tbuckley/cabot-search huggingface dataset:
Primary Selective Laser Trabeculoplasty for Open-Angle Glaucoma and Ocular Hypertension
Authors: Anurag Garg, Victoria Vickerstaff, Neil Nathwani, David Garway-Heath, Evgenia Konstantakopoulou, Gareth Ambler, Catey Bunce, Richard Wormald, Keith Barton, Gus Gazzard, Gareth Ambler, Keith Barton, Rupert Bourne, David Broadway, Catey Bunce, Marta Buszewicz, Amanda Davis, Anurag Garg, David Garway-Heath, Gus Gazzard, Rachael Hunter, Hari Jayaram, Yuzhen Jiang, Evgenia Konstantakopoulou, Sheng Lim, Joanna Liput, Timothy Manners, Stephen Morris, Neil Nathwani, Gary Rubin, Nicholas Strouthidis, Victoria Vickerstaff, Sarah Wilson, Richard Wormald, Haogang Zhu
Journal: Ophthalmology (2019)

PurposeTo report clinical efficacy, predictors of success, and safety of primary selective laser trabeculoplasty (SLT) used in treatment-naive patients with open-angle glaucoma (OAG) or ocular hypertension (OHT).DesignPost hoc analysis of a multicenter, prospective, randomized, controlled trial.ParticipantsTreatment-naive patients with OAG or OHT.MethodsPatients randomized to SLT or topical medication and treated to predefined target intraocular pressures (IOPs) requiring ≥20% IOP reduction from baseline for all disease severity levels.Outcome MeasuresInitial (early) absolute IOP-lowering at 2 months. Achievement of drop-free disease-control: meeting target IOP without disease progression or need for additional topical medication over 36 months after SLT. Predictors of early absolute IOP-lowering and drop-free disease-control after single initial SLT. Frequency of laser-related complications.ResultsA total of 611 eyes (195 OHT and 416 OAG) of 355 patients received SLT, and 622 eyes (185 OHT and 437 OAG) of 362 patients received topical medication at baseline. Early absolute IOP-lowering after SLT was no different between OHT and OAG eyes (adjusted mean difference = −0.05 mmHg; 95% confidence interval [CI], −0.6 to 0.5 mmHg; P = 0.85). No difference was noted in early absolute IOP-lowering between topical medication and primary SLT (adjusted mean difference = −0.1 mmHg; 95% CI, −0.6 to 0.4 mmHg; P = 0.67). Early absolute IOP-lowering with primary SLT was positively associated with baseline IOP (coefficient 0.58; 95% CI, 0.53–0.63; P < 0.001) and negatively with female gender (coefficient −0.63; 95% CI, −1.23 to −0.02; P = 0.04). At 36 months, 536 eyes (87.7% of 611 eyes) of 314 patients (88.5% of 355 patients) were available for analysis. Some 74.6% of eyes (400 eyes) treated with primary SLT achieved drop-free disease-control at 36 months; 58.2% (312 eyes) after single SLT. Total SLT power and 2-month IOP were predictors of drop-free disease-control at 36 months after single SLT. Six eyes of 6 patients experienced immediate post-laser IOP spike (>5 mmHg from pretreatment IOP) with 1 eye requiring treatment.ConclusionsPrimary SLT achieved comparable early absolute IOP-lowering in OHT versus OAG eyes. Drop-free disease-control was achieved in approximately 75% eyes at 36 months after 1 or 2 SLTs, the majority of these after single SLT. These analyses are exploratory but support primary SLT to be effective and safe in treatment-naive OAG and OHT eyes.
DIPG-33. HARMONIZATION AND CHARACTERIZATION OF POSTMORTEM DONATIONS FOR PEDIATRIC BRAIN TUMORS
Authors: Madhuri Kambhampati, Eshini Panditharatna, Sridevi Yadavilli, Cheng-Ying Ho, Isabel Almira-Suarez, Miriam Bornhorst, Lindsay Kilburn, Eugene Hwang, Brian Rood, Maria-Magdalena Georgescu, Naomi Rance, Sabine Mueller, Roger Packer, Javad Nazarian
Journal: Neuro-Oncology (2019)

RATIONALE: A major factor contributing to the expanding knowledge of CNS tumors, specifically DMG biology is the selfless gift from patients and their families of postmortem tumor tissue. To facilitate this, we developed a postmortem donation program for collection of tissue and biospecimens for accelerating biology studies of end stage disease for pediatric CNS tumors. METHODS: Our postmortem program entails coordinating tissue donations, compiling clinical data, processing of whole brain, spinal cord, biofluids, and germline controls. Through our protocol, primary and disseminated tumor specimens are designated for molecular characterization and for generation of a matched preclinical model. RESULTS: During the past eight years, we coordinated and accrued over 50 autopsy cases including diffuse midline gliomas, ATRT, ETANTR, CPC from 20 institutions across North America and the United Kingdom. We report that approaching a family at the time of progression has provided the most successful outcome for consent to our program. Patient age range was from 11months to 20 years old. The median time from postmortem donation to tissue processing range was 13 hours with the earliest time point being 4 hours and the longest being 96 hours. All collected specimens were successfully processed and assessed for DNA/RNA integrity using bioanalyzer, attempted primary neurosphere cultures and cryopreserved for future molecular studies. PDX generation from fresh tissue proved more successful compared to primary neurospheres and post mortem time did not seem to have an effect. We have successfully generated models that represent molecular subgroups of DMGs such as H3.3/ H3.1- K27M and H3 WT. All generated preclinical models were validated by STR analysis and immunohistochemical assays using human mitochondrial antibodies. IMPACT: Postmortem tissue donations serve as an invaluable source for access to end-stage disease biology, generation of PDX models, studying patterns of tumor migration, testing combination therapy and preclinical drug testing.
Deep Learning Predicts Lung Cancer Treatment Response from Serial Medical Imaging
Authors: Yiwen Xu, Ahmed Hosny, Roman Zeleznik, Chintan Parmar, Thibaud Coroller, Idalid Franco, Raymond H. Mak, Hugo J.W.L. Aerts
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Tumors are continuously evolving biological systems, and medical imaging is uniquely positioned to monitor changes throughout treatment. Although qualitatively tracking lesions over space and time may be trivial, the development of clinically relevant, automated radiomics methods that incorporate serial imaging data is far more challenging. In this study, we evaluated deep learning networks for predicting clinical outcomes through analyzing time series CT images of patients with locally advanced non–small cell lung cancer (NSCLC). Experimental Design: Dataset A consists of 179 patients with stage III NSCLC treated with definitive chemoradiation, with pretreatment and posttreatment CT images at 1, 3, and 6 months follow-up (581 scans). Models were developed using transfer learning of convolutional neural networks (CNN) with recurrent neural networks (RNN), using single seed-point tumor localization. Pathologic response validation was performed on dataset B, comprising 89 patients with NSCLC treated with chemoradiation and surgery (178 scans). Results: Deep learning models using time series scans were significantly predictive of survival and cancer-specific outcomes (progression, distant metastases, and local-regional recurrence). Model performance was enhanced with each additional follow-up scan into the CNN model (e.g., 2-year overall survival: AUC = 0.74, P &amp;lt; 0.05). The models stratified patients into low and high mortality risk groups, which were significantly associated with overall survival [HR = 6.16; 95% confidence interval (CI), 2.17–17.44; P &amp;lt; 0.001]. The model also significantly predicted pathologic response in dataset B (P = 0.016). Conclusions: We demonstrate that deep learning can integrate imaging scans at multiple timepoints to improve clinical outcome predictions. AI-based noninvasive radiomics biomarkers can have a significant impact in the clinic given their low cost and minimal requirements for human input.
Gold nanocluster-loaded hybrid albumin nanoparticles with fluorescence-based optical visualization and photothermal conversion for tumor detection/ablation
Authors: Sanghyun Park, Hanju Kim, Su Chan Lim, Kyungseop Lim, Eun Seong Lee, Kyung Taek Oh, Han-Gon Choi, Yu Seok Youn
Journal: Journal of Controlled Release (2019)
Abstract O.36: Kawasaki Disease and Systemic Juvenile Idiopathic Arthritis - Two Ends of the Same Spectrum
Authors: Rae S Yeung, Mira van Veenendaal, Cedric Manlhiot, Rayfel Schneider, Brian W McCrindle
Journal: Circulation (2015)

Background: Clinical similarities between Kawasaki disease (KD) and systemic Juvenile Idiopathic Arthritis (sJIA) are well known. We critically reviewed children with KD and sJIA to identify those with both diagnoses in order to characterize discriminating findings at baseline. Methods: Data from prospectively acquired KD (n=1765) and sJIA (n=112) cohorts were reviewed for common patients (1990-2011). Those with both diagnoses (KD/sJIA n=8) were reviewed for clinical presentation, laboratory investigations, treatment regimens, coronary artery outcome and complications including macrophage activation syndrome, and results were compared to the overall KD cohort. Results: All children with KD/sJIA fulfilled diagnostic criteria for KD and sJIA (ILAR classification). Co-diagnosis was present in 0.45% (8 of 1765) and 7.1% (8 of 112) of those with KD and sJIA, respectively. Time between diagnosis of KD and presumptive diagnosis of sJIA was a median of 24 days (IQR 21-45 days). KD/sJIA patients had bilateral conjunctival injection less frequently, lower hepatic transaminases together with signs of more intense inflammation as expressed a by higher white blood cell count and lower albumin than the KD cohort alone. All KD/sJIA patients had recalcitrant disease consisting of prolonged fever requiring multiple doses of intravenous immunoglobulin and steroids. Coronary artery abnormalities (CAAs) were observed in 5 KD/sJIA patients. Macrophage activation syndrome occurred in one KD/sJIA patient and in 0.9% and 8% of KD patients and sJIA patients respectively. Conclusions: A small portion of our patients with KD developed subsequent sJIA. KD/sJIA patients were characterized by more intense inflammation at initial presentation, a recalcitrant disease course and a high prevalence of CAAs. These patients may provide clues to potentially shared immunopathology. The clinical presentations of MAS, KD and sJIA are quite similar with fever, rash, hepatomegaly, and lymphadenopathy. All 3 entities are syndrome complexes defined by massive immune activation. We propose that the intensity and duration of the immune response may be the key distinguishing features, which dictate which one of these clinical syndromes the affected child presents with.
DIPG-34. PRECLINICAL PRECISION TESTING OF PNOC003 BIOPSY DERIVED MODELS OF DIPG
Authors: Eshini Panditharatna, Sridevi Yadavili, Xiaodong Yang, Jie Zhang, Nathalene Truffaux, Yuying Zhai, Madhuri Kambhampati, Bo Zhang, Yuankun Zhu, Payal Jain, Cassie Kline, Roger J Packer, Michael Prados, Nalin Gupta, Adam Resnick, Sabine Mueller, Javad Nazarian
Journal: Neuro-Oncology (2019)

RATIONALE: One of the major hurdles in developing effective treatment for children with DIPG includes the lack of extensive combinatorial studies targeting major driver oncogenic pathways. Combination of H3K27M and TP53 mutations are found in over 50% of DIPG tumors, however, there is a lack of effective combinatorial precision therapy. METHODS: Tissue specimens obtained from subjects with DIPG were used to generate preclinical models. Subjects were enrolled in a prospective molecular diagnostic clinical trial and specimens were obtained by surgical biopsy both at initial diagnosis, and at the time of progression. RESULTS: Fourteen primary neurosphere cell lines and nine xenograft mouse models were successfully generated. The success rate of generating primary neurospheres and xenograft models was 45% and 75%, respectively. Among the 14 cell lines, one was derived from a biopsy performed after tumor progression, and one from washing a biopsy needle. Whole genome analysis of three biopsy-derived primary neurospheres revealed that these samples shared genomic alterations when compared to the primary tumors. All cell lines retained major oncogenic driver mutations in genes such as H3F3A, HIST1H3B, TP53, PPM1D, PIK3R1, and ACVR1. The needle-wash derived cell line was immortalized with hTERT, and exhibited the most deviation in mutation profiles and copy number alterations compared to primary tumor. Global DNA methylation profiling of seven primary tumor biopsies and matched primary neurospheres revealed similar epigenetic profiles. Primary neurospheres derived from biopsies were treated with the same specialized panel of agents recommended by a personalized medicine tumor board, which was based on the mutational profiles of the original tumor. SIGNIFICANCE: All cell lines exhibited varying levels of sensitivity to single agent indicating patterns of intertumor heterogeneity. The use of these model systems allows testing of combinatorial precision therapy for patients with DIPG, where there is a need for rapid translation into clinical trials.
Suppression of mesenchymal stem cell (MSC) differentiation in myeloma (MM) is specific to the osteoblast (OBL) lineage
Authors: Flavia Esteve
Journal: Cancer Research (2008)

3679  Myeloma bone disease is characterized by increased bone resorption and decreased bone formation. Several inhibitors of OBL differentiation have been identified, including the WNT signaling inhibitors , Dickkopf1 and secreted Frizzle-Related Protein-2, as well as IL-3 and IL-7. However, it is unknown if osteoblast suppression in MM is reversible or if the capacity of MSC to differentiate to other lineages is also affected by MM.  Therefore, we developed an in vivo mouse model to determine the time course for OBL suppression and if OBL activity can be restored. We generated 5TGM1 murine myeloma cells stably expressing GFP and thymidine kinase (TK), which permits eradication of these cells with gancyclovir, and demonstrated that gancyclovir treatment did not affect hematopoietic progenitors differentiation or MSC differentiation to OBL in vivo. When SCID mice were injected intratibally with 5TGM1-TK cells, lytic lesions developed over three weeks. Treatment of SCID mice bearing 5TGM1-TK cells with gancyclovir for 2 weeks resulted in maintanence of trabecular bone volume compared to the saline treated control group. Further, MSC cultures from gancyclovir treated mice displayed increased OBL differentiation and had significantly higher alkaline phosphatase activity compared to the saline treated controls (p=0.03).  To delineate the mechanism of osteoblast dysfunction, MC4 cells, a pre-osteoblast murine cell line, was co-cultured with 5TGM1-TK cells and assessed for expression of markers of osteoblast differentiation by real time PCR and alkaline phosphatase staining. Expression of Runx2 mRNA in MC4 cells, a critical OBL transcription factor, was decreased by 60% on day 4 and osteocalcin mRNA was decreased by more than 80% on day 7 of co-culture with myeloma cells, whereas ATF4, another important OBL transcription factor, and alkaline phosphatase mRNA levels remained unchanged. As expected OBL differentiation was severely suppressed in the co-cultures although MC4 cell growth was unaffected . Further, cell to cell contact was not required for MM cells to inhibit OBL differentiation. In contrast, adipocytic differentiation of MSC was unaffected by co-culture with 5TGM1-TK cells.  These results suggest that myeloma cells specifically inhibit osteoblast differentiation early during MSC differentiation by releasing a soluble factor(s) that suppresses Runx2 mRNA expression without affecting the capacity of MSC to differentiate to other cell lineages. This in vivo model system should be useful for further dissecting the mechanisms responsible for OBL suppression in MM.
MicroRNA Dysregulation in Malignant Germ Cell Tumors: More Than a Biomarker?
Authors: Matthew J. Murray, Nicholas Coleman
Journal: Journal of Clinical Oncology (2019)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study. March 15, 2019 ARTICLE CITATION DOI: 10.1200/JCO.19.00578 Journal of Clinical Oncology - published online before print April 22, 2019 PMID: 31009274 MicroRNA Dysregulation in Malignant Germ Cell Tumors: More Than a Biomarker? Matthew J. Murray, MB BChir, PhD1,2xMatthew J. MurraySearch for articles by this author and Nicholas Coleman, MD, PhD1,2xNicholas ColemanSearch for articles by this author Show More 1University of Cambridge, Cambridge, United Kingdom2Cambridge University Hospitals NHS Foundation Trust, Cambridge, United KingdomM.J.M. and N.C. contributed equally to this work. https://doi.org/10.1200/JCO.19.00578 First Page Full Text PDF Figures and Tables © 2019 by American Society of Clinical Oncology Companion Serum Levels of MicroRNA-371a-3p (M371 Test) as a New Biomarker of Testicular Germ Cell Tumors: Results of a Prospective Multicentric Study
New World Health Organization Treatment Recommendations for Multidrug-Resistant Tuberculosis: Are We Well Enough Prepared?
Authors: Katharina Kranzer, Barbara Kalsdorf, Jan Heyckendorf, Sönke Andres, Matthias Merker, Sabine Hofmann-Thiel, Guido V. Bloemberg, Harald Hoffmann, Stefan Niemann, Christoph Lange, Florian P. Maurer
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

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Hydroxytryptamine transporter gene-linked polymorphic region (5HTTLPR) is associated with delusions in Alzheimer’s disease
Authors: Grazia D’Onofrio, Francesco Panza, Daniele Sancarlo, Michele Lauriola, Mariangela P. Dagostino, Giulia Paroni, Madia Lozupone, Antonio Mangiacotti, Paola Bisceglia, Carolina Gravina, Maria Urbano, Filomena Addante, Francesco Paris, Leandro Cascavilla, Antonio Greco, Davide Seripa
Journal: Translational Neurodegeneration (2019)

Serotoninergic pathways underlying delusion symptoms in Alzheimer's disease (AD) have not been fully clarified. 5-Hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is a variable number tandem repeats in the promoter region of serotonin transporter encoding-gene affecting transcription. We investigated the association of 5-HTTLPR with delusions in a total of 257 consecutive patients clinically diagnosed as AD according to the National Institute on Aging-Alzheimer's Association criteria. All participants underwent a comprehensive evaluation with a standardized comprehensive geriatric assessment and Neuropsychiatric Inventory. Delusion symptoms were observed in 171 patients (66.54%). In respect to AD patients without delusions, AD patients with delusions showed a low prevalence of S-plus carriers (5-HTTLPR-L/S + 5-HTTLPR-S/S genotypes) [p < 0.001; odds ratio (OR) = 0.240, 95% confidence interval (CI) = 0.121–0.471]. Logistic regression analysis adjusted for the apolipoprotein E polymorphism showed that in AD patients with delusions the presence of an 5-HTTLPR-S allele may reduce disease duration (p = 0.005; OR = 0.680, 95% CI = 0.522–0.886) and increase aberrant motor activity (p = 0.013; OR = 2.257, 95% CI = 1.195–4.260). The present findings suggested that 5-HTTLPR might be associated with delusions in AD. S-plus carriers might be associated with protective effect against delusions in AD. More studies on wider samples of high selected demented patients are needed to confirm our results. However, the present findings suggested that a genetic factor related to serotonin metabolism might exert a protective role on the clinical expression of neuropsychiatric clusters in AD with important implications regarding mechanisms underlying delusions and their possible treatment across the AD and dementia spectrum.
In Vivo PSMA Expression in Head and Neck Paragangliomas on 68Ga PSMA 11 PET/CT
Authors: Sarthak Tripathy, Madhavi Tripathi, Shreya Dattagupta, Girish Kumar Parida, Shamim Ahmed Shamim
Journal: Clinical Nuclear Medicine (2019)

Head and neck paragangliomas are rare and often asymptomatic tumors and mostly present as painless masses. We describe Ga PSMA 11 PET/CT and Ga DOTANOC PET/CT findings of a 40 year old man with triple head and neck paragangliomas with emphasis on exploring the possible theranostic options.
PD-1 Immune Checkpoint Inhibitors and Immune-Related Adverse Events
Authors: Diwakar Davar, John M. Kirkwood
Journal: JAMA Oncology (2019)

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