaxel plus carboplatin). A separate phase I/II trial evaluates the effectiveness of low dose suramin in pet dogs with naturally occurring tumors. The present study was to determine the pharmacokinetics of suramin in dogs, in order to identify the target suramin dose, in combination with chemotherapy. Eighteen dogs with late stage carcinoma, hemangiopericytoma, hemangiosarcoma or lymphoma were treated with suramin in combination with doxorubicin, receiving a total of 53 courses. Suramin was given at a fixed dose of 6.75 mg/kg as a 20-min infusion, and doxorubicin was given 3 hr later as 20-30 min infusion at a dose of 30 mg/m2 (or 1 mg/kg for body weight below 15 kg). The suramin pharmacokinetic data were analyzed using a nonlinear mixed-effect model (NONMEM) with a one-compartment model. The physiological parameters evaluated were age, body weight, body surface area (BSA), and gender. PBPK analysis of data obtained from 13 patients who received more than one treatment showed significant correlations between suramin clearance (CL) and BSA, CL and body weight, and volume of distribution (V) and BSA. Incorporation of the remaining covariates into the model did not significantly improve the model performance. These results led to a BSA-based suramin dose calculation method for individual patients, thereby eliminating the need of real-time pharmacokinetic monitoring for the use of low dose suramin as a chemosensitizer. Supported by R01CA 91457 and R01CA78577, NCI, NIH.
Abstract 13870: Association of Gait Speed and Cardiac Rehabilitation With Death and Disability Following Acute Myocardial Infarction
Authors: Kelsey M Flint, Kevin Kennedy, Suzanne V Arnold, John A Spertus, John A Dodson, Sharon Cresci, Karen P Alexander
Journal: Circulation (2016)

Background: Slow gait speed is associated with worse outcomes in older patients after acute myocardial infarction (AMI). Cardiac rehabilitation (CR) may improve outcomes in these patients, however participation in CR may be challenging in older patients with limited mobility. We assessed for an association between gait speed and CR participation, and examined whether CR modifies the association between slow gait speed (&lt;0.8m/sec) and 1-year outcomes. Methods: Among patients ≥ 65 years old enrolled in TRIUMPH (24-site US AMI registry) assessed with a 5-meter walk test at 1-month after AMI, we measured CR participation in patients with slow and normal gait speed. CR participation was self-reported 1 month after AMI. The association between slow gait speed and CR participation with death or disability (i.e., ADL loss) was assessed with multivariable logistic regression. We also measured the interaction between slow gait speed and CR participation with the outcomes. Results: Among 329 older patients, 177 (54%) had slow gait speed 1 month after AMI. 48 (27%) patients with slow gait speed participated in CR, whereas 62 (40%) patients with normal gait speed participated in CR (p=0.012). Patients with slow gait speed who did not participate in CR were most likely to experience death or disability at 1 year following AMI (43%), while similar outcomes were noted for slow gait speed/CR group (24%) and normal gait speed/no CR group (24%), with best outcomes in the normal gait speed/CR group (9%). In a multivariable model (Figure), lack of CR and slow gait speed were independently associated with death or loss of ADL at 1 year after adjustment for GRACE score and cognitive impairment. There was no interaction between gait speed, CR participation and 1-year mortality or disability (p interaction=0.67). Conclusions: Less CR participation is notable among older patients with slow gait speed; however, CR participation is associated with improved outcomes after AMI, regardless of gait speed.
Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases
Journal: Genome biology (2015)

To understand the contribution of Mendelian mutations to the burden of undiagnosed diseases that are suspected to be genetic in origin, we developed a next-generation sequencing-based multiplexing assay that encompasses the ~3000 known Mendelian genes. This assay, which we term the Mendeliome, comprises 13 gene panels based on clinical themes, covering the spectrum of pediatric and adult clinical genetic medicine. We explore how these panels compare with clinical whole exome sequencing (WES).We tested 2357 patients referred with suspected genetic diagnoses from virtually every medical specialty. A likely causal mutation was identified in 1018 patients, with an overall clinical sensitivity of 43 %, comparing favorably with WES. Furthermore, the cost of clinical-grade WES is high (typically more than 4500 US dollars), whereas the cost of running a sample on one of our panels is around 75-150 US dollars, depending on the panel. Of the "negative" cases, 11 % were subsequently found by WES to harbor a likely causal mutation in a known disease gene (largely in genes identified after the design of our assay), as inferred from a representative sample of 178. Although our study population is enriched for consanguinity, 245 (24 %) of solved cases were autosomal dominant and 35 (4 %) were X-linked, suggesting that our assay is also applicable to outbred populations.Despite missing a significant number of cases, the current version of the Mendeliome assay can account for a large proportion of suspected genetic disorders, and provides significant practical advantages over clinical WES.
NIMG-77. MULTIMODAL IMAGING OF GLIOBLASTOMA SUBREGIONS: IMPACT ON OVERALL SURVIVAL
Authors: Flora John, Edit Bosnyak, Geoffrey Barger, Natasha Robinette, Alit Amit-Yousif, Keval Shah, Sharon Michelhaugh, Sandeep Mittal, Csaba Juhasz
Journal: Neuro-Oncology (2018)

Glioblastomas are heterogeneous brain-infiltrating tumors with diverse histopathological and molecular genetic features. Although treatment is mostly focused on the contrast-enhancing tumor mass, combination of advanced structural and molecular imaging can enhance more accurate tumor delineation and capture glioblastoma heterogeneity. Here we combined conventional MRI with diffusion-weighted imaging (DWI) and amino acid PET characteristics to explore imaging-defined glioblastoma subregions and evaluate their potential prognostic value. Contrast-enhanced T1, T2/FLAIR MR images, apparent diffusion coefficient (ADC) maps from DWI, and alpha-[11C]-methyl-L-tryptophan (AMT)-PET images were analyzed in 30 patients (mean age: 59 years) with newly-diagnosed glioblastoma. Tumor subregions were identified based on a combination of MRI contrast enhancement, T2/FLAIR signal abnormalities, and AMT uptake on PET. ADC and AMT uptake tumor/contralateral normal cortex (T/N) ratios in these tumor subregions were measured, and their prognostic value for overall survival was determined. A total of 115 MRI/PET-defined subregions were analyzed in the 30 glioblastomas. Most tumors showed not only a high AMT uptake (T/N ratio >1.65, N=27) but also a low-uptake subregion (N=21) within the contrast-enhancing tumor mass. High AMT uptake extended beyond contrast enhancement in 25 cases and correlated with low ADC (r=-0.40, p=0.05), consistent with high cellularity in tumor-infiltrated brain. Non-enhancing T2/FLAIR abnormal subregions had low AMT uptake and high ADC, consistent with vasogenic edema (N=24) or central necrosis (N=18). Cox regression analysis showed that high AMT uptake in the contrast-enhancing tumor subregions was prognostic for overall survival (HR: 7.83 [95%CI: 1.98–31.02], p=0.003), independent of several clinical and molecular genetic prognostic variables. CONCLUSIONS: Amino acid uptake by PET can differentiate metabolically active glioblastoma subregions, often showing dense cellularity, vs. necrotic/edematous areas, both in enhancing and non-enhancing tumor portions. High tryptophan uptake in MRI contrast-enhancing tumor subregions is a strong, independent imaging marker for longer survival in patients with newly-diagnosed glioblastomas.
Training in communication of oncology clinicians: a position paper based on the third consensus meeting among European experts in 2018
Authors: F. Stiefel, A. Kiss, P. Salmon, S. Peters, D. Razavi, A. Cervantes, A. Margulies, C. Bourquin, Céline Bourquin, Andrés Cervantes, Sarah Dauchy, Vikki Entwistle, Luigi Grassi, Patrick Jermann, Wolf Langewitz, Anita Margulies, Solange Peters, Darius Razavi, Pär Salander, Peter Salmon, Ellen Smets, Wolfgang Söllner, Gilbert Zulian, Jürg Bernhard, Gabriella Bianchi Micheli, Christoph Hürny, Alexander Kiss, Patrick Nemeshazy, Friedrich Stiefel, Brigitta Wössmer
Journal: Annals of Oncology (2018)

BackgroundSince there is sound evidence that communication skills training (CST) programs modify communication behavior of oncology clinicians, they have been widely implemented over the last decades. However, more recently, certain aspects of this training have been criticized.MethodsBased on this background, a call to re-launch a discussion about the future of CST led to the third European consensus meeting on communication in cancer care, organized by the Swiss Cancer League. During this meeting, which brought together European experts in the field of clinical communication and training of communication in the oncology setting, oncology clinicians, representatives of the European Society of Medical Oncology and a member of the European Oncology Nursing Society, the recommendations of the second European consensus meeting were updated and expanded.ResultsThe expanded recommendations recall the guiding principles of communication in cancer care, underline the important role of clinician's self-awareness, and of relational and contextual factors in clinical communication, and provide direction for the further development of communication training.ConclusionThis third European consensus meeting defines key elements for the development of a next generation of communication training for oncology clinicians.
HOUT-33. FUNCTIONAL OUTCOME OF GLIOMA SURGERY UNDER AWAKE CONDITION AIMED FOR PRESERVATION OF SEVERAL FUNCTIONAL DOMAINS
Authors: Riho Nakajima, Masashi Kinoshita, Hirokazu Okita, Tetsutaro Yahata, Mitsutoshi Nakada
Journal: Neuro-Oncology (2018)

Awake surgery for the eloquent cortex is common strategy for glioma surgery. Although a recent emphasis has been placed on awake surgery for both dominant and non-dominant cerebral hemispheres to preserve neurological/neuropsychological functions, those functional outcomes are not well investigated since few studies focused on longitudinal recovery process. This study explored the outcome of neurological/neuropsychological functions following awake surgery until chronic phase. A total of 87 patients with glioma who underwent awake surgery between September 2013 and September 2017 were included, and of these 66 patients matched our inclusion criteria (age: mean, 46.0; range, 16–73). Each patient was assessed for neurological/neuropsychological functions including sensorimotor function, naming, working memory, low- and high-level mentalizing and visuospatial cognition at before surgery, as well as acute and chronic phase. Additionally, scores for the Karnofsky Performance Status (KPS) were collected. Almost all neurological/neuropsychological functions recovered within 3 months postoperatively, even when transient deficits were observed in the acute phase. However, deep sensory perception deficits and visuospatial cognitive disorders persisted into the chronic phase. Disorder probabilities at chronic phase were as follows: deep perception disorder, 15.4 % of patients with parietal lesions; visuospatial cognition, 14.3% of patients with right hemisphere. KPS score ≥ 90 was achieved in 86.0 % of patients with lower grade glioma, whereas only 52.2% of glioblastoma patients scored ≥ 90. Primary causes of declined KPS were disorder of visuospatial cognition, sensorimotor function including deep sensation, aphasia, and emotional function, which influence on their professional work and household work. Awake surgery leads good functional outcome at chronic phase on neurological/neuropsychological functions, except for deep sensory and visuospatial cognition. Since sensation and visuospatial cognitive disorder make major impact on patients’ independence level, further importance should be placed on preserving these functions during surgery.
CADD-57. THE EFFICACY OF THERAPY WITH ABT-414, AN EGFR-TARGETING ADC, IS POTENTIALLY ALTERED BY HETEROZYGOUS DELETION OF THE ENDOCYTIC TRAFFICKING REGULATOR RBSN
Authors: Gaelle Muller-Greven, Bianca-Maria Marin, Cathleen Carlin, Edward Reilly, Jeongwu Lee, Marcus Bredel, Jann Sarkaria, Candece Gladson
Journal: Neuro-Oncology (2018)

Therapy with ABT-414 (depatux-m), a humanized monoclonal antibody drug conjugate (ADC) directed toward EGFRvIII and activated wild-type EGFR linked to MMAF, has demonstrated promising clinical activity in glioblastoma (GBM) patients with amplified EGFR and is currently being evaluated in clinical trials in first-line GBM disease settings. However, not all patients with amplified EGFR respond to ABT-414 and the reason is unclear. Cancer stem-like cells (CSLCs) have been reported to be responsible for drug and radiation resistance, and we have shown previously that internalization and endocytic trafficking of the humanized mAb bevacizumab affected the survival of CSLCs. Thus, we examined the endocytic trafficking of ABT-414 in EGFRvIII+ CSLCs, and the effect of downregulating a regulator of endocytic trafficking, RBSN (rabenosyn-5). In CSLCs treated with 75µg/ml ABT-414, a fraction of ABT-414 was trafficked to a Rab4+ fast recycling compartment (40% at 5 and 15 min), and a fraction was trafficked to the Lamp1+ lysosome (20% at 30 min and 3 hr). Similarly, in a PDX model of GBM with amplified EGFR treated with ABT-414, a fraction of ABT-414 was detected in a Rab4+ fast recycling compartment and a fraction was detected in the Lamp1+ lysosome. Downregulation of RBSN with specific-siRNA resulted in increased targeting of ABT-414 to the Lamp1+ lysosome at 30 min and a trend-toward-an-increase at 180 min. This could potentially suggest an increased release of the drug conjugate MMAF; lysosomal trafficking is necessary for release of MMAF. Expression of RBSN in a GBM tissue microarray showed very weak/absent expression in 9% of GBM biopsies, consistent with the heterozygous deletion of RBSN in 8% of GBM tumors (TCGA database) and the corresponding significant decrease in RBSN mRNA in these tumors. These data suggest that alterations in endocytic trafficking genes, such as RBSN, could affect the efficacy of ABT-414 therapy in patients.
Response to: ‘Tocilizumab in patients with adult-onset Still’s disease refractory to glucocorticoid treatment’ by Lee
Authors: Yuko Kaneko, Hideto Kameda, Kei Ikeda, Tomonori Ishii, Kosaku Murakami, Hyota Takamatsu, Yoshiya Tanaka, Takayuki Abe, Tsutomu Takeuchi
Journal: Annals of the Rheumatic Diseases (2018)

Response to: 'Tocilizumab in patients with adult-onset Still's disease refractory to glucocorticoid treatment' by LeeWe would like to thank Dr Lee 1 for his interest in our paper 2 and for his comments providing futuristic insights into the management of adult-onset Still's disease.4][5] Although the safety of biological agents including tocilizumab have been shown in patients with rheumatoid arthritis, they are more expensive than conventional DMARDs, and the long-term safety of their use in patients with adult-onset Still's disease is still unknown.Some of patients in our trial had a history of not responding to DMARDs such as methotrexate or ciclosporine, but we did not collect precise information about patients' previous treatment other than glucocorticoids use.Our trial was a first step, aimed at proving the efficacy of antiinterleukin-6 treatment by a high-levelled evidence rather than case reports.As Dr Lee mentioned, further randomised studies are warranted to determine the optimal management of adultonset Still's disease, although the rarity and occasional fatal severity of adult-onset Still's disease would hinder determining appropriate endpoints and recruiting active patients who are refractory to glucocorticoids but can tolerate control treatment including placebo or conventional DMARDs.The next step will need worldwide cooperation to establish the optimal management of adult-onset Still's in clinical studies with a proper design and sample size.
ATIM-29. NRG BN002: SAFETY DATA FROM A PHASE I STUDY OF IPILIMUMAB (IPI), NIVOLUMAB (NIVO), AND THE COMBINATION FOR NEWLY DIAGNOSED GLIOBLASTOMA (GBM)
Authors: Mark Gilbert, Peixin Zhang, Andrew Sloan, Kenneth Aldape, Jing Wu, Lisa Rogers, Patrick Wen, Igor Barani, Fabio Iwamoto, Raju Raval, Alfredo Voloshin, John de Groot, Minhee Won, Minesh P Mehta
Journal: Neuro-Oncology (2018)

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in several solid tumors including brain metastases, but single agent ICIs have failed to improve outcome in recurrent (GBM). This study evaluated the safety of anti-CTLA-4 (IPI) and anti-PD-1 (NIVO) ICIs alone or in combination in newly diagnosed GBM during adjuvant temozolomide (TMZ) treatment. This phase I study evaluated IPI (3mg/kg), NIVO (3mg/kg), and the combination (1 mg/kg & 3 mg/kg respectively) followed by an expansion cohort for the combined treatment of adults with unifocal, supratentorial newly diagnosed GBM after gross or near total resection. ICIs were given with adjuvant TMZ. The primary endpoint was the dose limiting toxicity (DLT) within 8 weeks of starting ICIs. A standard up-and-down design was used with 6 evaluable patients enrolled at a given dose level; safety defined as 1 or fewer patients with DLTs. Thirty-two patients (31 analyzable; 1 not treated) were enrolled, 6 to each arm and 14 to the expansion cohort. Median age: 54 years (range: 23–74), 68% male and 84% white. Overall, treatment was well tolerated with a 16% rate of Grade 4 events; without increased toxicity of combination ICIs; there were no Grade 5 events. One DLT was seen in each single-agent arm; none in the combination arm. Median follow-up time was 8.4 months (range: 0.5–23.6), 10 had progressed (32%) and 8 had died (26%), 7 due to disease progression and 1 due to pulmonary embolism. IPI and NIVO are safe and tolerable with similar toxicity profiles noted with other cancers when given with adjuvant TMZ for newly diagnosed GBM. Combination IPI+NIVO is not more toxic than single agents. These results provide necessary safety data for a subsequent efficacy trial to test the combination of ICIs in newly diagnosed GBM. Funding: U10CA180868 and U10CA180822 (NCI).
Abstract 16058: Country Income Level, Protocol Completion, and Trial Endpoints Among Patients With Acute Heart Failure: Insights From the ASCEND-HF Trial
Authors: Stephen J Greene, Adrian F Hernandez, Jie-Lena Sun, Javed Butler, Paul W Armstrong, Justin A Ezekowitz, Faiez Zannad, João P Ferreira, Adrian Coles, Marco Metra, Adriaan A Voors, Robert M Califf, Christopher M O'Connor, Robert J Mentz
Journal: Circulation (2017)

Introduction: Globalization of clinical trials fosters inclusion of patients from higher and lower income countries. The influence of enrolling country income level on heart failure (HF) trial perf...
17‐Beta Hydroxysteroid Dehydrogenase 13 Is a Hepatic Retinol Dehydrogenase Associated With Histological Features of Nonalcoholic Fatty Liver Disease
Authors: Yanling Ma, Olga V. Belyaeva, Philip M. Brown, Koji Fujita, Katherine Valles, Suman Karki, Ynto S. de Boer, Christopher Koh, Yanhua Chen, Xiaomeng Du, Samuel K. Handelman, Vincent Chen, Elizabeth K. Speliotes, Cara Nestlerode, Emmanuel Thomas, David E. Kleiner, Joseph M. Zmuda, Arun J. Sanyal, Natalia Y. Kedishvili, T. Jake Liang, Yaron Rotman
Journal: Hepatology (2018)

Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single-nucleotide polymorphism (SNP), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13), to identify associations with histological features of NAFLD and to characterize the functional role of HSD17B13 in NAFLD pathogenesis. The minor allele of rs6834314 was significantly associated with increased steatosis but decreased inflammation, ballooning, Mallory-Denk bodies, and liver enzyme levels in 768 adult Caucasians with biopsy-proven NAFLD and with cirrhosis in the general population. We found two plausible causative variants in the HSD17B13 gene. rs72613567, a splice-site SNP in high linkage with rs6834314 (r2 = 0.94) generates splice variants and shows a similar pattern of association with NAFLD histology. Its minor allele generates simultaneous expression of exon 6-skipping and G-nucleotide insertion variants. Another SNP, rs62305723 (encoding a P260S mutation), is significantly associated with decreased ballooning and inflammation. Hepatic expression of HSD17B13 is 5.9-fold higher (P = 0.003) in patients with NAFLD. HSD17B13 is targeted to lipid droplets, requiring the conserved amino acid 22-28 sequence and amino acid 71-106 region. The protein has retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and cofactor binding site. The exon 6 deletion, G insertion, and naturally occurring P260S mutation all confer loss of enzymatic activity. Conclusion: We demonstrate the association of variants in HSD17B13 with specific features of NAFLD histology and identify the enzyme as a lipid droplet-associated RDH; our data suggest that HSD17B13 plays a role in NAFLD through its enzymatic activity.