tbuckley/cabot-search huggingface dataset:
OS5.1 Phase I clinical trial with oncolytic virus DNX-2401 for DIPGs
Authors: M M Alonso, I Iñigo, M Gonzalez-Huarriz, P Dominguez, A Patiño, C Jones, C Gomez-Manzano, J Fueyo, R Díez-Valle, S Tejada
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Despite our increased understanding of the genetic make-up and new therapies for pediatric high grade glioma (pHGG) and Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains grim. Delta-24-RGD (DNX-2401 in the clinic) has been tested for adult glioblastoma presenting a safe profile and promising efficacy. Recently our group has showed that the virus is safe and effective in preclinical models of pHGG and DIPG. Moreover, we showed that the virus is able to trigger an antitumor immune response. These outstanding preclinical results allowed us to propel a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy. MATERIALS AND METHODS A phase I clinical trial with DNX-2401 for patients with newly diagnosed DIPG to assess the MTD is taking place in our hospital (N=12). Tumor biopsy is performed through the cerebellar peduncle, followed by virus injection. The virus is injected using a cannula, MEMS cannula (Alcyone Lifesciences) that prevents the reflux. Virus will be injected starting with 1010 pv. The trial is uncontrolled, unicentric with a 3 + 3 design. The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in subjects with DIPG and to collect tumor samples of this type of tumor. Secondary endpoints are overall survival at 12 months (OS12), percentage of responses and induced immune response against tumor. The follow up includes close monitoring of neurological status, blood tests and brain MRI. If this trial shows evidence of safety and efficacy will propel a multicenter clinical trial. RESULTS All the clinical data from the trial available until September 2019 will be presented during the congress, to date 8 patients have been treated within the trial. Three patients were treated with the D1=1x1010vp and because the lack of toxicity we escalated to the D2= 5x1010vp. The procedure was well tolerated and safe. Patients were home 3–4 days after the injection. All the patients displayed a reduced tumor volume after combined treatment. We performed molecular studies in 6 out of the 8 patients. We are currently assessing the immune responses to the virus. CONCLUSIONS Information acquired within this clinical study would aid to understand the response of DIPGs to viral therapies and therefore to better tailor this strategy to improve the survival and the quality of life of pediatric brain tumors.
Reproducible Findings in Systematic Reviews and Meta-analyses in Oncology
Authors: Joseph M. Unger
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Modeling and identifying therapeutic targets in Hepatoblastoma.
Authors: Jordan L. Smith, Haiwei Mou, Xiao-Ou Zhang, Deniz Ozata, Wen Xue
Journal: Journal of Clinical Oncology (2019)

e21518 Background: Hepatoblastoma, an aggressive pediatric liver tumor, most often affects young children under five years of age. Surgical resection and chemotherapy have saved many children’s lives; yet, the overall five-year survival rate is 70%, and worse for children who present with unresectable tumors. Addressing the clinical need for HB-targeted therapies requires a better understanding of how HB tumors maintain their tumorigenic potential. Recent studies suggest that YAP1, the transcriptional co-regulator, and the Wnt/β-catenin pathway cooperate for HB tumor initiation. Further YAP1 is hyperactivated in nearly 80% of children’s HB tumors; however, will YAP1 inhibition result in therapeutic benefit for pediatric patients? Methods: To assess the role of YAP1 signaling in HB tumor maintenance, we generated a conditional mouse model of HB driven by doxycycline-inducible YAP1 S127A and constitutively active β-Catenin. Delivery of doxycycline induces YAP1 S127A expression and mice develop HB tumors within six weeks. After tumor formation, doxycycline is withdrawn, turning off YAP1 expression, and tumor progression is monitored using in vivo bioluminescent imaging. Results: Here we show in our conditional mouse model of HB that YAP1 is essential for tumor maintenance. In vivo YAP1 withdrawal leads to &gt; 90% tumor regression within 10 weeks. Transcriptional analyses reveal that YAP1 withdraw in regressing tumors potently induces hepatocyte differentiation and metabolism genes, including HNF4a and FoxA2 target genes. Conclusions: Establishment of a luminescent conditional model of HB provides a new platform to critically address and explore therapeutic vulnerabilities in HB. Specifically, our data suggest HB tumor maintenance requires YAP1. Finally, in vivo tumor regression following YAP1 withdraw serves as preclinical evidence for the therapeutic potential of YAP1 inhibitory therapies in children with HB.
Survival After Definitive Chemoradiotherapy With Concurrent Cisplatin or Carboplatin for Head and Neck Cancer
Authors: Michael Xiang, A. Dimitrios Colevas, F. Christopher Holsinger, Quynh-Thu X. Le, Beth M. Beadle
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: For definitive chemoradiotherapy (chemoRT) of head and neck squamous cell carcinoma (HNSCC), cisplatin is the preferred concurrent agent, with superiority over cetuximab for HPV-associated oropharyngeal squamous carcinoma recently shown in 2 randomized trials (RTOG 1016 and De-ESCALaTE). Patients who are not candidates for cisplatin may be treated with carboplatin instead, but its comparative efficacy is unclear. We analyzed nationwide patterns of care and cancer-specific outcomes after cisplatin- versus carboplatin-based chemoRT. Patients and Methods: Patients with locoregionally advanced (stages III–IVB according to the 6th and 7th editions of the AJCC Cancer Staging Manual) squamous cell carcinoma of the oropharynx, larynx, or hypopharynx who received definitive radiotherapy (RT) were identified in the linked SEER-Medicare database. The concurrent chemotherapy regimen was determined through corresponding Medicare claims. Death caused by HNSCC (cancer-specific mortality [CSM]) was analyzed with competing risks. Propensity score analysis and multivariable Fine-Gray regression were used to adjust for baseline differences, including age and comorbidity. Results: We identified 807 patients who received cisplatin-based chemoRT and 342 who received carboplatin-based chemoRT. Most carboplatin recipients (68%) had combination chemotherapy, predominantly with paclitaxel. Carboplatin- and cisplatin-based chemoRT had similar incidences of death attributable to HNSCC (3-year CSM, 29% vs 26%; P =.19), which persisted in propensity score–matched analysis. In addition, no significant difference in overall survival was seen in the matched cohorts. ChemoRT with either cisplatin or carboplatin was superior to RT alone and RT with concurrent cetuximab. In the multivariable model, the adjusted hazard ratio of CSM for carboplatin relative to cisplatin was 1.01 (95% CI, 0.79–1.28; P =.94). Conclusions: Definitive carboplatin-based chemoRT was equivalent to cisplatin-based therapy and superior to RT alone and RT with concurrent cetuximab. In light of recent results of the RTOG 1016 and De-ESCALaTE trials, our findings suggest that carboplatin-based regimens warrant prospective investigation as an alternative to cisplatin for patients who are not cisplatin candidates.
Recommendations from clinical practice guidelines on discussion of costs of care in adult patients with advanced cancer: A systematic review.
Authors: Anupriya Agarwal, Deme John Karikios, Martin R. Stockler, Philip James Beale, Rachael L. Morton
Journal: Journal of Clinical Oncology (2019)

e23175 Background: Optimising the care of cancer patients without imposing significant financial burden related to their anticancer treatment is becoming increasingly difficult. The 2009 American Society of Clinical Oncology’s (ASCO) Guidance Statement on the Cost of Cancer Care recommends that ‘patient-physician discussions regarding the cost of care are an important component of high-quality care’.(1) We sought information for oncologists to facilitate patient-clinician communication about the costs of care in published clinical practice guidelines (CPGs). Methods: We searched MEDLINE, EMBASE and multiple databases of CPG from January 2008 to 1 st June 2018 for recommendations about discussing the costs of care. We assessed quality with the AGREE II instrument for the assessment of guidelines. Results: We identified 471 publications, of which 25 guidelines met our eligibility criteria. Most guidelines were from ASCO (64%, 16/25) and the Scottish Intercollegiate Guidelines Network (SIGN, 24%, 6/25). Guidelines included recommendations on discussion or consideration of treatment costs when prescribing in 52% (13/25) with information about actual costs in only 20% (5/25). Recognition of the risk of financial burden or financial toxicity was described in 60% (15/25) of guidelines, however, only a minority of these, 28% (7/25) contained information regarding management of patients with financial concerns. Conclusions: Current CPGs have limited information to guide patient-clinician communication about the costs of anticancer treatment and management of financial burden. Future guidelines should contain more information about the optimal timing, frequency, and content of these discussions. Future guidelines should include more guidance about how oncologists should communicate the costs of care accurately and transparently, along with suggestions to reduce financial burden.
Abstract 15958: Early Repolarization and Testosterone Levels
Authors: Juhani Junttila, Jani T Tikkanen, Kimmo Porthan, Lasse Oikarinen, Antti Jula, Veikko Salomaa, Heikki V Huikuri
Journal: Circulation (2012)

Background. There is a significant age- and gender dependence in the prevalence of early repolarization (ER) in the inferior/lateral leads of a standard 12-lead ECG with male predominance and a hig...
P12.01 Local implantation of thermoresponsive interferon alpha-polypeptide conjugate combined with temozolomide for post-surgical glioblastoma chemoimmunotherapy
Authors: P Liang, W Zhuoran, G Weiping, W Guihuai
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma(GBM) is associated with gloomy prognosis despite maximal safe resection and following chemoradiation. In recent years, significant progress has been made in cancer immunotherapy except for GBM, which is largerly due to its local immunosuppressive microenvironment. Some research has demonstrated that local immunotherapy may be more efficient than systematic administrators. IFNα has been investigated as antitumor agent for some cancers, including glioma. Nevertheless, the short circulating half-life greatly limits its clinical application. Hence, a thermoresponsive IFNα-elastin-like polypeptide (IFNα-ELP) was genetically engineered for the earliest local intervention post-surgery. MATERIAL AND METHODS Firstly, IFNα-ELP(V) was constructed, expressed and purified, then, its physicochemical characterization was verified. The tumor was resected 10 days after U87MG-mCherry-luc cells orthotopic implantation, and IFNα-ELP(V) was injected into the resection cavity. Two days later, temozolomide(TMZ) was intraperitoneally injected. Using in vivo imaging technique, we could monitor the trends in tumor size. The survival time of mice was counted. Biosafety was evaluated by peripheral blood biochemistry analysis and pathology of the organs. RESULTS In this study, the bioconjugate not only in situ deposited in the resection cavity because of the thermoresponsive characteristic, but also showed zero-order release kinetics from the depot and dramatically improved pharmacokinetics and biodistribution of IFNα. Consequently, it showed the inhibition of tumor relapse in GBM orthotopic resection mice models. When followed by TMZ intraperitoneal injection, IFNα-ELP(V) could significantly prevent the tumor recurrence than itself or TMZ alone. Biosafety results indicated that the systemic toxicity of IFNα-ELP(V) in mice can be reduced to safe levels. CONCLUSION The results reveal that local implantation of thermoresponsive IFNα-ELP(V) combined with TMZ exhibits the synergy of post-surgical GBM chemoimmunotherapy.
Autocrine IFN-I inhibits isocitrate dehydrogenase in the TCA cycle of LPS-stimulated macrophages
Authors: David P. De Souza, Adrian Achuthan, Man K.S. Lee, Katrina J. Binger, Ming-Chin Lee, Sophia Davidson, Dedreia L. Tull, Malcolm J. McConville, Andrew D. Cook, Andrew J. Murphy, John A. Hamilton, Andrew J. Fleetwood
Journal: Journal of Clinical Investigation (2019)

Macrophage activation in response to LPS is coupled to profound metabolic changes, typified by accumulation of the TCA cycle intermediates citrate, itaconate, and succinate. We have identified that endogenous type I IFN controls the cellular citrate/α-ketoglutarate ratio and inhibits expression and activity of isocitrate dehydrogenase (IDH); and, via 13C-labeling studies, demonstrated that autocrine type I IFN controls carbon flow through IDH in LPS-activated macrophages. We also found that type I IFN–driven IL-10 contributes to inhibition of IDH activity and itaconate synthesis in LPS-stimulated macrophages. Our findings have identified the autocrine type I IFN pathway as being responsible for the inhibition of IDH in LPS-stimulated macrophages.
Is PKM2 Phosphorylation a Prerequisite for Oligomer Disassembly in Pulmonary Arterial Hypertension?
Authors: Tatyana Novoyatleva, Nabham Rai, Norbert Weissmann, Friedrich Grimminger, Hossein A. Ghofrani, Werner Seeger, Henning Gall, Ralph T. Schermuly
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Two stumbling blocks to a general account of selection: Replication and information
Authors: William M. Baum
Journal: Behavioral and Brain Sciences (2001)

When one takes the evolution of operant behavior as prototype, one sees that the term replication is too tied to the peculiarities of genetic evolution. A more general term is recurrence. The important problem raised by recurrence is not “information” but relationship: deciding when two occurrences belong to the same lineage. That is solved by looking at common environmental effects.
P14.105 High incidence of brain metastases in lung cancer patients at the time of primary diagnosis
Authors: E Kobyakova, E Nechipay, D Sashin, N Kobiakov, G L Kobyakov
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Brain metastases (BM) affect 8%-10% of all cancer patients and 40% of patients with metastatic cancer. The majority of BM originate from lung cancer (40%-50%), breast cancer (15%-25%), and melanoma (5%-20%). Total incidence proportions percentage (IP %) of brain metastases was reported as 9.6% for all primary sites combined, and was highest for lung cancer (19.9%). The incidence of BM is believed to be increasing, likely resulting from longer patient survival due to more effective systemic therapies for the primary cancer and the increased use of neuroimaging in neurologically asymptomatic patients. MATERIAL AND METHODS Our aim was to determine incidence of brain metastases in lung cancer patients at the time of primary diagnosis on cohort of our regular clinical practice. Since September 2014 till December 2017 189 primarily diagnosed patients with suspected lung cancer were evaluated with brain MRI as obligatory part of diagnostic protocol at N.N. Blokhin Russian Cancer Research Center. MR imaging protocol included T1, T2-weighted images, FLAIR, DWI, VIBE (with contrast enhancement, slice thickness &lt;1.2 mm). According to diagnostic guidelines for lung cancer in Russia, all patients underwent chest CT scan with contrast enhancement, bronchoscopy, abdominal ultrasonography, ultrasonography of cervical lymph nodes (+ CT to evaluate detected abnormalities), bone scintigraphy with X-ray control of detected abnormalities, surgical removal (in case of T1-T2 tumor) or tumor biopsy to determine morphology. Additionally, all patients underwent Whole Body MR DWI, some patients received FDG-PET/CT scan. RESULTS Brain metastases were detected in 89 (48%) of 189 patients, while only 9 patients (10.1% of patients with brain metastases) had neurological deficits. Lesion sizes were as follows: 0.1–0.5 cm in 46 (51.7%) patients, 0.5–1.0 cm in 21 (23.6%) patients, 1.0–2.0 cm in 7 (7.9%) patients, 2.0–3.0 cm in 8 (9.0%) patients and &gt;3.0 in 7 (7.9% patients). The majority of patients (45 - 50.56%) had solitary metastases, 10 patients (11.24%) had two lesions and 34 (38.20 %) patients had three and more lesions. Metastatic disease most commonly affected frontal lobes - 45 (50.56%) patients, temporal lobes - 36 (40.45%) patients, parietal lobes - 22 (24.72%) patients, occipital lobes - 22 (24.72%), basal ganglia and brainstem - 18 (20.22%), - 3 (3.37%), cerebellum - 30 (33.71%) patients. Concerning morphology, in 80 of 89 brain metastases NSCLC was identified and in 9 patients SCLC was observed. CONCLUSION Very high incidence of brain metastases in lung cancer patients at the time of primary diagnosis in our study cohort may be explained by the use of precision brain MRI as an obligatory part of diagnostic protocol at the time of primary admission. We suggest including precision brain MRI in guidelines for primary diagnosis of lung cancer patients as an obligatory examination
Endothelial microvesicles carrying Src-rich cargo impair adherens junction integrity and cytoskeleton homeostasis
Authors: Victor Chatterjee, Xiaoyuan Yang, Yonggang Ma, Byeong Cha, Jamie E Meegan, Mack Wu, Sarah Y Yuan
Journal: Cardiovascular Research (2019)

Abstract Aims Microvesicles (MVs) conduct intercellular communication and impact diverse biological processes by transferring bioactive cargos to other cells. We investigated whether and how endothelial production of MVs contribute to vascular dysfunction during inflammation. Methods and results We measured the levels and molecular properties of endothelial-derived MVs (EC-MVs) from mouse plasma following a septic injury elicited by cecal ligation and puncture, as well as those from supernatants of cultured endothelial cells stimulated by inflammatory agents including cytokines, thrombin, and complement 5a. The mouse studies showed that sepsis caused a significant increase in total plasma vesicles and VE-cadherin+ EC-MVs compared to sham control. In cultured ECs, different inflammatory agents caused diverse patterns of EC-MV production and cargo contents. When topically applied to endothelial cells, EC-MVs induced a cytoskeleton-junction response characterized by myosin light chain phosphorylation, contractile fibre reorganization, VE-cadherin phosphorylation, and adherens junction dissociation, functionally measured as increased albumin transendothelial flux and decreased barrier resistance. The endothelial response was coupled with protein tyrosine phosphorylation promoted by MV cargo containing c-Src kinase, whereas MVs produced from c-Src deficient cells did not exert barrier-disrupting effects. Additionally, EC-MVs contribute to endothelial inflammatory injury by promoting neutrophil-endothelium adhesion and release of neutrophil extracellular traps containing citrullinated histones and myeloperoxidase, a response unaltered by c-Src knockdown. Conclusion Endothelial-derived microparticles cause endothelial barrier dysfunction by impairing adherens junctions and activating neutrophils. The signalling mechanisms underlying the endothelial cytoskeleton-junction response to EC-MVs involve protein phosphorylation promoted by MV cargo carrying c-Src. However, EC-MV-induced neutrophil activation was not dependent on c-Src.
Salmonellosis outbreak with novel Salmonella enterica subspecies enterica serotype (11:z41:e,n,z15) attributable to sesame products in five European countries, 2016 to 2017
Authors: Anika Meinen, Sandra Simon, Sangeeta Banerji, Istvan Szabo, Burkhard Malorny, Maria Borowiak, Sead Hadziabdic, Natalie Becker, Petra Luber, Dorothee Lohr, Carolin Harms, Anita Plenge-Bönig, Kassiani Mellou, Georgia Mandilara, Joël Mossong, Catherine Ragimbeau, Pierre Weicherding, Patrick Hau, Daniela Dědičová, Lucie Šafaříková, Satheesh Nair, Timothy J Dallman, Lesley Larkin, Jacquelyn McCormick, Elizabeth De Pinna, Ettore Severi, Saara Kotila, Taina Niskanen, Valentina Rizzi, Domenico Deserio, Antje Flieger, Klaus Stark
Journal: Eurosurveillance (2019)

In spring 2016, Greece reported an outbreak caused by a previously undescribed Salmonella enterica subsp. enterica serotype (antigenic formula 11:z41:e,n,z15) via the Epidemic Intelligence Information System for Food- and Waterborne Diseases and Zoonoses (EPIS-FWD), with epidemiological evidence for sesame products as presumptive vehicle. Subsequently, Germany, Czech Republic, Luxembourg and the United Kingdom (UK) reported infections with this novel serotype via EPIS-FWD. Concerned countries in collaboration with the European Centre for Disease Prevention and Control (ECDC) and European Food Safety Authority (EFSA) adopted a common outbreak case definition. An outbreak case was defined as a laboratory-confirmed notification of the novel Salmonella serotype. Between March 2016 and April 2017, 47 outbreak cases were notified (Greece: n = 22; Germany: n = 13; Czech Republic: n = 5; Luxembourg: n = 4; UK: n = 3). Whole genome sequencing revealed the very close genetic relatedness of isolates from all affected countries. Interviews focusing on sesame product consumption, suspicious food item testing and trace-back analysis following Salmonella spp. detection in food products identified a company in Greece where sesame seeds from different countries were processed. Through European collaboration, it was possible to identify and recall sesame spread as one contaminated food item serving as vehicle of infection and trace it back to its origin.