tbuckley/cabot-search huggingface dataset:
Improved local relapse-free and overall survival with secondary surgery after a first R1 or R2 resection in soft tissue sarcoma (STS) of the limbs or trunk wall: An analysis 10,931 patients (pts) in NETSARC.
Authors: Francois Gouin, Eberhard Stoeckle, Sylvie Bonvalot, Charles Honoré, Gauthier Decanter, Philippe Anract, Emmanuelle Bompas, Gwenael Ferron, Francois Sirveaux, Richard Rochwerger, Sebastien Carrere, Antonio DiMarco, Mikael Ropars, Loic-Romée Le Nail, Oren Marco, Jerome Guiramand, Antoine Italiano, Axel Le Cesne, Nicolas Penel, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2019)

11056 Background: We previously reported that secondary resection (2Surg) improved local relapse free (LRFS) but not overall survival (OS) in a retrospective series of pts with localized STS after unplanned 1st excision. Here we investigated the impact of 2Surg specifically after a first R1 or R2 resection in the 10931 pts with STS of the limb or trunk wall included in the nationwide NETSARC database from 2010 to 2017. Methods: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDT), funded by the French NCI (INCa). Since 2010, presentation to an MDTB and second pathological review are mandatory for sarcoma pts. Statistics were performed with SPSS23.0. LRFS, metastasis-free survival (MFS), OS compared with the logrank test. Results: The series included 5598 (51.2%) males. Median age was 56.7. Tumor sites: 5295 (49.4%) lower limb, 3670 (33.6%) trunk wall. 1966 (18.0%) upper limb. As previously reported in the entire series, local RFS (LRFS) and RFS (p&lt;0.001), but not OS, were superior for pts presented to a NETSARC MDT (NMDT), or operated in a NETSARC center (N=4417, 41%). LRFS &amp; OS were best for pts presented to a NMDT AND operated in NETSARC centers; while the worst LRFS &amp; OS were observed in pts presented in a NMDT but not operated there (p&lt;0.001). Among the 2081 pts with a first R1 resection in whom 2Surg was documented, 1047 (50.3%) were reoperated. R1 reoperated pts had a superior LRFS, metastatic free survival (MFS) and OS (p&lt;0.001). LRFS (p&lt;0.001), MFS (p=0.05) and OS (p&lt;0.001) were superior after 2Surg only in pts operated 1st outside a Netsarc center. There were 823 pts with a first surgery with R2 resection in whom 2Surg was documented: 619 (75.2%) were reoperated. R2 reoperated patients had a superior LRFS and OS (p=0.01). MFS was not different. LRFS (p&lt;0.001) &amp; OS (p&lt;0.001) were superior after 2Surg only in pts operated 1st outside a Netsarc center. 2028 (%) pts had 2Surg. Pts for whom 2Surg was in a NetSARC center had a superior LRFS (p&lt;0.001) and OS (p=0.01) when operated first outside a NETSARC center. Conclusions: In this nationwide series of limb or trunk wall STS, 2Surg after a R1 or R2 primary excision improves LRFS &amp; OS when the pts were operated 1st outside a reference center. 2Surg in a NETSARC center was associated with a better LRFS and OS.
Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy
Authors: Hari Menon, Dawei Chen, Rishab Ramapriyan, Vivek Verma, Hampartsoum B. Barsoumian, Taylor R. Cushman, Ahmed I. Younes, Maria A. Cortez, Jeremy J. Erasmus, Patricia de Groot, Brett W. Carter, David S. Hong, Isabella C. Glitza, Renata Ferrarotto, Mehmet Altan, Adi Diab, Stephen G. Chun, John V. Heymach, Chad Tang, Quynh N. Nguyen, James W. Welsh
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor's response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this combination in a clinical setting. <h3>Methods</h3> A post-hoc analysis of 3 ongoing immunoradiation trials was performed. Twenty-six (of 155) patients received low-dose radiation (1–20 Gy total), either as scatter from high-dose radiation or from intentional treatment of a second isocenter with low-dose radiation, were evaluated for response. The low-dose lesions were compared to lesions that received no radiation (&lt; 1 Gy total). Response rates, both defined as complete and partial responses as defined by RECIST criteria were used to compare lesion types. <h3>Results</h3> The 26 patients had a total of 83 lesions for comparison (38 receiving low-dose, 45 receiving no-dose). The average dose given to low-dose lesions was 7.3 Gy (1.1–19.4 Gy), and the average time to response was 56 days. Twenty-two out of 38 (58%) low-dose lesions met the PR/CR criteria for RECIST compared with 8 out of 45 (18%) no-dose lesions (<i>P</i> = 0.0001). The median change for longest diameter size for low-dose lesions was − 38.5% compared to 8% in no-dose lesions (<i>P</i> &lt; 0.0001). Among the low-dose lesions that had at least one no-dose lesion within the same patient as a control (33 and 45 lesions respectively), 12 low-dose lesions (36%) responded without a corresponding response in their no-dose lesions; Conversely, two (4%) of the no-dose lesions responded without a corresponding response in their low-dose lesion (<i>P</i> = 0.0004). <h3>Conclusions</h3> Low-dose radiation may increase systemic response rates of metastatic disease treated with high-dose radiation and immunotherapy.
P14.08 Bevacizumab treatment for the lesion emerging after the radiotherapy for malignant glioma
Authors: K Miwa, T Ito, K Yokoyama, J Shinoda
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Because blocking vascular endothelial growth factor from reaching leaky capillaries is a logical strategy for the treatment, we reasoned that bevacizumab might be an eﬀective treatment on recurrent malignant glioma and radiation necrosis (RN). In this study, the authors examined to diﬀerentiate RN from recurrent malignant glioma, and evaluated the results of bevacizumab treatment in each diagnosis. MATERIAL AND METHODS Four patients of malignant glioma (2 glioblastomas and 2 anaplastic astrocytomas), which demonstrated symptomatic lesion after radiotherapy, were involved in this study. All four patients were treated with bevacizumab on a 10 mg/kg biweekly (one cycle), for a total dose of 30 mg/kg (3 cycles) or furthermore. RN was diﬀerentiated from local recurrence in all four patients on the basis of 11C-methionine positron emission tomography and/or clinical course. Clinical evaluation and MRI studies were obtained after bevacizumab treatment in all cases repeatedly as possible. RESULTS Two patients were diagnosed as RN, and another two patients as tumor recurrence. Of the two patients with RN, neurological dysfunction was distinctly alleviated after bevacizumab treatment. Other two patients with tumor recurrence demonstrated no remarkable improvement in neurological dysfunction after bevacizumab treatment. Of all the two patients with RN, post-treatment MRI performed after the bevacizumab therapy showed a significant reduction of the massive lesion. CONCLUSION We concluded that bevacizumab could control the symptomatic massive lesion occurring after radiotherapy, and it might be more eﬀective with the patients of RN, than with those of recurrent tumor.
P11.12 Periostin is expressed by pericytes and is crucial for angiogenesis in glioma
Authors: K Huizer, J M Kros, C Zhu, I Chirifi, B Krist, C Cheng, D Mustafa
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The expression of the matricellular protein periostin has recently been associated with glioma progression and angiogenesis. The aim of the present study was to identify the cellular source of periostin expression in human gliomas and to study the role of periostin in an in vitro model for angiogenesis. MATERIAL AND METHODS The expression of periostin in various types and grades of brain tumors was investigated at the genetics level by RT-PCR and at the protein level by immunohistochemistry. In addition, the expression of periostin in glioma samples was studied by double labeling and in situ RNA techniques. Subsequently, by silencing periostin in a 3D in vitro angiogenesis model, its effects on angiogenesis were studied. RESULTS Periostin RNA and protein expression was found to be elevated in pilocytic astrocytoma and glioblastoma, but not in grade II/III astrocytomas. The expression of periostin co-localized with PDGFRβ + cells, but not with Olig2+ / Sox2+ glioma stem cells. Silencing of periostin in pericytes resulted in the attenuation of the number and the length of the vessels, and in decrease in the number of vessel junctions formed. CONCLUSION The results prove that pericytes are the main source of periostin in human gliomas. We demonstrate that periostin plays an essential role in the growth and branching of blood vessels. Therefore, periostin and / or its molecular interactions should be explored as a novel target for developing a new anti-angiogenic therapy for glioma.
P11.38 The Galectin-1 inhibitor OTX-008 has antiproliferative effects on human glioblastoma cells independent of MGMT-promotor status
Authors: H Goett, M Kolodziej, J Pons-Kühnemann, F Schwarm, C Koch, E Uhl, M Stein
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The protein Galectin-1 (gal-1) is known to be involved in proliferation and progression of several malignancies. The allosteric gal-1 inhibitor OTX-008 has an antiproliferative effect on various tumors in vitro and in vivo. However, the effect of OTX-008 on patient derived GBM cultures is unknown. The aim of our study was to investigate the antiproliferative effects of OTX-008 on U87-MG and A172 cells, patient derived GBM cultures, and cultured human astrocytes (HCA). MATERIAL AND METHODS GBM specimens from 10 patients were intraoperatively retrieved out of the 5-ALA-positive areas and were cultured in DMEM. In these cell cultures, U87-MG and A172 cell lines, and in HCA the gal-1 expression was determined by quantitative RT-PCR. Gal-1 expression below the median was defined as low-gal-1 expression (LGE), above as high-gal-1 expression (HGE). OTX-008 was administered and cell viability was assessed after 72h with MTT assay. Dose-response curves and influence of gal-1 expression were calculated by probit analysis in a logit model with logarithmic transformation of x-axis. Comparison between MGMT promotor methylated and unmethylated cells was performed using the Mann-Whitney U test. RESULTS OTX-008 inhibited cell proliferation of all 10 patient derived GBM cell cultures with a mean ED50 of 34.28 (95% CI: 20.29- 61.57) μM and a mean ED95 of 100.90 (59.30- 199.33) μM. Antiproliferative effects of OTX-008 for U87-MG and A172 cells were found with an ED50 of 17.44 (95% CI: 13.24- 22.52) μM and 33.36 (95% CI: 24.30- 45.86) μM. In 5 cell cultures of the patient derived cells LGE and in the other 5 HGE was determined. Probit analysis showed an ED50 of 20.43 (95% CI: 16.03- 24.89) μM for the LGE group and an ED50 of 33.98 (95% CI: 28.15- 40.89) μM for the HGE-group. Between MGMT-promotor methylated and unmethylated cells no statistically significant difference for the ED50 was observed (38.36 vs. 31.56; P=0.454). Probit analysis of OTX-008 administration in HCA showed no dose-response-relation. CONCLUSION OTX-008 has antiproliferative effects on human glioblastoma cells independent of MGMT-promotor methylation status. The sensitivity of GBM cells to OTX-008 depends on the gal-1 expression level. In HCA no effect on cell viability was observed. OTX-008 seems a promising novel substance in glioblastoma therapy.
OS9.8 Genomic landscape of medulloblastoma in adults
Authors: T Goschzik, A zur Mühlen, E Dörner, A Waha, C Friedrich, P Hau, T Pietsch
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Medulloblastoma (MB) is a rare disease in adults. Therefore, only few cohorts have been studied so far. METHODS Histological features were evaluated and annotation of the tumors to WNT-MB, SHH-MB, and non-WNT/non-SHH-MB was performed by immunohistochemistry. Systematic analysis of tumor samples for genome-wide copy alterations was done by molecular inversion probe array. WNT- and SHH-activated MB were screened by NGS panel and Sanger sequencing for known MB-related genes. RESULTS The cohort of tumors from 117 patients contained 14.5% WNT-MB, 63.2% SHH-MB, and 22.2% non-WNT/non-SHH MB. Classic histology was found in WNT-MB, non-WNT/non-SHH-MB and 22% of SHH-MB; 78% of SHH-MB showed desmoplastic/nodular histology. In WNT-MB, CTNNB1 mutations were found in 88.2% and monosomy 6 in 52.9% of cases. In SHH-MB, PTCH1 mutations were present in 40% of cases and chromosome 9q loss including the PTCH1 locus was the most frequent copy number event in SHH-MB (50%), while SMO and SUFU mutations were found only in 15.4% resp. 7.7%. Mutations in the TERT promoter region were found in 92.3% of SHH-MBs. Only 2 (3%) of the SHH-MB were TP53-mutated (1.7% of the whole cohort). In non-WNT/non-SHH-MB, isochromosome 17q was the most frequent chromosomal alteration (84.6%). A previously published whole chromosomal aberration (WCA) signature with ≥1 WCA was found in 69.2% of cases. For 85 cases, survival data were available. WNT-MB presented no relapses (5-year OS: 100%), while SHH-MB with wildtype TP53 and non-WNT/non-SHH-MB showed similar outcomes (5-year OS: 78.1% and 69.1%, respectively). Both SHH-MB patients with mutant TP53 died of disease. Patients with non-WNT/non-SHH-MB characterized by the cytogenetic WCA phenotype showed - as described in pediatric standard-risk MB - significant better overall survival compared to patients with tumors lacking any WCA (p=0.01). CONCLUSIONS Adult MB represent four defined biological/genomic entities. In contrast to previously published data adult patients with WNT-MBs showed excellent survival. However, the number of patients with WNT-MB was limited so that this result has to be interpreted with caution. While in our cohort SHH-MB-TP53wt were standard risk independent of their mutational or chromosomal status, non-WNT/non-SHH-MB patients could be divided into two risk-groups according to the presence or absence of WCA in the tumors as previously published for childhood standard-risk MB by our group.
Metagenomic discovery of a distinct inflammatory subtype of human angiosarcoma associated with human herpesvirus 7.
Authors: Jason Yongsheng Chan, Jing Quan Lim, Vinod Ravi, Peiyong Guan, Timothy Kwang Yong Tay, Sathiyamoorthy Selvarajan, Choon Kiat Ong, Dachuan Huang, Tan Jing, Cedric Chuan Young Ng, Ken Wing-Kin Sung, Mohamad Farid Rin Harunal Rashid, Richard Hong Hui Quek, Ngian Chye Tan, Melissa Ching Ching Teo, Steven Rozen, Patrick Tan, Andrew Futreal, Bin Tean Teh, Khee Chee Soo
Journal: Journal of Clinical Oncology (2019)

11047 Background: Angiosarcomas are rare, clinically-aggressive endothelial tumors with remarkable heterogeneity in terms of anatomical and etiological origins, amongst which UV-radiation and oncogenic viruses have been implicated. Methods: The genomic and transcriptomic landscapes of human angiosarcomas were examined using whole genome sequencing (n = 18) and RNAseq (n = 14). Results were validated in an extended cohort of FFPE tissue (n = 57) on various platforms. Results: We observed recurrent mutations in known angiosarcoma-associated genes including TP53, KDR, POT1 and PTPRB. The median tumor mutation burden (TMB) was 1.95 mutations per megabase and was highest in a subset of head and neck angiosarcomas (HN-AS, n = 6) harboring UV signatures. The remaining cases, including seven HN-AS, contained a significantly lower TMB (5.04 vs 0.91, p= 0.0007). In corroboration, UV exposures were validated by cyclobutane pyrimidine dimer immunohistochemistry in 15 of 35 (42.9%) HN-AS and cutaneous angiosarcomas, but not in visceral or breast angiosarcomas. Gene set enrichment analysis (GSEA) revealed upregulation of “cell cycle” and “inflammation” pathways in angiosarcomas. Notably, drug inhibition of overexpressed kinases including aurora kinase, polo-like kinase and checkpoint kinase-1 potently reduced viability in two angiosarcoma cell lines, achieving IC50s of &lt; 1µM. Metagenomic analysis detected viral reads mapping to the human herpesvirus-7 (HHV-7) genome, which were verified by PCR and immunohistochemistry. Genomic integration of HHV-7 was demonstrated at its flanking DRR telomeric repeat sequence adjoining the subtelomeric region of chromosome 17p. Overall, HHV-7 was detected in 38 of 57 (66.7%) angiosarcomas and inversely correlated with UV exposure ( p= 0.01). GSEA and Nanostring IO360 profiling showed that “inflammation” pathways were enriched in viral-positive angiosarcomas, while “cell cycle” pathways were enriched in viral-negative cases. Compared with HHV-7 negative cases, HHV-7 positive angiosarcomas were associated with high tumor inflammation scores (TIS ≥ median 6.74) (73.3% vs 25.0%, p = 0.02). Conclusions: We identified distinct subtypes of angiosarcoma characterized by HHV7-positive “inflammation” and UV-associated “cell cycle” phenotypes.
Abstract 17070: Bmpr1a and Its Role in Endomt in Pulmonary Arterial Hypertension
Authors: Heon-Woo Lee, Takaomi Adachi, Saejeong Park, Piotr Kowalski, Daniel Anderson, Michael Simons, Suk won Jin, Hyung J Chun
Journal: Circulation (2018)

There is emerging evidence that the aberrant pulmonary vascular remodeling that occurs in pulmonary arterial hypertension (PAH) is at least in part driven by the transformation of endothelial cells to mesenchymal cells (EndoMT), but the mechanism driving this pathobiology remains to be fully elucidated. Bone morphogenetic protein (BMP) signaling has been implicated to be involved in EndoMT in different vascular contexts, but the exact mechanism in the pulmonary vasculature remains to be defined. We describe the role of BMP receptor type 1A (BMPR1A or ALK3) as a key factor for maintenance of endothelial fate and suppression of EndoMT in the pulmonary vasculature. We found that inducible endothelial specific deletion of Bmpr1a in mice ( Bmpr1a iECKO ) resulted in spontaneous EndoMT, with significant increase in smooth muscle actin (SMA) positive cells, associated with extensive pulmonary vascular remodeling and fibrosis. Bmpr1a iECKO mice developed spontaneous pulmonary hypertension (PH) that was mediated by augmented TGF-β signaling driven by increased TGFBR2 expression, resulting in aberrant SMAD2/3 activation. Increased TGFBR2 expression in BMPR1A deficient state was secondary to increased activity of the transcription factor TCF3, whose negative inhibition by ID2 is abrogated in BMPR1A deficient state. EndoMT and PH secondary to loss of endothelial BMPR1A was effectively rescued by concurrent knockdown of TGFBR2. Overall, these studies define a mechanism of EndoMT driven by loss of endothelial BMPR1A, and demonstrate the efficacy of inhibiting EndoMT as a potential novel therapeutic strategy in PAH and other EndoMT-related vascular disorders.
The Landscape of Early Clinical Gene Therapies outside of Oncology
Authors: Laure Rittié, Takis Athanasopoulos, Miguel Calero-Garcia, Marie L. Davies, David J. Dow, Steven J. Howe, Alastair Morrison, Ida Ricciardelli, Aurore Saudemont, Laurent Jespers, Timothy M. Clay
Journal: Molecular Therapy (2019)

The field of cell and gene therapy (GT) is expanding rapidly and there is undoubtedly a wave of enthusiasm and anticipation for what these treatments could achieve next. Here we assessed the worldwide landscape of GT assets currently in early clinical development (clinical trial phase 1/2 or about to enter clinical trial). We included all gene therapies, i.e., strategies that modify an individual's protein make-up by introducing exogenous nucleic acid or nucleic acid modifiers, regardless of delivery. Unmodified cell therapies, oncology therapies (reviewed elsewhere), and vaccine programs (distinct therapeutic strategy) were not included. Using a December 31, 2018 cutoff date, we identified 336 gene therapies being developed for 138 different indications covering 165 genetic targets. In all, we found that the early clinical GT landscape comprises a very disparate group of drug candidates in terms of indications, organizations, and delivery methods. We also highlight interesting trends, revealing the evolution of the field toward in vivo therapies and adeno-associated virus vector-based delivery systems. It will be interesting to witness what proportion of this current list effectively translates into new medicines.
Assessment and Comparison of Hepatitis C Viremia in the Prison Systems of New Mexico and Georgia
Authors: Anne C. Spaulding, Junyu Chen, Carolyn A. Mackey, Madeline G. Adee, Chava J. Bowden, W. David Selvage, Karla A. Thornton
Journal: JAMA Network Open (2019)

This cross-sectional study assesses and compares the prevalence of hepatitis C virus among criminal justice populations in New Mexico, a state with high hepatitis C virus prevalence, and Georgia, a state with low hepatitis C virus prevalence.
“Lost and Found”: snoRNA Annotation in the Xenopus Genome and Implications for Evolutionary Studies
Authors: Svetlana Deryusheva, Gaëlle J S Talhouarne, Joseph G Gall
Journal: Molecular Biology and Evolution (2019)

Small nucleolar RNAs (snoRNAs) function primarily as guide RNAs for posttranscriptional modification of rRNAs and spliceosomal snRNAs, both of which are functionally important and evolutionarily conserved molecules. It is commonly believed that snoRNAs and the modifications they mediate are highly conserved across species. However, most relevant data on snoRNA annotation and RNA modification are limited to studies on human and yeast. Here, we used RNA-sequencing data from the giant oocyte nucleus of the frog Xenopus tropicalis to annotate a nearly complete set of snoRNAs. We compared the frog data with snoRNA sets from human and other vertebrate genomes, including mammals, birds, reptiles, and fish. We identified many Xenopus-specific (or nonhuman) snoRNAs and Xenopus-specific domains in snoRNAs from conserved RNA families. We predicted that some of these nonhuman snoRNAs and domains mediate modifications at unexpected positions in rRNAs and snRNAs. These modifications were mapped as predicted when RNA modification assays were applied to RNA from nine vertebrate species: frogs X. tropicalis and X. laevis, newt Notophthalmus viridescens, axolotl Ambystoma mexicanum, whiptail lizard Aspidoscelis neomexicana, zebrafish Danio rerio, chicken, mouse, and human. This analysis revealed that only a subset of RNA modifications is evolutionarily conserved and that modification patterns may vary even between closely related species. We speculate that each functional domain in snoRNAs (half of an snoRNA) may evolve independently and shuffle between different snoRNAs.