tbuckley/cabot-search huggingface dataset:
Prognostic factors among older adults with advanced non-small cell lung cancer (NSCLC): A multisite cohort study.
Authors: Melisa L. Wong, Christine Miaskowski, Alexander K. Smith, W. John Boscardin, Harvey Jay Cohen, Arti Hurria, Vivian Lam, Carling Jade Ursem, Collin Michael Blakely, Matthew A. Gubens, Thierry Marie Jahan, Caroline Elizabeth McCoach, Gregory Maners Allen, Julia Rotow, Niharika Dixit, Vivek Musinipally, Katey R. Webber, Louise Christie Walter
Journal: Journal of Clinical Oncology (2019)

11540 Background: Prognosis in NSCLC is vital for clinical decision making. With the aging US population and rapidly changing treatment landscape, we aimed to identify prognostic factors among older adults with advanced NSCLC receiving chemo-, immuno-, and/or targeted therapy. Methods: We conducted a prospective cohort study of adults age ≥65 with advanced NSCLC starting a new non-curative systemic treatment (chemo-, immuno-, and/or targeted therapy) at a Comprehensive Cancer Center, Veterans Affairs Medical Center, and safety-net hospital. Prior to treatment initiation, patients completed a geriatric assessment including cognition, function, comorbidities, mood, social support, and quality of life. Cox proportional hazards models were performed to identify prognostic factors for overall survival (OS). Results: In a sample of 51 patients, median age was 73 (range 65-94). The majority of patients had stage IVB (59%) or IVA (39%) NSCLC. Current treatment included immunotherapy (37%), targeted therapy (29%), chemoimmunotherapy (18%), and chemo (16%). Most patients had received prior NSCLC treatment (80%): chemo (51%), targeted therapy (35%), immunotherapy (22%), radiation (RT; 47%), and/or surgery (19%). At enrollment, 73% had an abnormal Montreal Cognitive Assessment score &lt; 26 (MoCA; median score 23) and 35% had an abnormal Timed Up and Go time ≥13.5 secs (TUG; median time 12.7 secs). Median OS was 12.5 months. In univariable analyses, stage IVB disease (HR 6.99, 95% CI 1.55-31.5), prior RT (HR 2.98, 95% CI 1.08-8.21), worse MoCA score (HR 1.15 per 1 point change, 95% CI 1.03-1.28), and longer TUG time (HR 1.13 per 1 sec change, 95% CI 1.05-1.23) were associated with worse OS. Of note, age, current NSCLC treatment, line of therapy, and Karnofsky Performance Status were not associated with OS. In multivariable analysis, MoCA score was the only statistically significant prognostic factor (HR 1.15, 95% CI 1.01-1.30). Conclusions: We found that abnormal pretreatment cognition is very common and an important prognostic factor among older adults with advanced NSCLC. Pretreatment screening for cognitive impairment should be considered to inform prognostication, decision making, and treatment planning.
Correction: Antibody-Targeted Chemotherapy for the Treatment of Melanoma
Authors: Wendy K. Nevala, Sarah A. Buhrow, Daniel J. Knauer, Joel M. Reid, Elena A. Atanasova, Svetomir N. Markovic
Journal: Cancer Research (2019)

In the original version of [this article][1] ([1][2]), the test groups in Fig. 3B were incorrectly listed. The error has been corrected in the latest online HTML and PDF versions of the article. The authors regret this error.

1.  1.[↵][3]1.  Nevala WK,     2.  Buhrow SA,     3.  Knauer DJ
P05.05 Safety and feasibility of temporary blood-brain barrier disruption with the SonoCloud-1/3 implantable ultrasound device in recurrent glioblastoma
Authors: A Idbaih, M Canney, G Bouchoux, C Desseaux, A Vignot, C Lafon, J Chapelon, J Delattre, L Belin, A Carpentier
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The blood-brain barrier (BBB) limits penetration of drug therapies to the brain and may account for the limited effectiveness of chemotherapies in patients with primary brain cancer. An implantable ultrasound (US) device, SonoCloud, was developed to temporarily disrupt the BBB in patients with recurrent glioblastoma (rGBM) prior to carboplatin chemotherapy administration to enhance brain drug concentrations. BBB disruption was investigated with a single emitter device, SonoCloud-1 (SC1) and a three-emitter device, SonoCloud-3 (SC3) in a safety and feasibility study in rGBM patients at the Hôpitaux Universitaires La Pitié Salpêtrière in Paris, France (NCT02253212). MATERIAL AND METHODS The SC1 implant consisted of a 1 MHz, 10-mm diameter ultrasound transducer encapsulated in a biocompatible housing while the SC3 consisted of (3) separate SC1 emitters implanted in a triangular pattern to disrupt the BBB over a 3x larger volume. Patients were implanted with the SonoCloud device during tumor debulking or in a dedicated surgical procedure. The devices were activated monthly by connecting the device to an external generator via a transdermal needle. Intravenous injection of SonoVue® microbubbles was performed with device activation to temporarily disrupt the BBB. Magnetic resonance imaging (MRI) was performed after sonications with gadolinium contrast to verify BBB disruption followed by carboplatin infusion at AUC4-6. Patients received treatments until disease progression. RESULTS Between 2014 and 2016, 21 patients were registered for the study and implanted with the SC1; 19 patients received at least one sonication. Six additional patients were implanted and received sonications with the SC3. A total of 89 US sessions were performed to disrupt the BBB - 65 with the SC1 and 24 with the SC3. Treatment-related adverse events observed were transient and manageable. No carboplatin-related neurotoxicity was observed. SC1 patients with no or poor BBB disruption (n=8) visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. SC1 patients with clear BBB disruption (n=11) had a median PFS of 4.11 months, and a median OS of 12.94 months. The SC3 device was as well-tolerated as the SC1 device, with SC3 patients receiving between 1–12 monthly sonications. CONCLUSION These results provide the first safety data on the effects of disrupting the BBB in rGBM patients prior to carboplatin chemotherapy using an implantable low intensity pulsed ultrasound device on enlarged areas of brain. This study has now been completed. A new safety study with a larger device, SonoCloud-9, that covers the tumor and surrounding infiltrative regions, has started in France in early 2019 (NCT03744026). Work supported by CarThera and APHP.
P14.40 Incidence and risk factors identification for lung cancer brain metastasis
Authors: H Fariña, M Rodríguez-Salazar, M Rodríguez-Yanes, J Plata-Bello
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Lung Cancer (LC) is the most frequent malignant neoplasm around the world and it is one of the most frequent brain metastasis origins. The aim of the present work is to measure the incidence of brain metastasis in new-diagnosed LC patients and to identify the risk factors associated with its development. MATERIAL AND METHODS A retrospective observational study has been performed. Patients with new diagnosis of LC between January 2015 and December 2016 in our Center were included. Demographic, clinical and molecular variables were studied. Statistical analysis included a uni- and multivariate COX regression, survival analysis (log-rank test) and non-parametric two-independent sample tests. RESULTS Three-hundred and thirty-nine patients were diagnosed with LC in our Center between 2015 and 2016 (99 female; mean age: 66.1 years, SD=10.89). The incidence of brain metastasis was 16.25 cases each year since the initial diagnosis (19.2% of all patients). The risk of brain metastasis was increased in the first year after the diagnosis of LC (83.07% of cases). Patients with metastasis were younger than non-metastatic patients (64.0 vs. 66.6 years of age; p=.041). Small-cell lung carcinoma was the most frequent histological subtype associated with the development of metastasis (HR=2.267; p=.011), followed by the adenocarcinoma (HR=1.131; p=.624) and epidermoid (HR=.546; p=.067). No molecular factor (EGFR, ALK or p63 expression) was identified as risk factor. The overall survival of brain-metastatic patients was significantly lower than non-metastatic patients (167.0 vs. 273.0 days; p=.0002). CONCLUSION Brain metastasis are diagnosed in almost 20% of LC patients with, at least, three-years follow-up. Small-cell carcinoma subtype and younger patients were associated with a higher risk of brain metastasis, which is associated with a bad prognosis.
P09.08 Increased incidence of intracranial meningiomas in patients with acromegaly
Authors: J Engelhardt, M Nunes, C Pouchieu, F San-Galli, E Gimbert, J Vignes, F Laurent, J Berge, I Baldi, A Tabarin, H Loiseau
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND An increased incidence of various neoplasms has been described in patients with acromegaly and there is evidence to suggest that growth factors are risk factors for the development of meningiomas. We aimed to study if patients with acromegaly are more at risk for developing intracranial meningiomas MATERIAL AND METHODS We conducted an observational study on 221 consecutive acromegalic patients recruited between January 1, 2000 and December 31, 2015, and 357 consecutive patients with a non-somatotropic pituitary adenoma recruited between March 1, 2015 and December 31, 2016 in our institution. Patients underwent a gadolinium-enhanced 3D T1 brain MRI to look for meningiomas. The proportion of meningiomas was compared between the two groups and the standardized incidence ratio (SIR) was computed from the incidence rates of meningiomas observed in the population of acromegalic patients and compared to that of the general population given by the local registry of central nervous system tumors. RESULTS Patients with acromegaly had a significant risk for developing intracranial meningiomas as compared to patients without acromegaly (7.7% vs. 2.2%, p = .005, OR = 3.45 [1.46; 8.15]). There was a significant increased incidence of intracranial meningiomas in patients with acromegaly (SIR = 126 [25; 367]) as compared to the general population. CONCLUSION Our study provides the first evidence that patients with acromegaly are more at risk for developing intracranial meningiomas.
A library of human gut bacterial isolates paired with longitudinal multiomics data enables mechanistic microbiome research
Authors: M. Poyet, M. Groussin, S. M. Gibbons, J. Avila-Pacheco, X. Jiang, S. M. Kearney, A. R. Perrotta, B. Berdy, S. Zhao, T. D. Lieberman, P. K. Swanson, M. Smith, S. Roesemann, J. E. Alexander, S. A. Rich, J. Livny, H. Vlamakis, C. Clish, K. Bullock, A. Deik, J. Scott, K. A. Pierce, R. J. Xavier, E. J. Alm
Journal: Nature Medicine (2019)
Comparative genomic analysis of six Glossina genomes, vectors of African trypanosomes
Authors: Geoffrey M. Attardo, Adly M. M. Abd-Alla, Alvaro Acosta-Serrano, James E. Allen, Rosemary Bateta, Joshua B. Benoit, Kostas Bourtzis, Jelle Caers, Guy Caljon, Mikkel B. Christensen, David W. Farrow, Markus Friedrich, Aurélie Hua-Van, Emily C. Jennings, Denis M. Larkin, Daniel Lawson, Michael J. Lehane, Vasileios P. Lenis, Ernesto Lowy-Gallego, Rosaline W. Macharia, Anna R. Malacrida, Heather G. Marco, Daniel Masiga, Gareth L. Maslen, Irina Matetovici, Richard P. Meisel, Irene Meki, Veronika Michalkova, Wolfgang J. Miller, Patrick Minx, Paul O. Mireji, Lino Ometto, Andrew G. Parker, Rita Rio, Clair Rose, Andrew J. Rosendale, Omar Rota-Stabelli, Grazia Savini, Liliane Schoofs, Francesca Scolari, Martin T. Swain, Peter Takáč, Chad Tomlinson, George Tsiamis, Jan Van Den Abbeele, Aurelien Vigneron, Jingwen Wang, Wesley C. Warren, Robert M. Waterhouse, Matthew T. Weirauch, Brian L. Weiss, Richard K. Wilson, Xin Zhao, Serap Aksoy
Journal: Genome biology (2019)

Tsetse flies (Glossina sp.) are the vectors of human and animal trypanosomiasis throughout sub-Saharan Africa. Tsetse flies are distinguished from other Diptera by unique adaptations, including lactation and the birthing of live young (obligate viviparity), a vertebrate blood-specific diet by both sexes, and obligate bacterial symbiosis. This work describes the comparative analysis of six Glossina genomes representing three sub-genera: Morsitans (G. morsitans morsitans, G. pallidipes, G. austeni), Palpalis (G. palpalis, G. fuscipes), and Fusca (G. brevipalpis) which represent different habitats, host preferences, and vectorial capacity.Genomic analyses validate established evolutionary relationships and sub-genera. Syntenic analysis of Glossina relative to Drosophila melanogaster shows reduced structural conservation across the sex-linked X chromosome. Sex-linked scaffolds show increased rates of female-specific gene expression and lower evolutionary rates relative to autosome associated genes. Tsetse-specific genes are enriched in protease, odorant-binding, and helicase activities. Lactation-associated genes are conserved across all Glossina species while male seminal proteins are rapidly evolving. Olfactory and gustatory genes are reduced across the genus relative to other insects. Vision-associated Rhodopsin genes show conservation of motion detection/tracking functions and variance in the Rhodopsin detecting colors in the blue wavelength ranges.Expanded genomic discoveries reveal the genetics underlying Glossina biology and provide a rich body of knowledge for basic science and disease control. They also provide insight into the evolutionary biology underlying novel adaptations and are relevant to applied aspects of vector control such as trap design and discovery of novel pest and disease control strategies.
P14.85 Brain metastasis from Hodgkin’s Lymphoma: case report and literature review
Authors: F Bruno, E Pronello, S Bortolani, R Palmiero, A Melcarne, A Chiappella, C Mantovani, R Soffietti, R Rudà
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Central nervous system (CNS) metastases from Hodgkin’s Lymphoma (HL) are very rare, occurring in 0.02–0.5% of cases. They are usually associated to systemic relapse of the disease. Treatment options for HL brain metastases include surgery, radiotherapy, and systemic chemotherapy. CASE REPORT A 54 year-old woman presented with thoracic pain and dyspnea. Chest CT showed a thoracic bulky mass larger than 10 cm. Biopsy confirmed HL stage IIA, nodular sclerosing variant. No typical B symptoms, such as fever, night sweats or weight loss, were observed. The patient underwent chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD scheme), followed by 30Gy mediastinic radiotherapy (RT), which led to complete remission in September 2017. After 3 months, she presented with headache and rapidly progressing gait disorder. MRI showed a contrast-enhanced lesion in the right occipital lobe, with central necrosis and massive edema. Total-body CT scan and FDG-PET ruled out either the presence of new solid tumors or systemic relapses of HL. Gross total resection of the brain lesion was carried out, and HL histology was confirmed. CSF analysis from lumbar puncture was normal. Afterwards, the patient underwent 2 cycles of high dose cytarabine, but she rapidly progressed, and received salvage RT (30 Gy). Nevertheless, further systemic progression occurred: the patient developed headache, diplopia and dysphagia and, unfortunately, she died 6 months after the diagnosis of brain metastasis. DISCUSSION Thus far, only 45 cases of CNS HL have been reported from 2000 to 2018. Whole brain radiotherapy, with or without chemotherapy, was the most common treatment. In our patient, we chose surgical resection for the solitary brain metastasis followed by chemotherapy, delaying RT at recurrence. In the literature, median overall survival of patients diagnosed with brain metastases from HL is 18 months (1–273): 17 patients (38%) showed a progression (local / systemic: 12/17 - 71%), while 28 (62%) showed complete remission after a median follow-up of 20 months (6–273). CONCLUSION Intracranial localisation of Hodgkin’s Lymphoma is a rare entity but still has to be taken into account. Advanced brain imaging could be of help in case of uncertain radiological presentation. A multidisciplinary approach is needed as there is no consensus on the best treatment to choose: surgery, radiotherapy and chemotherapy should be considered on individual basis.
Mortality and survival rates in children and adolescents enrolled in early phase trials with a dose-finding/dose-confirmation component: An innovative therapies for children with cancer (ITCC) study.
Authors: Fernando Carceller, Francisco Bautista, Alicia Castañeda, Aurore Surun, Ajla Wasti, Gabriel Revon-Riviere, Marta Cortes, Luca Bergamaschi, Antonio Juan Ribelles, Gerard Millen, Quentin Campbell Hewson, Loredana Amoroso, Jasper Van der Lugt, Franca Fagioli, Michel Zwaan, Lynley V Marshall, Gilles Vassal, Andrew DJ Pearson, Birgit Geoerger, Lucas Moreno
Journal: Journal of Clinical Oncology (2019)

e21509 Background: Participation of children with advanced solid cancers in phase I trials raises ethical and logistic dilemmas. Life-expectancy beyond 8-12 weeks is a common inclusion criterion, but it can be difficult to gauge. This multicentric European study assessed the mortality and survival rates in pediatric phase I trials. Methods: Retrospective study of patients aged &lt; 18 years with solid tumors enrolled in phase I trials in ITCC centres between 2015-2017. Outcome variables were described and prognostic factors analysed. Results: 256 patients across 12 centres in 5 countries were eligible. Median age 11.8 years (range, 0.5-17.9). Female:Male ratio 1:1.9. Tumor location: central nervous system (CNS) 66% vs extra-CNS 34%. Main diagnoses: 22% soft tissue sarcomas, 13% high grade gliomas, 11% osteosarcomas. Most frequent therapy: single targeted agent (63%). Ten cases (4%) were not evaluable for response and 128 (50%) had progressive disease at first evaluation. Best responses were complete in 12 cases (5%), partial in 29 (11%) and stable disease in 77 (30%). Median follow-up 7 months (range, 0.5-42.4). Median Time On Study (TOS) 2.1 months (range, 0.2-38.1). The 30 and 90-day mortality on trial were 3% (8/256) and 21% (54/256), respectively. The 90-day survival (95%CI) for patients with CNS vs extra-CNS tumors was 88% (78-93) vs 76% (68-82), respectively. One-year Overall Survival (95%CI) for the whole sample was 40% (33-46). No toxic deaths on trial were reported. Twenty-five cases (10%) survived ≥365 days on trial. Median TOS 21.5 months (range, 12.3-38.1). Compared to patients who died within 365 days from Cycle1-Day1, those on trial ≥365 days had lower rates of metastatic disease (74% vs 28%, respectively, p &lt; 0.001), higher objective response rates (13% vs 44%, respectively, p &lt; 0.001) and higher disease stabilization (27% vs 56%, respectively, p &lt; 0.001). Conclusions: Currently few patients die within the first cycle of treatment. However a fifth of all patients died within 3 months from trial initiation. Patients with CNS tumors have comparable survival rates to those with extra-CNS and should not be excluded from phase I trials solely because of their diagnosis. The survival rates beyond one year remain modest.
PL3.4 Intrinsic tumor plasticity in Glioblastoma allows for recreation of stem like-states and efficient tumor cell adaptation to new microenvironments
Authors: A Golebiewska, A Dirkse, T Buder, Y A Yabo, S Poovathingal, A Muller, P V Nazarov, C Herold-Mende, R Bjerkvig, A Skupin, A Deutsch, A Voss-Bohme, S P Niclou
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Cellular heterogeneity has been well established within numerous cancer types, including malignant brain tumours. Initially, cancer stem cells (CSC) have been accounted for formation of phenotypic heterogeneity and tumor progression in glioblastoma (GBM). Recent data, however, suggest that CSCs may not represent a stable entity and intrinsic plasticity plays a key role in tumor adaptation to changing microenvironments. The question arises whether CSCs are a defined subpopulation of tumor cells or whether they represent a changing entity that any cancer cell can adopt depending on the environmental conditions. MATERIAL AND METHODS Intra-tumoral phenotypic heterogeneity was interrogated at the single cell transcriptomic and proteomic level in GBM patient-derived orthotopic xenografts (PDOXs) and stem-like cultures. Tumor cell subpopulations were further classified based on expression of four stem cell-associated membrane markers (CD133, CD15, A2B5 and CD44). The resulting 16 subpopulations were FACS isolated and functionally analyzed. Mathematical Markov modelling was applied to calculate state transitions between cell states. RESULTS GBM patient biopsies, PDOXs and stem-like cell cultures display remarkable stem cell-associated intra-tumoral heterogeneity. Independent of marker expression, all analysed tumor subpopulations carried stem-cell properties and had the capacity to recreate phenotypic heterogeneity. Mathematical modeling revealed a different propensity in reforming the original heterogeneity over time, which was independent of the proliferation index but linked to tumorigenic potential. Although subpopulations varied in their potential to adapt to new environments, all were able to reach a steady state microenvironment-specific equilibrium. CONCLUSION Our results suggest that phenotypic heterogeneity in GBM results from intrinsic plasticity allowing tumor cells to effectively adapt to new microenvironments. Cellular states are non-hierarchical, reversible and occur via stochastic state transitions of existing populations, striving towards an equilibrium instructed by the microenvironment. Our data provides evidence that CSCs do not represent a clonal entity defined by distinct functional properties and transcriptomic signatures, but rather a cellular state that is determined by environmental conditions, which has implications for the design of treatment strategies targeting CSC-like states.