tbuckley/cabot-search huggingface dataset:
P12.04 Synergistic effects of combination therapy of CAR-NK cells and anti-PD-1 antibody result in high efficacy against advanced stage orthotopic glioblastoma grafts in a syngeneic mouse model and induce protective anti-tumor immunity in vivo
Authors: F Strassheimer, M I Strecker, C Zhang, I C Mildenberger, P N Harter, T Tonn, J P Steinbach, W S Wels, M C Burger
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Checkpoint inhibitors as well as adoptive cell therapy hold great promise for cancer treatment and encouraging treatment responses have already been demonstrated in different cancer indications. Glioblastoma (GB) is the most common and aggressive primary brain tumor. Standard therapy has very limited efficacy in the majority of patients. Analysis of the GB tumor microenvironment (TME) has shown prominent immunosuppressive features including expression of PD-L1 on tumor cells and increased frequency of FOX-P3 positive regulatory T cells. While the surrounding brain is HER2-negative, GB tumors are frequently HER2-positive, suggesting HER2 as a promising target for adoptive immunotherapy. MATERIALS AND METHODS The murine glioma cell line GL261 was transfected with HER2. Tumor cells were orthotopically implanted into C57BL/6 mice and treated either with HER2-specific NK-92/5.28.z cells alone or in combination with an anti-PD-1 antibody. Effects on tumor growth and survival were determined, lymphocyte infiltration and immunosuppressive TME were characterized. RESULTS Combined treatment with NK-92/5.28.z cells and anti-PD-1 antibody resulted in synergistic tumor regression and long-term survival of advanced-stage tumor bearing mice. Analysis of TME showed enhanced cytotoxic lymphocyte infiltration and altered profiles of exhaustion markers in tumor and immune cells. CONCLUSION These data demonstrate that efficacy of NK-92/5.28.z cells can be enhanced by co-therapy with checkpoint inhibitors, resulting in successful treatment of advanced tumors refractory to mono-therapy. Furthermore, this combination therapy induces a cytotoxic rather than immunosuppressive TME, leading to a primed immune system. To address this question in a clinical setting, we are planning a phase I clinical study (CAR2BRAIN-CHECK).
Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years
Authors: Bernard Iung, Xavier Armoiry, Alec Vahanian, Florent Boutitie, Nathan Mewton, Jean‐Noël Trochu, Thierry Lefèvre, David Messika‐Zeitoun, Patrice Guerin, Bertrand Cormier, Eric Brochet, Hélène Thibault, Dominique Himbert, Sophie Thivolet, Guillaume Leurent, Guillaume Bonnet, Erwan Donal, Nicolas Piriou, Christophe Piot, Gilbert Habib, Frédéric Rouleau, Didier Carrié, Mohammed Nejjari, Patrick Ohlmann, Christophe Saint Etienne, Lionel Leroux, Martine Gilard, Géraldine Samson, Gilles Rioufol, Delphine Maucort‐Boulch, Jean François Obadia
Journal: European Journal of Heart Failure (2019)
The ERS fellowship portfolio: fostering excellence and diversity
Authors: Rory E. Morty, Louise E. Donnelly, Daiana Stolz, Nicolas Roche, Tobias Welte, Kathryn A. Forrest, Christopher E. Brightling, Guy G. Brusselle
Journal: European Respiratory Journal (2019)

<b>The ERS fellowship portfolio continues to be refined, to respond to the changing needs of our Society. Under the 2016–2019 Fellowship strategy, a wide range of programmes is available, reflecting the diversity and global dimension of the ERS membership.</b>http://bit.ly/2YEpOnv
No-deal Brexit: U-turn on immigration provides no stability for NHS, says BMA
Authors: Jacqui Wise
Journal: BMJ (2019)

The government has been forced into a U-turn on plans to immediately end freedom of movement in a no-deal Brexit, instead returning to the previous policy of giving new EU migrants three years’ temporary leave to remain.

Chaand Nagpaul, the BMA’s council chair, said that “common sense has prevailed to a degree” but added that the new proposals would still be highly disruptive for the healthcare workforce and for the health service itself, as three years would provide no sense of stability.

He said, “Our …
Clinical availability of chemotherapy response assay using adenosine triphosphate in breast cancer patients
Authors: J. Jeong, S. Lee, S. Yoon, W. Jung, H. Lee, I. Lee
Journal: Journal of Clinical Oncology (2006)

10592 Background: The response to chemotherapeutic agents of breast cancer is heterogeneous from patient to patient. Several methods were developed to decide chemotherapeutic agents which were sensitive to individual patients but so far, there are no ways which is commonly used in the clinic to tailor the treatment. In this study, we performed the chemotherapy response assay using adenosine triphosphate (ATP-CRA) in breast cancer patients and assessed the clinical availability. Methods: From March 2004 to February 2005, 65 breast cancer patients were enrolled in this study. After elimination of normal contaminated cells, cancer cells were evenly divided and treated with commonly used chemotherapeutic drugs in breast cancer(doxorubicin, epirubicin, 5-FU, paclitaxel, docetaxel, vinorelbine, and gemcitabine). 7 Drug-treated cancer cells and untreated cancer cells were cultured for 48 hours and then ATP was measured. To verify in vitro ATP-CRA indirectly, we analyzed the correlation between cell death rate of doxorubicin and epirubicin, and between doxorubicin and paclitaxel. We also analyzed the mean death rate of doxorubicin, epirubicin and paclitaxel by HER-2 status. Results: The ATP-CRA was performed sucessfully in 62 patients. (95.4%) In all cases, we can get the results within 7 days. The range of cell death rate was very wide, from 0 to more than 50%, except gemcitabine. Epirubicin showed the highest mean cell death rate (35.7%) and doxorubicin, paclitaxel in order. According to the chemosensitivity index, paclitaxel is the most frequently first-ranked and doxorubicin, epirubicin in order. Correlation coefficient between the cell death rate of doxorubicin and epirubicin is 0.58 and 0.2 between paclitaxel and epirubicin. In HER-2 positive group, mean cell death rate of epirubicin and paclitaxel was significantly higher than in HER-2 negative group (p = 0.017, p = 0.036) and same trend was seen in doxorubicin but not statistically significant (p = 0.060). Conclusions: ATP-CRA showed heterogeneous results in individual patients. ATP-CRA was successful and can be performed within short time period. With indirect comparison, it showed similar results with in vivo studies but for clinical use, the prospective randomized controlled trial should be preceded. No significant financial relationships to disclose.
High temporal variability of clinical side effects with and without adjuvant chemotherapy in 4,684 early breast cancer patients in the CANTO trial.
Authors: Paul H. Cottu, Marie-Laure Tanguy, Enora Laas, Olivier Tredan, Sylvie Giacchetti, Sophie Guillermet, Jean-Marc Ferrero, Olivier Rigal, Carole Tarpin, Mario Campone, Christelle Levy, Patrick Soulie, Laurence Vanlemmens, Marion Fournié, Christelle Jouannaud, Sibille Everhard, Jerome Lemonnier, Patrick Arveux, Ines Maria Vaz Duarte Luis, Fabrice Andre
Journal: Journal of Clinical Oncology (2019)

11566 Background: CANTO (CANcer TOxicities - NCT01993498) is a French multicenter prospective longitudinal study dedicated to the quantification and characterization of side effects after treatment for patients with stage I-III breast cancer, and to the development of predictors of toxicities. Methods: The CANTO study has included &gt; 12,000 patients, assessed at diagnosis, and 3-6 months (T0), 15 months (T12), and year 3 and 5 after treatment completion. In the current report, we focus on key toxicities at T0 and T12 according to chemotherapy (CT) administration. For each side effect, 4 populations were defined according to its occurrence at T0 and/or T12 (no/no, no/yes, yes/no, yes/yes). Results: We analyzed 4684 patients with T0 and T12 consolidated data. Median age at diagnosis was 57y (22-89). Patients (pts) had HR+/HER2-, HER2+ or triple negative tumors in 78.9%, 12.4% and 8.7% of cases, respectively. Overall, 2516 pts (53.7%) received CT. Most CT pts (81%) received a sequential anthracyclines– taxanes schedule. As an example, a high proportion of patients presented neurological symptoms including cognitive symptoms, sensory or motor neuropathy, paresthesia, headache, etc (all grades) at either T0 or T12. Overall, CT was strongly associated with neurotoxicity at all times (OR = 2.27, p &lt; 0.0001). However, proportions of patients with neurological side effects changed between T0 and T12. The table shows the proportions of the 4 categories of pts in the CT and no CT groups. Furthermore, at T12, neurological symptoms remained more frequent in the CT group, whether pts had symptoms at T0 (CT vs no CT, 81% vs 77%, p = 0.007) or not (CT vs no CT, 41% vs 36%, p = 0.03). Similar temporal trends were observed (with specific percentages for each considered side effect) for detailed neurological toxicities, pain and joint/bone toxicity (stratified on endocrine therapy), gastro-intestinal, pulmonary and cardiac toxicities. Conclusions: Overall, symptoms burden is extremely high at T0 and T12 after treatment, and much higher in pts receiving CT. A high temporal variability was observed in all subsets, including a clinically meaningful delayed onset of e.g. neurological side effects. Clinical trial information: NCT01993498. [Table: see text]
P11.61 Development of a novel preclinical GBM model and therapeutic impact of IRE1 inhibition
Authors: P Le Reste, R Pineau, F Jouan, J Samal, G Jegou, J Patterson, E Vauleon, T Avril, A Pandit, E Chevet
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma Multiforme (GBM) is the most severe primary brain tumor and represents more than 15% of all brain tumors. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy, patient’s survival post diagnosis remains short with a median overall survival of 15 months. The lack of efficacy of the current treatments is mostly due to the tumor heterogeneity with different tumor cell types that exhibit various sensitivity to anti-cancer agents and to the diffuse feature of GBM that complicates the efficacy of complete resection. Another limitation for finding new valuable therapy approaches is the lack of relevant animal models that extensively recapitulate the current GBM patients’ standard of care. In the past couple of years, it has been demonstrated that the Unfolded Protein Response (UPR) plays an instrumental role in GBM development. It has been shown that IRE1, the most conserved UPR sensor, signals in tumor cells to reshape the tumor microenvironment to favor tumor growth and most likely to alter the response to treatment. The IRE1/XBP1s signaling axis exhibits pro-oncogenic properties and has a direct impact on patients’ survival. These observations point toward the IRE1/XBP1s axis as a potentially relevant therapeutic target. To further test the potential impact of the pharmacological targeting IRE1/XBP1 signaling, we proposed to use MKC8866, an inhibitors of IRE1, in preclinical models of GBM. As such we developed a novel GBM animal model that recapitulates the different steps engaged in GBM patient clinical handling (including surgical resection, irradiation and chemotherapy), and use this to demonstrate the relevance of IRE1 inhibition in GBM. Considering that IRE1 inhibitors do not cross the blood-brain barrier, we proposed an intraoperative delivery of the drugs though fibrin glue plugs applicated within the resection cavity, and then studied the impact on survival and tumor microenvironment. We showed that local delivery of IRE1 inhibitors combined with radio/chemotherapy had a positive effect on survival and induced tumoral and microenvironment remodeling, pointing at its high therapeutic potential and the need for an early clinical trial.
P14.38 Clinical experience with tumor treating fields (TTFields) treatment for posterior fossa tumors
Authors: A Taliansky, T Vagner, E Jan, L Zach
Journal: Neuro-Oncology (2019)

Abstract Introduction: TTFields brought a new concept in the treatment of brain tumors. It was tested and recommended for use in supra-tentorial lesions. There is a paucity of data available about TTFields safety and efficacy for infra-tentorial lesion. Method: Patients with posterior fossa tumors were treated with the Optune® system. Initial transducer array positioning and all technical characteristic were performed with technical support from Novocure. Results: Two patients with posterior fossa glial tumors were treated. The first is a 27 years old male with DIPG (without pathological confirmation of the tumor grade) who was treated with Stupp protocol. Treatment with TTFields commenced with TMZ adjuvant phase. The second patient is a 33 years old female with cerebello-pontine astrocytoma WHO grade III, IDH I mutated. This patient was treated with partial resection and Stupp protocol. TTFields treatment was started after completing 12 TMZ adjuvant cycles with measurable stable disease. Duration and compliance of TTFields treatment for first patient is 286 days and 86% and for second patient is 168 days and 93.6%. The skin toxicity is minimal and did not require treatment interruption. There is no other TTFields related toxicity. The MRI evaluation had showed improvement in the first patient and stable disease in the second. Conclusion: According to our knowledge, this is the first report of clinical experience with TTFields treatment for posterior fossa tumors. In our experience, the treatment is feasible and with equal toxicity to previously reported supra-tentorial lesions. Small patient population and short follow up do not allow efficacy evaluation.
Qualitative and Quantitative Contrast-enhanced Endoscopic Ultrasound Improves Evaluation of Focal Pancreatic Lesions
Authors: James Buxbaum, Chris Ko, Nino Varghese, Alice Lee, Ara Sahakian, Kevin King, Jessica Serna, Helen Lee, Hisham Tchelepi, Jacques Van Dam, Vinay Duddalwar
Journal: Clinical Gastroenterology and Hepatology (2019)
Olaratumab plus anthracyline in advanced/metastatic soft tissue sarcoma: Data of real-world utilization in Austria.
Authors: Florian Kocher, Andreas Seeber, Lukas Weiss, Franz Romeder, Joanna Szkandera, Thomas Kuhr, Susanne Kostner, Petra Pichler, Thomas Jäger, Richard Greil, Thomas Brodowicz
Journal: Journal of Clinical Oncology (2019)

e22550 Background: Olaratumab is a humanized monoclonal anti platelet-derived growth factor receptor α antibody that has been approved in combination with doxorubicin for the treatment of patients with metastatic soft tissue sarcoma (STS). The purpose of this retrospective study was to assess the clinical efficacy in STS patients treated with olaratumab in a real-world setting in Austria. Methods: Retrospectively collected, longitudinal data from patients treated between November 2016 and September 2018 at 9 Austrian centers were obtained from respective medical charts. Eligible patients were all patients who received at least one dose of olaratumab. Parameters of most interest collected were response rates, progression-free survival (PFS) and overall survival (OS). Results: Altogether 55 patients were included into analysis. Median age was 58 years. In total, 65.5% (n = 36), 21.8% (n = 12) and 12.7% (n = 7) received olaratumab as first-, second- or ≥ third-line treatment, respectively. Olaratumab was administered either in combination with doxorubicin (81.8%, n = 45) or liposomal doxorubicin (16.4%, n = 9); 1 patient received olaratumab as upfront monotherapy. Median PFS and OS were 2.6 and 11.4 months. The objective response rate was 11.4 % and the disease control rate was 40.9 %. Conclusions: In this real-world analysis outcome was less pronounced compared to the results of the Phase Ib/II approval trial ( Tap WD et al. Lancet 2016). Thus, the results of the ongoing phase III trial (NCT02451943) are urgently needed to confirm the efficacy of the combination of olaratumab and doxorubicin in STS patients.
P12.02 Glioblastoma Multiforme immunological blockades and the implications of glioma cancer stem cells
Authors: L D Robilliard, C MacDonald, C E Angel, G J Finlay, W Joseph, E S Graham
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma Multiforme (GBM) is classified as a WHO grade IV astrocytoma that continues to circumvent classical and novel chemo-, radio- and immuno-therapies. The recent FDA approvals for the use of targeted immunotherapies against inhibitory checkpoint ligands (for melanoma; ipilimumab and nivolumab) have brought the use of monoclonal antibody therapies to the forefront of GBM research. However, poor immunological responses, exemplified by down-regulation of anti-tumour T-cell activity, and up-regulation of immunosuppressive cells and secreted factors within the tumour micro-environment, have limited the effectiveness of immunotherapy in GBM to date. Therefore, understanding how GBM modulates an extensive repertoire of immune checkpoint ligands and the functional consequence on immune evasion is necessary to develop more targeted immuno-therapeutics. MATERIAL AND METHODS Patient derived glioblastoma cell lines were cultured using established serum-based or glioma cancer stem cell (gCSC) conditions. The phenotypes of resultant GBM cells and gCSC’s were characterised using flow cytometry and immunocytochemistry, to assess expression of neural lineage and stem cell-associated markers. Thereafter, cells were screened for the expression of an extensive range of inhibitory checkpoint ligands by flow cytometry. Finally, the secretion of immune modulating factors by GBM cells and gCSC’s were evaluated by using XL cytokine proteome arrays. Cytokines that appeared to be differentially expressed were subsequently measured using Cytometric Bead Arrays. RESULTS Adherent gCSC’s and gCSC derived glioma-spheres express nestin, CD44, A2B5 and vimentin, consistent with a stem cell phenotype. Furthermore, the gCSC’s exhibited reduced expression of the neural lineage markers NeuN and OSP. Flow cytometry analyses revealed that glioblastoma cells expressed all 11 checkpoint ligands investigated. Interestingly, gCSC’s showed higher levels of PD-L1, B7-H3, CD155 and HVEM expression than GBM cells. CONCLUSION Glioblastoma Multiforme is highly immuno-suppressive, which is reinforced by this study. Glioblastoma cells express all the inhibitory checkpoint ligands investigated and glioma cancer stem cell cultures up-regulate expression levels further. This implies that GBM cells are heavily equipped to inhibit infiltrating T-cells, exemplifying the need to find suitable therapeutics that target multiple immuno-suppressive mechanisms simultaneously.
P11.59 Integrin a5 heterogeneous expression in glioblastoma is related to glioma stem cell subpopulations
Authors: M Dontenwill, M Mercier, G Gillmann, D Reita, I Lelong-Rebel, F Noulet, A Idbaih, C Herold-Mende, D Bagnard, C Spenlé, S Martin
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive primary brain tumor. Treatment failure and recurrence are explained in part by tumoral heterogeneity. Our previous results showed that the integrin α5β1 is implicated in GBM aggressiveness and represents a relevant therapeutic target. Recently, we observed intra- and inter-tumor heterogeneity of integrin α5β1 expression. Heterogeneity may be linked to different glioma stem cell populations. MATERIAL AND METHODS Ten glioma stem cell lines were grown as neurospheres in stem cell medium and their differentiation was induced by serum and/or ATRA. Two cell lines (NCH421k and NCH644) were selected and were modified by depletion (CrisprCas9) or transfection of the α5 integrin gene. Polyclonal lines and individual clones were analyzed phenotypically in vitro, before and after differentiation, and in vivo in orthotopic xenografts of 2x104 cells in nude mice. TCGA datasets were used to validate the heterogeneous expression of α5 integrin in GBM. RESULTS TCGA data validate that α5 integrin mRNA was only over-expressed in the mesenchymal subclass of GBM. Our results show that α5 integrin protein is not expressed in stem cell culture conditions. However, α5 integrin expression is induced after differentiation in only half of the cell lines supporting the notion of tumoral heterogeneity of glioma stem cells. Interestingly, single cell-derived clone evaluation showed that intra-tumoral stem cell heterogeneity also exists at the level of α5 protein expression. When glioma stem cells are programmed or transduced to express α5 integrin, differentiated cells became more aggressive. Notably, they acquired a fibronectin-dependent motility and a proliferative phenotype. Interestingly, integrin α5 remained expressed in secondary stem cells obtained after dedifferentiation. The in vivo assays suggested that glioma stem cells, programmed to express the integrin, were prone to form larger tumors. CONCLUSION Our data support the hypothesis that some glioma stem cells are programmed to express the α5 integrin subunit in their differentiated progeny to form a more aggressive tumor. They add new evidences that both cell populations may be considered for new therapeutic strategies against GBM.
P14.01 Differential diagnosis of IDH mutant/IDH wildtype of glioma by using 11C-methionine, 11C-choline, and18F-fluorodeoxyglucose positron emission tomography
Authors: H Takei, J Shinoda, S Ikuta, T Maruyama, Y Muragaki, T Kawasaki, Y Ikegame, M Okada, T Ito, Y Asano, K Yokoyama, N Nakayama, H Yano, T Iwama
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Positron emission tomography (PET) is important in noninvasive diagnostic imaging of gliomas. There are many PET studies on glioma diagnosis based on the 2007 World Health Organization (WHO) classification; however, there are no studies on glioma diagnosis using the new classification (the 2016 WHO classification).Here we investigated the relationship between PET imaging using 11C-methionine (MET), 11C-choline (CHO), and 18F-fluorodeoxyglucose (FDG) and wildtype isocitrate dehydrogenase (IDH) (IDH-wt)/mutant IDH (IDH-mut) in astrocytic and oligodendroglial tumors according to the 2016 WHO classification. MATERIAL AND METHODS In total, 105 patients with newly diagnosed cerebral gliomas (six diffuse astrocytomas [DAs] with IDH-wt, six DAs with IDH-mut, seven anaplastic astrocytomas [AAs] with IDH-wt, 24 AAs with IDH-mut, 26 glioblastomas [GBMs] with IDH-wt, five GBMs with IDH-mut, 19 oligodendrogliomas [ODs], and 12 anaplastic oligodendrogliomas [AOs]) were included. All OD and AO patients had both IDH-mut and 1p/19q codeletion. The maximum standardized uptake values (SUVs) of the tumor/normal cortex mean SUV ratios (T/N ratios) for MET, CHO, and FDG were calculated; the mean T/N ratios of DA, AA, and GBM with IDH-wt/IDH-mut were compared. The diagnostic accuracy for distinguishing gliomas with IDH-wt from those with IDH-mut was assessed using receiver operating characteristic (ROC) curve analysis of the mean T/N ratios for the three PET tracers. RESULTS There were significant differences in the mean T/N ratios for all three PET tracers between the IDH-wt and IDH-mut groups including all histological classifications (p&lt;0.001). Among the 27 gliomas with mean T/N ratios higher than the cutoff values for all three PET tracers, 23 (85.2%) were classified into the IDH-wt group using ROC analysis. In DA, there were no significant differences in the T/N ratios for MET, CHO, and FDG between the IDH-wt and IDH-mut groups. In AA, the mean T/N ratios of all three PET tracers in the IDH-wt group were significantly higher than those in the IDH-mut group (p&lt;0.001). In GBM, the mean T/N ratio in the IDH-wt group was significantly higher than that of the IDH-mut group for both MET (p=0.034) and CHO (p=0.01). However, there was no significant difference in the ratio for FDG. CONCLUSIONS PET imaging using MET, CHO, and FDG was confirmed to be informative for preoperatively differentiating gliomas according to the 2016 WHO classification, particularly for differentiating IDH-wt and IDH-mut tumors.