tbuckley/cabot-search huggingface dataset:
P06.10 Dose-response relationship of ALECSAT immunotherapy in autologous patient-derived glioblastoma stem cell cultures
Authors: K. Werlenius, A. Wenger, M. Blomstrand, A. Jakola, B. Rydenhag, H. Carén
Journal: Neuro-Oncology (2017)

Introduction: Glioblastoma (GBM) is a highly malignant brain tumor with dismal prognosis in which few treatment modalities have been proven efficacious. ALECSAT (Autologous Lymphoid Effector Cells Specific Against Tumour Cells) is a novel type of immunotherapy based on adoptively transferred autologous lymphocytes expanded and activated in vitro. ALECSAT is produced and kindly provided by the Danish biotech company CytoVac A/S. In an ongoing clinical phase II randomized trial we are investigating the efficacy and safety of ALECSAT treatment in newly diagnosed GBM. In a parallel preclinical study we aim to further investigate the rationale for ALECSAT in GBM, with focus on better understanding the underlying mechanisms of action and potential of predicting response to treatment using matched patient-derived GBM cancer stem cells. MATERIAL AND METHODS: For patients randomized to ALECSAT-treatment in the clinical study we established patient-derived cell cultures from fresh tumor tissue, collected at the patients’ diagnostic neurosurgical tumor resection. The cells were cultured adherently in serum-free neural stem cell media, thus selecting for stem cells, which was verified by immunocytochemistry staining of the cells. The autologous GBM cancer stem cells were treated in vitro for 24 hours with ALECSAT produced for the specific patient with an ALECSAT to cancer stem cells ratio between 0.1:1 and 20:1 and a control, with triplicates for each condition. The effect on the autologous cancer stem cells was evaluated with a cell count after 24 hours of treatment (using DAPI staining). Results: So far we have established cell lines for four patients randomized to ALECSAT-treatment in the clinical study. The cells were proliferative as indicated by positive EdU staining and expressed the stem cell markers Nestin, SOX2 and Vimentin. ALECSAT had an effect on all autologous patient-derived cell lines with a very high cell death of the cancer stem cells at the highest doses already after 24 hours. We observed cases with >90% cell death. Further, for all patients there was a dose-response relationship with increased dose of ALECSAT corresponding to higher cell death of the GBM cancer stem cells. Conclusions: ALECSAT was highly effective in vitro killing most of the autologous GBM cancer stem cells within 24 hours at high doses. As cancer stem cells are considered more resistant to treatments this result is encouraging. We observed a strong dose-response relationship when patient-derived GBM cancer stem cells were co-cultured with autologous ALECSAT, thus suggesting that the amount of ALECSAT cells the patient receives, might be of importance for clinical efficacy. If these in vitro findings can be correlated to outcome for the individual patient in the ongoing clinical study, it might help select patients suitable for ALECSAT immunotherapy.
Breast cancer staging: Sentinel node biopsy using a fluorescence navigation versus standard technique.
Authors: Jakub Krzysztof Rzepka, Marcin Misiek, Artur Bocian, Kamil Zalewski, Jacek Haduch, Stanislaw Gozdz
Journal: Journal of Clinical Oncology (2014)

e12018 Background: Sentinel lymph node (SLN) biopsy with radioisotope has been used successfully for axillary staging in breast cancer. This study evaluated the feasibility of fluorescence detection of SLNs with indocyanine green (ICG) for lymphatic mapping and SLN biopsy. Study evaluated a fluorescence-guided technique for sentinel node biopsy (SLNB) against the standard (radioisotope). This technique requires two devices: A fluorescence tracer – ICG and the hand held near infrared camera. The standard technique for SLNB has drawbacks, including exposure to radiation, legislation on use of radiation and poor preoperative imaging. Therefore fluorescence guided with its advantages may by an alternative method for SLN visualization. Methods: Patients with T1 and T2 primary breast cancer treated between Sept. 2012 - Jan. 2013 without clinical and radiological lymph node involvement were included into this study. Standard SLN technique using blue dye and radioisotope was used. Additionally ICG as a fluorescence-emitting source was injected into the tumor area prior to the surgery. Sentinel node biopsy was undertaken using NIR camera initially and than with gammaprobe. The proportion of sentinel nodes detected (sentinel node identification rate) with either the standard or the fluorescence techniques was calculated. Results: Twenty-one SLNB procedures were undertaken in 20 patients. The proportion of successful identification rate with the ICG was 69%, whereas with standard technique 73%. One procedure was unsuccessful with standard technique and patient was found to have no metastases to SLN. Three patients who were unsuccessful with ICG had lymph node involvement. Of 32 lymph nodes removed 29 were true sentinel nodes identified by the radioisotope. Lymph node retrieval rate was 1.38 nodes per patient overall, 1.4 nodes per patient with the standard technique and 1.3 nodes per patient with the fluorescence-guided technique Conclusions: Moderate rate of SLN detection was achieved using both the ICG and radioisotope. The first SLN identified by fluorescence imaging provided an exact indication of the axillary status. Therefore, the ICG method provided sufficient information required to avoid unnecessary ALND.
Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction
Authors: Weier Qi, Hillary A Keenan, Qian Li, Atsushi Ishikado, Aimo Kannt, Thorsten Sadowski, Mark A Yorek, I-Hsien Wu, Samuel Lockhart, Lawrence J Coppey, Anja Pfenninger, Chong Wee Liew, Guifen Qiang, Alison M Burkart, Stephanie Hastings, David Pober, Christopher Cahill, Monika A Niewczas, William J Israelsen, Liane Tinsley, Isaac E Stillman, Peter S Amenta, Edward P Feener, Matthew G Vander Heiden, Robert C Stanton, George L King
Journal: Nature Medicine (2017)
The extracellular matrix in myocardial injury, repair, and remodeling
Authors: Nikolaos G. Frangogiannis
Journal: Journal of Clinical Investigation (2017)

The cardiac extracellular matrix (ECM) not only provides mechanical support, but also transduces essential molecular signals in health and disease. Following myocardial infarction, dynamic ECM changes drive inflammation and repair. Early generation of bioactive matrix fragments activates proinflammatory signaling. The formation of a highly plastic provisional matrix facilitates leukocyte infiltration and activates infarct myofibroblasts. Deposition of matricellular proteins modulates growth factor signaling and contributes to the spatial and temporal regulation of the reparative response. Mechanical stress due to pressure and volume overload and metabolic dysfunction also induce profound changes in ECM composition that contribute to the pathogenesis of heart failure. This manuscript reviews the role of the ECM in cardiac repair and remodeling and discusses matrix-based therapies that may attenuate remodeling while promoting repair and regeneration.
The lung is a host defense niche for immediate neutrophil-mediated vascular protection
Authors: Bryan G. Yipp, Jung Hwan Kim, Ronald Lima, Lori D. Zbytnuik, Bjӧrn Petri, Nick Swanlund, May Ho, Vivian G. Szeto, Tamar Tak, Leo Koenderman, Peter Pickkers, Anton T. J. Tool, Taco W. Kuijpers, Timo K. van den Berg, Mark R. Looney, Matthew F. Krummel, Paul Kubes
Journal: Science Immunology (2017)

Bloodstream infection is a hallmark of sepsis, a medically emergent condition requiring rapid treatment. However, upregulation of host defense proteins through toll-like receptors and NFκB requires hours after endotoxin detection. Using confocal pulmonary intravital microscopy, we identified that the lung provides a TLR4-Myd88-and abl tyrosine kinase-dependent niche for immediate CD11b-dependent neutrophil responses to endotoxin and Gram-negative bloodstream pathogens. In an in vivo model of bacteremia, neutrophils crawled to and rapidly phagocytosed Escherichia coli sequestered to the lung endothelium. Therefore, the lung capillaries provide a vascular defensive niche whereby endothelium and neutrophils cooperate for immediate detection and capture of disseminating pathogens.
Burden of non-tuberculous mycobacterial pulmonary disease in Germany
Authors: Roland Diel, Josephine Jacob, Niklas Lampenius, Michael Loebinger, Albert Nienhaus, Klaus F. Rabe, Felix C. Ringshausen
Journal: European Respiratory Journal (2017)

The objective of this study was to estimate the burden of disease in incident patients with non-tuberculous mycobacterial pulmonary disease (NTM-PD). A sample of 7 073 357 anonymised persons covered by German public statutory health insurances was used to identify patients with NTM-PD. In total, 125 patients with newly diagnosed NTM-PD in 2010 and 2011 were matched with 1250 control patients by age, sex and Charlson Comorbidity Index, and followed for 39 months. The incidence rate for NTM-PD was 2.6 per 100 000 insured persons (95% CI 2.2–3.1). The mortality rate for patients with NTM-PD and the control group in the observational period was 22.4% and 6%, respectively (p&lt;0.001). Mean direct expenditure per NTM-PD patient was €39 559.60 (95% CI 26 916.49–52 202.71), nearly 4-fold (3.95, 95% CI 3.73–4.19) that for a matched control (€10 006.71, 95% CI 8907.24–11 106.17). Hospitalisations were three times higher in the NTM-PD group and accounted for 63% of the total costs. Attributable annual direct costs and indirect work-loss costs in NTM-PD patients were €9093.20 and €1221.05 per control patient, respectively. Only 74% of NTM-PD patients received antibiotics and nearly 12% were prescribed macrolide monotherapy. Although NTM-PD is considered rare, the attributable mortality and financial burden in Germany are high. Efforts to heighten awareness of appropriate therapy are urgently needed.
P11.06 Metachronous adrenocortical carcinoma and gliosarcoma in patient with Li-Fraumeni Syndrome
Authors: M. Guidi, L. Giunti
Journal: Neuro-Oncology (2017)

Introdution: Li-Fraumeni Syndrome (LFS) is an cancer susceptibility condition, characterized by an autosomal dominant transmission that increases an individuals risk of developing early synchronous and metachronous primary tumors. Classic LFS is associated with the development of sarcomas, diagnosed before 45 years of age with a ﬁrst-degree relative with cancer before 45 years of age, and another close (ﬁrst- or second-degree relative) with any cancer diagnosed under 45 years of age or with sarcoma at any age. The typical tumors include breast carcinoma, osteosarcoma soft tissue sarcomas, adrenocortical carcinoma (ACC), leukemias, CNS tumors and lung cancer. Classic LFS has an approximate frequency of 70% compare to whole cancer-predisposition syndromes. The only gene that has been consistently associated with LFS is TP53. Materials and Methods: In 1998 a 16-month-old female was evaluated for early puberty. Abdominal ultrasound demonstrated a lesion located at adrenal gland. The patient was subjected to resection of an ACC followed by therapy with mitotane and corticosteroid. In December 2014, the patient was admitted to our Hospital for an episode of loss of consciousness with generalized epileptic episodes. Cranial TC scans showed a right parietal lesion which was subsequently confirmed by a brain MRI. The patient underwent gross total removal of the lesion, without complications and good neurological improvement. Results: The histopathological diagnosis was gliosarcoma (WHO-grade IV).Cerebrospinal fluid (CSF) cytology was negative. The patient underwent radiotherapy for a total dose of 59,4 Gy (1.8 Gy/fraction) given with Volumetric Modulated Arc Therapy (VMAT). The radiotherapy was associated with concomitant and sequential chemotherapy with temozolomide, vinorelbine and valproic acid. The patient remains alive without evidence of recurrent disease 30 months after starting chemotherapy. She maintains a Karnofsky Performance Score of greater than 90. At the beginning oncologic family history was negative. After 5 years from this diagnosis, her father died from a leiomyosarcoma at the age of 40. In 2013 her brother died at 19-year-old from an acute myeloid leukemia. Interestingly, the paternal grandmother died at 60-year-old due to melanoma after a previously having breast cancer. The family history supported such a LFS. TP53 gene analysis of our patient showed the germ-line mutation c.796G>A (p.Gly266Arg) in heterozygous. Conclusion: The description of this case highlights the importance of a correct clinical monitoring of patients with LFS for the high risk of cancer. A brain MRI every 6 months starting from 18 years of age is essential; indeed it was reported that 10% of LFS patients with develops a glioma before age 45 and 5% develops a PNET (primitive neuroectodermal tumors), a medulloblastoma, a choroid plexus carcinoma or an ependymoma.
OS10.2 R-2-Hydroxyglutarate shapes the immune microenvironment in IDH1-mutant gliomas
Authors: M. Friedrich, L. Bunse, T. Bunse, S. Pusch, F. Sahm, K. Sanghvi, M. Steadman, B. Niemeyer, W. Wick, M. Platten
Journal: Neuro-Oncology (2017)

Background: IDH1-mutant tumors form the majority of grade II and grade III gliomas, qualifying as a new entity in the 2016 WHO classification of CNS tumors. We have previously shown that a peptide vaccine encoding the IDH1(R132H) epitope evokes an MHC II-restricted CD4+ T Helper-1 cell (Th1) immune response and is therapeutic in an MHC-humanized A2.DR1 mouse tumor model. Ongoing efforts focus on further unleashing both the innate and adaptive immune system in targeting IDH1(R132H)-mutant gliomas. While the tumor-cell-intrinsic consequences of R-2-hydroxyglutarate (R-2-HG)-production, rendered by the IDH1-mutation, are well characterized, potential paracrine effects influencing antitumor immunity remain enigmatic. However, they are important to decipher, as immunotherapies targeting IDH1-mutant gliomas are emerging. Aim: This study aimed at characterizing a potential cell-specific modulatory role of the oncometabolite R-2-HG in shaping the immune microenvironment of IDH1-mutant gliomas. Methods and results: By means of expression dataset analyses, syngeneic murine tumor models and human glioma tissue, as well as a novel astrocyte-specific IDH1R132H-knock in model, we demonstrate that R-2-HG impairs endogenous and IDH1(R132H)-specific antitumor T cell immunity. This is underlined by functional and transcriptomic analyses of myeloid cells indicating a R-2-HG-driven induction of tolerogenicity and compromised antigen presentation. Metabolomic profiling was complemented by mitochondrial respiration assays, calcium measurements and pathway analyses in primary human and mouse immune cells to delineate key molecular mechanisms by which tumor-derived R-2-HG corrupts the glioma immunoenvironment. The functional relevance of R-2-HG-mediated impairment of antitumor immunity was demonstrated in vivo and potential pharmacological strategies abrogating its effects were assessed. Conclusion: Glioma-derived R-2-HG impairs antitumor immunity by affecting both infiltrating T-cells and the associated myeloid compartment, thus contributing to tumorigenesis and resistance to therapy. Immunotherapeutic strategies against IDH-mutant gliomas may benefit from approaches to prevent excess R-2-HG production or its uptake by immune cells.
P14.22 Whole-Brain Radiotherapy versus Stereotactic Radiosurgery after Resection for Intracranial Metastasis: a systematic review and meta-analysis
Authors: N. Lamba, I. S. Muskens, L. Meijer, V. Briceno, H. Edrees, B. Aslam, S. Minhas, T. R. Smith, R. A. Mekary, M. L. D. Broekman
Journal: Neuro-Oncology (2017)

Introduction: In patients with one to three brain metastases and minimal extracranial disease, treatment of choice has traditionally been surgical resection followed by whole-brain radiotherapy (WBRT) or, alternatively, stereotactic radiosurgery (SRS) of the resection cavity. In this review, we sought to compare the efficacy of each post-operative radiation modality with respect to tumor recurrence and patient survival. Methods: Pubmed, Embase and Cochrane databases were searched through June 2016 for studies reporting outcomes of SRS or WBRT after metastasis resection. Studies were included if survival, progression-free survival or disease recurrence was reported for adults with systemic cancer and a brain metastasis resected before either SRS or WBRT. Comprehensive Meta-Analysis (CMA) software was used to calculate pooled effect estimates using fixed-effects and random-effect models for local recurrence, distant recurrence, and patient survival time. Results: Out of 9,098 studies, only 9 restrospective cohort studies with 776 patients (474 with WBRT versus 302 with SRS) satisfied inclusion criteria and were included in the final analysis. For local recurrence, the overall crude risk ratio of five studies comparing WBRT to SRS was 0.79 (95%-CI: 0.48-1.29, I2: 49.4%, p-heterogeneity=0.34). For distant recurrence, the overall risk ratio of four studies was 1.16 (95%-CI: 0.87-1.53, I2: 30.2%, p-heterogeneity = 0.23) comparing WBRT to SRS. Median survival time for patients treated with adjuvant WBRT ranged from 6.81 to 22.9 months versus 7 to 24 months for patients treated with SRS. One study reported an increased incidence of leukoencephalopathy following adjuvant WBRT, but increased radiation necrosis after adjuvant SRS. Conclusion: SRS of the resection cavity of brain metastases offers comparable survival and similar local and distant control as adjuvant WBRT. Future research on SRS should focus on achieving a better understanding of the various factors that may favour SRS over WBRT.
Morphologic evaluation of circulating colon cancer tumor cells
Authors: Dena Marrinucci, Jennifer Fisher, Kelly Bethel, Nicole Lazarus, Daniel Lazar, Richard Bruce, Peter Kuhn
Journal: Cancer Research (2008)

4460  Circulating tumor cells (CTCs) are described in numerous epithelial malignancies. Usual detection methods rely on immunomagnetic enrichment-based fluorescence techniques, with resultant images that provide scant morphologic detail. In contrast, our technology enables the use of standard cytopathologic stains, revealing cellular features not previously described in circulating colon cancer cells. A cell attachment protocol using indirect immunofluorescence for epithelial-derived cells, used in conjunction with fiber-optic array scanning technology (FAST) and automated microscopy, allows us to identify cytokeratin positive CTCs in a variety of malignancies. The detected CTCs are subsequently stained with Wright-Giemsa which allows for detailed nuclear and cytoplasmic morphologic evaluation. We report on a 53 year old male with widely metastatic colon cancer who was found to have 6 CTCs in a 10 ml blood sample. Subsequent Wright-Giemsa staining of these cells demonstrates large nuclear size and high nuclear/cytoplasmic ratios (80-90%), features that correlate with the well-described immunofluorescent features of CTCs. In addition, with Wright-Giemsa staining, we demonstrate fine irregularities of nuclear contour and uneven chromatin condensation within the malignant nuclei. Finally, in comparison with a previous morphologic study of circulating breast cancer cells, we note a marked eccentricity of the cytokeratin-rich cytoplasm in the circulating colon cancer cells. This morphologic feature is likely related to the tissue origin of the tumor, as colon carcinoma cells are generally more columnar in shape than breast carcinoma cells. Identifying detailed morphologic differences and similarities among CTCs from different tumor types provides a foundation for further investigation of the significance of these rare events.
Serum IgG and risk of exacerbations and hospitalizations in chronic obstructive pulmonary disease
Authors: Fernando Sergio Leitao Filho, Seung Won Ra, Andre Mattman, Robert S. Schellenberg, Nick Fishbane, Gerard J. Criner, Prescott G. Woodruff, Stephen C. Lazarus, Richard Albert, John E. Connett, Meilan K. Han, Fernando J. Martinez, Janice M. Leung, S.F. Paul Man, Shawn D. Aaron, Robert M. Reed, Don D. Sin
Journal: Journal of Allergy and Clinical Immunology (2017)
P16.16 High-field intraoperative MRI: a major interest in low-grade glioma resection
Authors: H. Leroy, C. Delmaire
Journal: Neuro-Oncology (2017)

BACKGROUND: High-field Intraoperative MRI (IoMRI) is a useful tool to improve the extent of resection (EOR) of gliomas. For which kind of glioma is IoMRI the most beneficial? Objective: To compare the interest of a 1.5T IoMRI in glioma surgery for enhancing and non-enhancing tumors based on volumetric analyses. METHODS: In this prospective monocentric study, consecutive patients operated on for glioma using IoMRI, excluding pediatric patients, were reported. Tumors were distributed into 2 groups depending on their constrast enhancement: T2/FLAIR (for non or minimally enhancing tumors) and T1G+ (for enhanced tumors). Pre- intra- and postoperative volumes were assessed. We evaluated the residual tumor volume (RTV), the EOR, the workflow and the clinical outcomes (depicting Karnofsky performance score (KPS)). Results: 100 surgeries were performed from July 2014 to October 2016. 71 patients benefited from one IoMRI, and 29 from 2 IoMRI controls. For T2/FLAIR tumors, intraoperative RTV at 1st IoMRI was higher than T1G+ tumors (7.25 cm3 vs. 0.74 cm3; p=0.008), whereas the RTV at 2nd IoMRI and the final RTV were no more statistically different. After IoMRI, 72% of patients benefited from additional resections. For T2/FLAIR group, the EOR increased from 77,3% at 1st control to 97,4% at last MRI (p<0.001). All tumors confounded, the final RTV was: median=0 cm3, mean=3.9 cm3. The mean final EOR was 91%. No difference was found between the preoperative KPS and the 6 months postoperative KPS (p=0.15). CONCLUSION: IoMRI guided surgery significantly enhanced the EOR of gliomas, especially for non-or minimally enhancing tumors, without functional impairment.
Patients with MS show increased consultations several years before diagnosis
Authors: Susan Mayor
Journal: BMJ (2017)

Patients with multiple sclerosis (MS) experienced problems that prompted increased consultations with doctors in the five years before having the condition diagnosed, a large study has found. The authors said that the findings may help to identify and treat patients earlier.1

Pathophysiological changes involved in MS start long before clinical recognition of the disease, but limited information exists on what happens to patients during this period.

Researchers matched 14 428 patients who had MS with 72 059 controls and …