tbuckley/cabot-search huggingface dataset:
Phase II study of third-line panitumumab rechallenge in patients with metastatic wild-type KRAS colorectal cancer who achieved a clinical benefit in response to first-line panitumumab plus chemotherapy
Authors: A. Tsuji, M. Nakamura, T. Watanabe, D. Manaka, H. Matsuoka, M. Kataoka, M. Takeuchi, W. Ichikawa, M. Fujii
Journal: Annals of Oncology (2018)

Introduction: Cetuximab rechallenge has been reported to be promising (Santini D et al. Ann Oncol 2012 and Tsuji A et al. Annals of Oncology, Volume 27, Issue suppl_6, 2016, 510P,).On the other hand, usefulness of panitumumab for cetuximab is expected (WJOG6510G, ASCO-GI 2017). We performed a multicenter phase II prospective study panitumumab rechallenge in Japan. Methods: The study cohort comprised patients with metastatic wild-type KRAS colorectal cancer who achieved a clinical benefit (confirmed stable disease for at least 6 months or clinical response) in response to first-line panitumumab plus chemotherapy, then had disease progression and received second-line chemotherapy, and finally had a clear new progression of disease. Patients received bi-weekly irinotecan (150 mg/m2) combined with panitumumab (8 mg/m2 bi-weekly). The primary endpoint was the 3-month progression-free rate. The required sample size was estimated to be at least 30 patients, assuming a 3-month progression-free rate of less than 15% as the null hypothesis versus a 3-month progression-free rate of higher than 35% as the alternative hypothesis, a power of 80%, and an alpha value of 0.05. Results: A total of 25 patients were recruited. One patients were excluded: one did not receive the study treatment because of poor condition at the time scheduled for treatment. 22 of 25 patients received bevacizumab combined therapy before this trial. The 3-month progression-free rate of 54.2% (95% confidence interval: 34.2-74.1) met the primary endpoint, with a median progression-free survival time of 3.8months and an overall survival time of 8.9 months. The overall response rate and disease-control rate were 8.3% and 50.0%, respectively. The most frequent grade 3 to 4 adverse event was neutropenia (8.3%), and skin toxicities (all grade) occurred in 91.7% of all patients, as expected. Conclusion: Third-line panitumumab rechallenge may be clinically beneficial treatment before regorafenib and TAS102, with manageable toxicity. Clinical trial identification: Trial protocol number: UMINUMIN000011440, UMIN release date: 2018/01/17.
Smoke-Free and Tobacco-Free Policies in Colleges and Universities ― United States and Territories, 2017
Authors: Teresa W. Wang, Michael A. Tynan, Cynthia Hallett, Laura Walpert, Maggie Hopkins, Darryl Konter, Brian A. King
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Each year in the United States, cigarette smoking causes an estimated 480,000 deaths, including approximately 41,000 deaths from secondhand smoke exposure among nonsmoking adults (1). Smoke-free policies protect nonsmokers from secondhand smoke exposure, reduce the social acceptability of smoking, help in preventing youth and young adult smoking initiation, and increase smokers' efforts to quit smoking (1,2). Given that 99% of adult cigarette smokers first start smoking before age 26 years and many smokers transition to regular, daily use during young adulthood (2),* colleges and universities represent an important venue for protecting students, faculty, staff members, and guests from secondhand smoke exposure through tobacco control policies (3). To assess smoke-free and tobacco-free policies in U.S. colleges and universities, CDC and the American Nonsmokers' Rights Foundation (ANRF) determined the number of campuses nationwide that completely prohibit smoking (smoke-free) or both smoking and smokeless tobacco product use (tobacco-free) in all indoor and outdoor areas. As of November 2017, at least 2,082 U.S. college and university campuses had smoke-free policies. Among these campuses, 1,743 (83.7%) were tobacco-free; 1,658 (79.6%) specifically prohibited electronic cigarette (e-cigarette) use; and 854 (41.0%) specifically prohibited hookah smoking. Smoke-free and tobacco-free policies on college and university campuses can help reduce secondhand smoke exposure, tobacco use initiation, and the social acceptability of tobacco use (1-3).
LGG-34. EVALUATION OF MOLECULAR CHARACTERISTICS OF DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR
Authors: Erin Wright, Alexis Judd, Jennifer Stanke, Dimitri Agamanolis, Sarah Rush
Journal: Neuro-Oncology (2018)

Diffuse leptomeningeal glioneuronal tumors are rare pediatric CNS tumors that often present with disseminated disease of the brain and spinal cord. These tumors can present as widespread leptomeningeal enhancement or with discrete intraparenchymal lesions and were recently codified in the WHO classification of CNS tumors in 2016. While these tumors have a benign appearance, they behave more aggressively and are often unresponsive to standard chemotherapy. These tumors have been shown to harbor BRAF rearrangements/duplications, loss of chromosome 1p, and 1p19q co-deletions; however, there is little reported regarding the full mutational signature of these tumors that may lead to a better understanding their aggressive phenotype. We performed a retrospective case review of 5 patients with disseminated disease consistent with diffuse leptomeningeal glioneuronal tumors that presented to Akron Children’s Hospital. Their presentation, outcome, and response to therapy was reviewed to assess for similarities across the patient group. In addition, mutational analysis of these tumors utilizing comprehensive genomic profiling was performed to evaluate for distinct mutational similarities across these patients. Upon initial review of these tumors, these samples demonstrated similar BRAF changes to those reported previously. Additionally, two out of three samples noted a mutation in the FRS2 gene which plays an important role in the activation of MAP kinases and in the phosphorylation of the regulatory subunit of PIK3. Our goal was to expand this cohort to help identify other commonalities across this tumor group and better characterize potential prognostic features and targeted therapies based their unique molecular signature.
Assessing the Economic and Societal Benefits of SRP-Funded Research
Authors: William A. Suk, Michelle L. Heacock, Brittany A. Trottier, Sara M. Amolegbe, Maureen D. Avakian, Heather F. Henry, Danielle J. Carlin, Larry G. Reed
Journal: Environmental Health Perspectives (2018)

The National Institute of Environmental Health Sciences (NIEHS) Superfund Basic Research and Training Program (SRP) funds a wide range of transdisciplinary research projects spanning the biomedical and environmental sciences and engineering, supporting and promoting the application of that research to solving real-world problems.We used a case study approach to identify the economic and societal benefits of SRP-funded research, focusing on the use of potentially hazardous substance remediation and site monitoring tools. We also identified successes and challenges involved in translating SRP grantees' research findings and advances into application.We identified remediation and detection research projects supported by the SRP with the most potential for economic and societal benefits and selected 36 for analysis. To examine the benefits of these applied technologies, we interviewed 28 SRP-supported researchers and 41 partners. Five case studies emerged with the most complete information on cost savings-total savings estimated at >$100 million. Our analysis identified added societal benefits such as creation of small businesses, land and water reuse, sustainable technologies, exposure reduction, and university-industry partnerships.Research funded by the SRP has yielded significant cost savings while providing additional societal benefits. https://doi.org/10.1289/EHP3534.
Somatic Bi-allelic Loss of TSC Genes in Eosinophilic Solid and Cystic Renal Cell Carcinoma
Authors: Rohit Mehra, Pankaj Vats, Xuhong Cao, Fengyun Su, Nicole D. Lee, Robert Lonigro, Kumpati Premkumar, Kiril Trpkov, Jesse K. McKenney, Saravana M. Dhanasekaran, Arul M. Chinnaiyan
Journal: European Urology (2018)
Combined analysis of KRAS, NRAS, BRAF mutations and mismatch repair deficiency testing in Indian patients with metastatic colorectal carcinoma: A single centre experience
Authors: T. Sood, A. Rauthan, P. Patil, S. Kulkarni
Journal: Annals of Oncology (2018)

Introduction: Molecular evaluation of KRAS, NRAS and BRAF mutation has become an important part in colorectal carcinoma evaluation as their alterations determine the therapeutic response to anti-EGFR therapy and prognosis. MMR deficiency is important for identification of Lynch syndrome families and it has now become an important biomarker of response to immunotherapy in metastatic CRC. The aim of this study is to investigate the distribution of these mutations by tumor localization and to determine the prevalence of MMR deficiency in metastatic colorectal cancer. Methods: A retrospective analysis of 149 patients was done who presented between May 2016 to February 2018 with metastatic colorectal cancer. Molecular analysis was done on paraffin blocks of tumour tissue for KRAS, NRAS, BRAF mutations by PCR and Mismatch Repair protein expression was evaluated by immunohistochemistry. Results: The mean of age for patients at diagnosis was 57.67±13.20 years (range, 28-80 years), 95 patients (63.7%) were male and 54 patients (36.3%) were female. Location of tumour was left sided in 100 patients and right sided in 49 patients. 58 patients (39%) had KRAS mutation and 5 patients (3.3%) had NRAS mutation. Out of 149 patients, 89 underwent BRAF mutation analysis of which 6 patients (6.8%) had mutation (V600E). 51% patients had RAS mutation and 6% had BRAF mutation with tumour localised to right side. 38% patients had RAS mutation and 7.1% had BRAF mutation with left sided disease. BRAF showed no significant difference between prevalence in right and left sided disease. No concomitant mutation of KRAS, NRAS and BRAF mutations was observed. MMR by IHC revealed deficiency in 12 (17.1%) out of 70 patients evaluated, of which 21.4% were right sided and 14.2% were left sided. All of these had BRAF wild type suggestive of Lynch syndrome. Conclusion: To our knowledge this is the first study to evaluate MMR deficiency by IHC in Indian patients with tumour localisation. 12 (17.1%) patients with MMR deficiency qualified as likely candidates for immunotherapy and these families would benefit from cancer screening for Lynch syndrome and genetic counselling. The frequency of KRAS mutation was 39% which is similar to worldwide reports and in our study, by evaluating NRAS and BRAF mutants, we were able to classify an additional 10.2% patients as likely non-responders to anti-EGFR therapy. In present therapeutic landscape, it is imperative to test genetic biomarkers for colorectal cancer patients.
DIPG-05. PRECLINICAL EFFICACY OF MELK INHIBITION IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Michaël Meel, Mark de Gooijer, Miriam Guillén Navarro, Piotr Waranecki, Marjolein Breur, Levi Buil, Laurine Wedekind, Jos Twisk, Jan Koster, Rintaro Hashizume, Eric Raabe, Ángel Montero Carcaboso, Marianna Bugiani, Olaf van Tellingen, Dannis van Vuurden, Gertjan Kaspers, Esther Hulleman
Journal: Neuro-Oncology (2018)

Maternal embryonic leucine zipper kinase (MELK) is a highly overexpressed kinase in diffuse intrinsic pontine glioma (DIPG). Inhibition of MELK by the small molecule OTSSP167 effectively reduces proliferation and induces cell death in primary DIPG cell lines at low nanomolar concentrations. RNA sequencing of DIPG cells treated with OTSSP167 reveals upregulation of genes associated with the PPAR transcription factors as well as upregulation of PPARγ target genes. Western blot and immunofluorescence assays demonstrate reduced inhibitory phosphorylation and increased nuclear localization of PPARγ upon MELK inhibition. Consequently, combined treatment of DIPG cells with OTSSP167 and PPARγ agonists synergistically reduces cell survival. Pharmacokinetic analyses reveal OTSSP167 to be a strong substrate of both MDR1 and BCRP, multidrug transporters on the blood-brain barrier, limiting the brain bioavailability of the compound. To demonstrate the potential of MELK inhibition for the treatment of DIPG, Mdr1a/b -/-; Bcrp1-/- athymic nude mice were xenografted with primary DIPG tumors and treated with a low dose of OTSSP167 for six weeks. In these models, treatment of the mice with OTSSP167 resulted in a significant delay in tumor growth, induction of remissions in almost half of the mice, and significantly prolonged survival of the xenograft-bearing mice. Efficacy was comparable among pre-treatment biopsy-derived and post-treatment autopsy-derived xenograft models. These strong preclinical therapeutic effects of OTSSP167 demonstrate the potential of MELK inhibition for the treatment of DIPG and encourage the development of BBB-penetrable MELK inhibitors.
QOL-24. NEUROCOGNITIVE STATUS IN SUPRATENTORIAL PNET TREATED ON COG ACNS0332 WITHIN THE FIRST 30 MONTHS FROM DIAGNOSIS: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP
Authors: Karin Walsh, Eugene Hwang, Kristina Hardy, Leanne Embry, Anthony Gioia, Tess Kennedy, Catherine Billups, Yimei Li, Roger Packer, James Olson
Journal: Neuro-Oncology (2018)

Supratentorial primitive neuroectodermal tumors (sPNETs) in children are aggressive tumors that require intensive chemotherapy and craniospinal irradiation, but we have little information on long-term neurocognitive outcomes. Eighty-five children were enrolled on ACNS0332 based on histopathological criteria consistent with WHO guidelines; 27 of these (61% female) co-enrolled on the neurocognitive study ALTE07C1, and have complete T1 data (~9 months post-diagnosis); 20 also completed testing at T2 (~30 months post-diagnosis). Mean age at T1 was 9.7 (4.52) years, and 11.6 (4.50) at T2. Tumors with pineal involvement made up 45% of the sample. Memory, intellectual and executive function were analyzed at T1 and T2. At T1, the entire group showed deficits in processing speed (WISC PSI M=79.5, SD=14.86), spatial memory (CMS Dots M=7.4, SD=2.57), and working memory (BRIEF WMI M=64.5, SD=16.45) with average IQ (M=90.4, SD=19.05). There were no T1 differences between patients with pineal versus non-pineal tumors. At T2, a broader range of deficits emerged; areas impaired at T1 worsened at T2, and broader memory dysfunction appeared. By T2, significant group differences were evident in favor of patients with pineal involvement in processing speed (WISC Coding pineal M=6.2 (2.71), non-pineal M=3.4 (1.71)) and working memory (BRIEF WM pineal M=56.8 (11.96), non-pineal M=73.3 (11.81)). Children with sPNETS appear to develop substantial cognitive morbidity within the first 30 months after diagnosis, with worse outcomes in non-pineal tumors. These findings have implications for understanding mechanisms of cognitive late effects in these patients and may provide novel and important opportunities for individualized, patient-centered neuropsychological care.
HGG-25. INFANT GLIOMAS COMPRISE MULTIPLE BIOLOGICAL AND CLINICOPATHOLOGICAL SUBGROUPS
Authors: Matthew T Clarke, David TW Jones, Alan Mackay, Diana Carvalho, Elisa Izquierdo, Lotte Hiddingh, Sara Temelso, Anna Burford, Valeria Molinari, Jessica KR Boult, Alex Virasami, Fernando Carceller, Lynley V Marshall, Bassel Zebian, Chris Chandler, Safa Al-Sarraj, Stephen Lowis, Jeffrey Knipstein, Simon Bailey, Stephen Crosier, Angela Mastronuzzi, Andrea Carai, David W Ellison, Suzanne J Baker, David Capper, Mellissa Maybury, Andrew S Moore, Maria Vinci, Darren Hargrave, Sergey Popov, Thomas S Jacques, Chris Jones
Journal: Neuro-Oncology (2018)

Infant gliomas have been considered as early-onset examples of tumour types found throughout paediatric populations. Interestingly, infant high-grade gliomas (HGG) have a better overall survival compared to older children, indicating that grading may not accurately reflect the biology of these tumours. We have to-date collected 181 cases of diffuse glioma (WHO II-IV) occurring in children aged <4 years for histological review, methylation profiling, gene fusion panel and whole genome/exome sequencing. Of 147 samples profiled using the Heidelberg methylation classifier, 20 were reassigned as established brain tumour entities (e.g. pilocytic astrocytoma, HGNET-BCOR), whilst a further 23 fell into recognised HGG subgroups. The remaining 104 cases formed four distinct subgroups by consensus clustering. Two groups were mostly classified as ‘infantile hemispheric gliomas’ (IHG), one of these showing enrichment for ALK/NTRK fusion genes, the other a male predominance, and both with a median age ≤1 year. IHG had a highly cellular, uniform architecture with gemistocytic-like or spindle cell morphology. A third group did not fit with established methylation subgroups but were largely female, ≤6 months, and harboured ALK/NTRK fusions. The fourth group were older, comprising desmoplastic infantile gliomas and poorly-scoring cases of other low-grade tumours. We established three novel patient-derived cultures of IHG, with TPM3:NTRK1, KCTD16:NTRK2 and ETV6:NTRK3 fusions. Drug screening with multiple NTRK inhibitors revealed marked sensitivity in vitro, making such patients excellent candidates for clinical trials of these compounds. The clinical, histological and molecular features of infant gliomas suggest the presence of novel tumour subgroups, which may have targetable driving alterations.
Tissue engineering toward temporomandibular joint disc regeneration
Authors: Natalia Vapniarsky, Le W. Huwe, Boaz Arzi, Meghan K. Houghton, Mark E. Wong, James W. Wilson, David C. Hatcher, Jerry C. Hu, Kyriacos A. Athanasiou
Journal: Science Translational Medicine (2018)

Tissue-engineered implants integrate with native tissue, are capable of adaptive remodeling, and improve healing of temporomandibular joint disc defects in minipigs.
Preliminary safety and efficacy of evofosfamide (TH-302), an investigational hypoxia-activated prodrug, combined with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma (RR MM).
Authors: Jacob Laubach, Noopur S. Raje, Andrew Jenho Yee, Philippe Armand, Robert L. Schlossman, Jacalyn Rosenblatt, Jacquelyn Ann Hedlund, Michael Gary Martin, Craig H. Reynolds, Kenneth H. Shain, Ira Zackon, Laura Stampleman, Erica Boswell, Stacey Chuma, Rebecca Liguori, Damian Handisides, Stew Kroll, Kenneth Carl Anderson, Paul G. Richardson, Irene M. Ghobrial
Journal: Journal of Clinical Oncology (2015)

8579 Background: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma (MM) (Colla, Leukemia 2010). Evofosfamide (EVO; formerly TH-302) is a novel 2-nitroimidazole prodrug of the DNA alkylator bromo-isophosphoramide mustard that is selectively activated under hypoxia and is investigated in multiple Phase 1-3 trials. Synergistic induction of apoptosis in MM cells by EVO and bortezomib (Bor) was shown in vivo and in vitro (Hu et al, Mol Cancer Ther2013). An ongoing phase 1/2 study investigates EVO in combination with Bor and dexamethasone (D) in RR MM (NCT01522872). Methods: This phase 1/2 open-label multicenter study investigates IV EVO (240-480 mg/m²), IV or SC Bor (1.3 mg/m2), plus PO D (40 mg) on Days 1, 4, 8 and 11 of a 21-day cycle. At the maximum tolerated dose, a Simon two-stage optimal design was implemented to pursue a regimen with ≥ 50% response rate or discontinue if ≤ 25% (85% power, 10% alpha). Results: Nine patients (pts; 4 male, 5 female) have been reported (3 at 240 mg/m2 EVO and 6 at 340 mg/m2 EVO). Pts were heavily pre-treated; median number of prior therapies was 8 (4 – 12). Median age was 57 years (45 – 68). All had previously received Bor and lenalidomide or thalidomide. No pt had a dose limiting toxicity and the recommended phase 2 dose (RP2D) was established at 340 mg/m2 EVO. The most common ≥ Gr 3 adverse events (AEs) were thrombocytopenia (5 pts), lymphopenia (2 pts), leukopenia (2 pts) and anemia (2 pts). Limited skin toxicity has been observed (2 pts, grade 2 rash or skin lesions). Four pts had SAEs; one SAE of thrombocytopenia was related to EVO. Seven pts discontinued for progressive disease; no pts have discontinued due to an AE. IMWG assessments were 1 CR, 2 PR, 4 SD and 2 PD (1 CR and 2 PRs out of 6 pts at 340 mg/m2 EVO). Two pts with a CR and PR continue on study. To date, 17 of 24 pts have been enrolled to evaluate safety and efficacy at the RP2D. Conclusions: EVO can be administered at 340 mg/m2 twice a week with Bor and D. Preliminary clinical activity has been noted in pts with heavily pre-treated RR MM. Data from pts treated at the RP2D will be updated and presented at the meeting. Clinical trial information: NCT01522872.
Abstract 16439: Role of Caspase-1 in HIV-Associated Atherosclerosis
Authors: Alison Kearns, Fengming Liu, Shen Dai, Jake Robinson, Elizabeth Kiernan, Jennifer Gordon, Janet Lo, Steven Grinspoon, Tricia Burdo, Xuebin Qin
Journal: Circulation (2017)

Human immunodeficiency virus (HIV) cardiovascular disease and its complications, including heart attack and stroke, is now a leading cause of mortality in HIV+ patients. Extensive clinical evidence suggests well controlled HIV infection with or without combined antiretroviral therapy (cART) (eg. HIV+ patients or HIV+ elite controllers) accelerates atherogenesis. In patients on cART, HIV infection not only activates immune cells (macrophages), but also triggers an array of molecular pathways, such as caspase-1 activation and its cleavage products IL-18 and IL-1β. The immune cell activation in the periphery or lymph nodes may not be reflective of cardiovascular inflammation, indicating the pathogenesis of HIV-associated vascular inflammation may differ from the periphery. Understanding mechanisms of HIV-associated atherogenesis will help to better design and develop novel therapeutics for treatment/prevention. However, the pathogenesis of HIV-associated atherosclerosis has not been investigated due to the lack of a mouse model. Here, we present the development and characterization of a new mouse model for HIV-associated atherosclerosis, and its use in understanding the atherogenic role of caspase-1 in HIV infection. By crossing Tg26 mice (Tg26+/-), which contain a transgene encoding the HIV genome with Apolipoprotein E deficient mice (ApoE-/-) on a C57BL/6J background, we introduced Tg26 mice to hyperlipidemia conditions to induce atherosclerosis. We demonstrate that 1) Tg26/ApoE -/-  develop an accelerated atherogenesis with normal renal function, 2) HIV expression increases activation of caspase-1 in circulating monocytes and vasculature of Tg26/ApoE-/-, and 3) Tg26/ApoE-/- have significantly higher levels of IL-1β in the serum after 8 weeks on high fat diet compared to ApoE-/- mice. Importantly, in the serum of 102 HIV+ vs. 41 HIV- patients with coronary atherosclerosis determined by computed tomography coronary angiography, IL-18 levels are higher and significantly correlate with the presence of plaque. Together, these results not only shed light on the atherogenic role of caspase-1 activation in HIV infection but also indicate that Tg26/ApoE-/- mice provide a new mouse model for investigating HIV-associated atherogenesis.