tbuckley/cabot-search huggingface dataset:
Head-to-Head Comparison of 18F-DOPA PET/CT and 68Ga-DOTANOC PET/CT in Patients With Midgut Neuroendocrine Tumors
Authors: Catherine Ansquer, Yann Touchefeu, Alain Faivre-Chauvet, Christophe Leux, Maëlle Le Bras, Nicolas Régenet, Vincent Fleury, Bruno Maucherat, Hélène Senellart, Serge Guyetant, Thomas Carlier, Evelyne Scotet-Cérato, Aurore Rauscher, Eric Frampas, Françoise Kraeber-Bodéré
Journal: Clinical Nuclear Medicine (2020)

The aim of this study was to compare retrospectively 18F-DOPA PET/CT versus 68Ga-DOTANOC PET/CT in a group of patients affected by midgut NET.Patients with histologically proven grade 1 or grade 2 midgut NET were explored after injection of 150 MBq of 68Ga-DOTANOC and 210 MBq of 18F-DOPA. The PET/CTs were analyzed visually and semiquantitatively at the patient level, regional level (7 defined regions), and lesion level (maximum of 5 lesions/organ). The criterion standard was determined on the basis of histology and imaging follow-up.Thirty patients (17 males and 13 females; median age, 63.5 years [37-82 years]) were included. Both PET/CTs were negative in 3 patients and positive in 25 patients. PET/CTs were discordant in 2 patients, with 18F-DOPA positive and 68Ga-DOTANOC negative. 18F-DOPA PET/CT detected more involved regions and more metastatic lesions than 68Ga-DOTANOC PET/CT in 6 (20%) and 10 (33.3%) patients, respectively. Of the 81 confirmed affected regions, 77 (95%) were detected by 18F-DOPA PET/CT and 71 (87.7%) by 68Ga-DOTANOC PET/CT (P < 0.0001). 18F-DOPA PET/CT detected significantly more lesions (211/221) than 68Ga-DOTANOC PET/CT (195/221), corresponding to a sensitivity of 95.5% and 88.2%, respectively (P < 0.0001). Tumor-to-background ratios were more favorable in liver for 18F-DOPA than for 68Ga-DOTANOC. Interestingly, a correlation was found between 18F-DOPA SUVmax and tumor burden and especially with the number of regions involved by the disease (P = 0.019).18F-DOPA PET/CT is superior to 68Ga-DOTANOC PET/CT for the detection of lesions, and when available, this tracer may be recommended as the first-line examination for an accurate staging of midgut NET.
Food‐dependent NSAID‐induced hypersensitivity (FDNIH) reactions: Unraveling the clinical features and risk factors
Authors: Jaime Sánchez‐López, Giovanna Araujo, Victoria Cardona, Alba García‐Moral, Rocío Casas‐Saucedo, Mar Guilarte, María José Torres, Inmaculada Doña, Cesar Picado, Mariona Pascal, Rosa Muñoz‐Cano, Joan Bartra
Journal: Allergy (2020)

In up to 70%-80% of patients with a suspected non-steroidal anti-inflammatory drug hypersensitivity (NSAIDH), challenge tests with the culprit drug yield negative results. On the other hand, there could be a NSAIDH overdiagnosis when anaphylaxis is the clinical manifestation. We hypothesize that some negative NSAID challenge tests and an overdiagnosis of NSAIDH occur in patients with food-dependent NSAID-induced hypersensitivity (FDNIH).We studied 328 patients with a suspected acute NSAIDH. FDNIH was diagnosed in patients meeting all the following: (1) tolerance to the food ingested more temporally closed before the reaction, later the episode, (2) respiratory or cutaneous symptoms or anaphylaxis related to NSAID, (3) positive skin prick test to foods and/or specific IgE to food allergens (Pru p 3, Tri a 19, Pen a 1) involved in the reaction, and (4) negative oral provocation test to the culprit NSAID.199 patients (60%) were diagnosed with NSAIDH and 52 (16%) with FDNIH. Pru p 3 was involved in 44 cases (84.6%) and Tri a 19 in 6 cases (11%). FDNIH subjects were younger (p < .001), with a higher prevalence of rhinitis (p < .001) and previous food allergy (p < .001), together with a higher proportion of subjects sensitized to pollens (p < .001) and foods (p < .001). Using just four variables (Pru p 3 sensitization, Tri a 19 sensitization, anaphylaxis, and any NSAID different from pyrazolones), 95.3% of cases were correctly classified, with a sensitivity of 92% and specificity of 96%.Evaluation of FDNIH should be included in the diagnostic workup of NSAIDH.
EXTH-09. NEO-ADJUVANT TEMOZOLOMIDE INCREASES THE EFFICACY OF SUBSEQUENT CONCURRENT CHEMORADIATION IN A TRANSGLUTAMINASE-2 DEPENDENT MANNER
Authors: Paul Daniel, Brian Meehan, Siham Sabri, George Shenouda, Jann Sarkaria, Janusz Rak, Bassam Abdulkarim
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is invariably fatal due to failure of current chemoradiation (Stupp) regimes. Biomarkers such as MGMT have proven to predict response to Temozolomide (TMZ). An equivalent biomarker for radiation (RT) has not yet been identified. Transglutaminase-2 (TGM2) has been implicated in driving radiation resistance; but the mechanism is poorly understood. We have investigated how exposure to neoadjuvant TMZ in glioma stem cells (GSCs) with different levels of TGM2 would affect the response to RT. MATERIALS/METHODS: Primary GSCs lines with different TGM2 levels (high: 1123, 83; low: 528, OPK49) were used to explore the role of TGM2 in RT response and modulation of expression by TMZ in vitro and in-vivo. RESULTS: We showed that TGM2 drives radioresistance in GSCs through restriction of p53 mediated repression of RAD51 expression. We demonstrate that exposure of GSCs to TMZ drives rapid downregulation of TGM2 in vitro and this phenomenon is recapitulated in vivo. Interestingly, we confirm that RT is able to drive reciprocal changes in TGM2 and promotes reactivation of TGM2 in TGM2-high tumours but not TGM2-low tumours. Given these observations, we hypothesized that exposure to neoadjuvant TMZ in TGM2-low tumours would increase the efficacy of subsequent RT in these tumours. Comparison of the effect of standard treatment consisting of 3 weeks of concurrent TMZ and RT (Stupp) to a novel regime (neo-Stupp) consisting of 1 week of neoadjuvant TMZ followed by two weeks of TMZ and hypofractionated RT revealed a superior survival benefit of this novel regime in TGM2-low tumours but not in TGM2-high tumours. Utilization of the TGM2 inhibitor GK921 in combination with neo-Stupp prevented rapid relapse previously observed in TGM2-high tumours. CONCLUSION: We provide evidence that TGM2 is a biomarker of RT response and can be used to tailor chemoradiation protocols to the unique biology of each individual GBM patient.
Defective STING expression potentiates IL-13 signaling in epithelial cells in eosinophilic chronic rhinosinusitis with nasal polyps
Authors: Hai Wang, Dan-Qing Hu, Qiao Xiao, Yi-Bo Liu, Jia Song, Yuxia Liang, Jian-Wen Ruan, Zhe-Zheng Wang, Jing-Xian Li, Li Pan, Meng-Chen Wang, Ming Zeng, Li-Li Shi, Kai Xu, Qin Ning, Guohua Zhen, Di Yu, De-Yun Wang, Sally E. Wenzel, Zheng Liu
Journal: Journal of Allergy and Clinical Immunology (2020)
IMMU-08. MODELING UPFRONT GLIOBLASTOMA SURGICAL RESECTION AND STEROID USE REVEALS IMMUNOSUPPRESSIVE CHANGES AND SUGGESTS THAT PERIPHERAL LYMPHOCYTE COUNTS ARE ASSOCIATED WITH TUMOR VOLUME AND PROGNOSIS
Authors: Balint Otvos, Tyler Alban, Matthew Grabowski, Defne Bayik, Robert Winkelman, Sarah Johnson, Anja Rabljenovic, Michael Vogelbaum, Manmeet Ahluwalia, Peter Fecci, Justin Lathia
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) and its treatment produces systemic immunosuppression, which is being targeted by immunotherapies. However, it remains unclear how surgical resection and steroids specifically in GBM alter the immune system. To further explore this issue, immunocompetent C57Bl/6 mice were intracranially inoculated with syngeneic glioma cells (GL261 and CT-2A) and growth of tumors was evaluated by MRI. Host immune cell populations were analyzed during surgical resection and steroid administration. Mice with surgically resected tumors had a longer median survival compared to mice subjected to tumor biopsies, and had increased bone marrow sequestration of both CD4 and CD8 T cells with corresponding decreased blood lymphocytes. Furthermore, physiologic doses of dexamethasone administered perioperatively decreased tumor edema, but increased the number and proliferative capacity of both marrow and circulating MDSCs while generating no survival benefit. Independent of therapy or dexamethasone, intracranial tumor volume correlated linearly with decreased CD4 and CD8 T cells in peripheral blood, and increased T cell sequestration within the bone marrow. We validated these parameters in steroid-naïve newly diagnosed GBM patients and observed decreased lymphocytes correlated linearly with increased tumor volume. When initial lymphocyte counts in both steroid-naïve and steroid-administered patients were used in univariate and multivariate models predicting progression-free survival and overall survival, decreased initial lymphocyte counts were an independent predictor of decreased progression free survival and decreased overall survival, with steroid use and initial tumor size falling out of significance during stepwise selection. Taken together, tumor volume is linearly correlated with marrow sequestration of lymphoid cells, but both surgery and steroid administration further suppress active immune responses along lymphoid and myeloid lineages. Furthermore, decreasing peripheral lymphocyte counts at diagnosis of GBM indicate an immune system less able to mount responses to the tumor and portent a worse progression free and overall survival.
OUTSTEP‐HF: randomised controlled trial comparing short‐term effects of sacubitril/valsartan versus enalapril on daily physical activity in patients with chronic heart failure with reduced ejection fraction
Authors: Massimo F. Piepoli, Rizwan I. Hussain, Josep Comin‐Colet, Ramon Dosantos, Philippe Ferber, Tiny Jaarsma, Frank Edelmann
Journal: European Journal of Heart Failure (2020)
Adenoviral vaccines promote protective tissue-resident memory T cell populations against cancer
Authors: Esmé TI van der Gracht, Mark JA Schoonderwoerd, Suzanne van Duikeren, Ayse N Yilmaz, Felix M Behr, Julia M Colston, Lian N Lee, Hideo Yagita, Klaas PJM van Gisbergen, Lukas JAC Hawinkels, Frits Koning, Paul Klenerman, Ramon Arens
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Adenoviral vectors emerged as important platforms for cancer immunotherapy. Vaccination with adenoviral vectors is promising in this respect, however, their specific mechanisms of action are not fully understood. Here, we assessed the development and maintenance of vaccine-induced tumor-specific CD8 + T cells elicited upon immunization with adenoviral vectors. Methods Adenoviral vaccine vectors encoding the full-length E7 protein from human papilloma virus (HPV) or the immunodominant epitope from E7 were generated, and mice were immunized intravenously with different quantities (10 7 , 10 8 or 10 9 infectious units). The magnitude, kinetics and tumor protection capacity of the induced vaccine-specific T cell responses were evaluated. Results The adenoviral vaccines elicited inflationary E7-specific memory CD8 + T cell responses in a dose-dependent manner. The magnitude of these vaccine-specific CD8 + T cells in the circulation related to the development of E7-specific CD8 + tissue-resident memory T (T RM ) cells, which were maintained for months in multiple tissues after vaccination. The vaccine-specific CD8 + T cell responses conferred long-term protection against HPV-induced carcinomas in the skin and liver, and this protection required the induction and accumulation of CD8 + T RM cells. Moreover, the formation of CD8 + T RM cells could be enhanced by temporal targeting CD80/CD86 costimulatory interactions via CTLA-4 blockade early after immunization. Conclusions Together, these data show that adenoviral vector-induced CD8 + T cell inflation promotes protective T RM cell populations, and this can be enhanced by targeting CTLA-4.
Variation in Biosimilar Uptake in Europe
Authors: Jon Trærup Andersen, Thomas Bo Jensen
Journal: JAMA Internal Medicine (2020)

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STEM-17. NOT ALL GBM STEM CELLS ARE EQUAL: IMPLICATIONS FOR RESEARCH AND THERAPY
Authors: Luciano Galdieri, Arijita Jash, Olga Malkova, Diane Mao, Jian Campian, Cameron Brennan, Stephen Oh, Albert Kim, Milan Chheda
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) kills almost all patients within 2 years. A subpopulation of cells, GBM stem cells (GSCs), contributes to treatment resistance and recurrence. A major therapeutic goal is to kill GSCs, but no targeted therapy yet exists. Since their discovery, GSCs have been isolated using single surface markers, such as CD15, CD44, CD133, and a-6 integrin. It remains unknown how these single surface marker-defined GSC populations compare to each other in terms of signal transduction and function and whether expression of different combinations of these markers is associated with distinct phenotypes. Using mass cytometry and fresh operating room specimens, we found that 15 distinct GSC subpopulations exist in vivo and they differ in their MEK/ERK, WNT, and AKT pathway activation status. In culture, some subpopulations were lost and previously undetectable ones materialized. GSCs highly expressing all four surface markers had the greatest self-renewal capacity and in vivo tumorigenicity as well as the strongest WNT pathway activation. This work highlights the signaling and phenotypic diversity in GSC subpopulations, together suggesting that not all GSCs are equivalent. These observations should be considered when studying GSCs in the laboratory, with implications for the development of treatments that target GSCs and prevent tumor recurrence in patients.
Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome
Authors: Katharina Röltgen, Abigail E. Powell, Oliver F. Wirz, Bryan A. Stevens, Catherine A. Hogan, Javaria Najeeb, Molly Hunter, Hannah Wang, Malaya K. Sahoo, ChunHong Huang, Fumiko Yamamoto, Monali Manohar, Justin Manalac, Ana R. Otrelo-Cardoso, Tho D. Pham, Arjun Rustagi, Angela J. Rogers, Nigam H. Shah, Catherine A. Blish, Jennifer R. Cochran, Theodore S. Jardetzky, James L. Zehnder, Taia T. Wang, Balasubramanian Narasimhan, Saurabh Gombar, Robert Tibshirani, Kari C. Nadeau, Peter S. Kim, Benjamin A. Pinsky, Scott D. Boyd
Journal: Science Immunology (2020)

SARS-CoV-2-specific antibodies, particularly those preventing viral spike receptor binding domain (RBD) interaction with host angiotensin-converting enzyme 2 (ACE2) receptor, can neutralize the virus. It is, however, unknown which features of the serological response may affect clinical outcomes of COVID-19 patients. We analyzed 983 longitudinal plasma samples from 79 hospitalized COVID-19 patients and 175 SARS-CoV-2-infected outpatients and asymptomatic individuals. Within this cohort, 25 patients died of their illness. Higher ratios of IgG antibodies targeting S1 or RBD domains of spike compared to nucleocapsid antigen were seen in outpatients who had mild illness versus severely ill patients. Plasma antibody increases correlated with decreases in viral RNAemia, but antibody responses in acute illness were insufficient to predict inpatient outcomes. Pseudovirus neutralization assays and a scalable ELISA measuring antibodies blocking RBD-ACE2 interaction were well correlated with patient IgG titers to RBD. Outpatient and asymptomatic individuals' SARS-CoV-2 antibodies, including IgG, progressively decreased during observation up to five months post-infection.
LGG-18. EVEROLIMUS TREATMENT IN PEDIATRIC PATIENTS AFFECTED BY LOW-GRADE GLIOMAS (pLGG) NON-TSC, BRAF v600-WT
Authors: Antonella Cacchione, Evelina Miele, Maria Chiara Lodi, Andrea Carai, Giovanna Stefania Colafati, Francesca Diomedi Camassei, Franco Locatelli, Angela Mastronuzzi
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND MAPK pathway is the hallmark of pediatric low grade gliomas (pLGGs); hyperactivation of mTOR (mammalian target of rapamycin) might be a suitable biomarker for therapeutic response. We investigated the feasibility of Everolimus, mTOR inhibitor, in patients affected by pLGGs. METHODS Patients 1 to 18 years old, diagnosed with pLGG, with a positive tumor biopsy for mTOR/phospho-mTOR and radiological and / or clinical disease progression, treated at Bambino Gesù Children’s Hospital in Rome were evaluated. Tumor DNA methylation analysis was performed in 10 cases. Exclusion criteria included: Tuberous Sclerosis patients, Sub Ependymal Giant Astrocytoma. Everolimus was administered orally at a dose of 2.5 mg or 5 mg daily based on body weight. Patients were evaluated with brain MRI every 4, 8 and 12 months after treatment start and every six months thereafter. RESULTS 16 patients were enrolled from September 2014 and 2019. The median age was 7.5 years old. All patients had at least one adverse event. Events rated as severe (grade 3/4) were reported in 6 patients. Stomatitis was the most frequent adverse event. One patient discontinued treatment due to grade 4 toxicity (ulcerative stomatitis and fatigue). The median duration of treatment was 21 months (4–57 months). Brain MRI evaluations have showed disease stability in 11 patients, partial response in 2 patients and disease progression in 3 patients. CONCLUSIONS Everolimus has proven to be well tolerated and effective treatment in terms of disease stability in patients with pLGGs. It’s also an excellent example of chemo-free personalized approach.
GCT-46. MULTI-KINASE INHIBITORS AS NOVEL THERAPEUTIC AGENTS AGAINST INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMORS
Authors: Eita Uchida, Tatsuya Ozawa, Masamichi Takahashi, Ryo Nishikawa, Koichi Ichimura, Arata Tomiyama
Journal: Neuro-Oncology (2020)

Abstract Central nervous system germ cell tumors (CNS GCTs) are rare intracranial malignancies developing in adolescents and young adults which relatively frequently occur in East Asia region of the world including Japan. However, among CNS GCTs, non-germinomatous germ cell tumors (NGGCTs) are highly resistant to the current chemoradiotherapies, and the prognosis of CNS NGGCTs is still extremely poor. Therefore, development of novel therapeutic strategy against CNS NGGCTs is urgently needed. In this study, we screened small molecule inhibitors of kinases specifically targeting cell membrane receptors, such as receptor tyrosine kinases, and their related molecular signaling, which could effectively exert antitumor effects against NGGCT cells. As the NGGCT model cells, the Tcam2 cell, a mixed germ cell tumor cell line composed of germinoma and embryonal carcinoma components, and the YST1 cell, a novel yolk sac tumor cell line established in our institute, were used. As a result, effective induction of cell death in both cell lines was confirmed only by treatment with two multi-kinase inhibitors. Immunoblotting revealed these multi-kinase inhibitors suppressed activation of various kinases concurrently. Furthermore, these multi-kinase inhibitors also triggered cell death in the Tcam2 cell stably expressing mutant KIT, the most common oncogenic driver genes of CNS GCTs, suggesting that these inhibitors would be also effective against CNS GCTs harboring activated KIT mutants. In vivo studies of these multi-kinase inhibitors using CNS GCT xenografts are currently on going.
Increased Hyperglycemia and Hospital-Acquired Infections Following Withdrawal of the RAPIDS Early Intervention Model of Diabetes Care in Medical and Surgical Inpatients
Authors: Mervyn Kyi, Joanna Wang, Spiros Fourlanos
Journal: Diabetes Care (2020)

Hyperglycemia is associated with hospital-acquired infection (HAI) and mortality, and treating hyperglycemia can improve outcomes in noncritical care (1,2). We previously reported the cluster Randomized Study of a Proactive Inpatient Diabetes Service (RAPIDS), where an early intervention model of diabetes care was investigated in medical and surgical inpatients (3). A proactive specialist diabetes team performed electronic glycemic surveillance and provided early bedside management for all inpatients with diabetes or hyperglycemia and demonstrated a 55% reduction in severe hyperglycemia (patient-days with mean blood glucose [BG] >270 mg/dL) and a 62% reduction in HAI. At the conclusion of RAPIDS, the proactive model of care was ceased due to lack of ongoing funding for this health care initiative. We performed this RAPIDS-extension observational study to evaluate glycemic and clinical outcomes after cessation of early intervention care, hypothesizing that hyperglycemia and HAI incidence would deteriorate back to baseline levels.

RAPIDS included patients of eight medical and surgical wards at the tertiary Royal Melbourne Hospital, who were randomized to control or intervention arms. RAPIDS comprised a 10-week baseline period, where patients in all wards received usual care (diabetes management mostly performed by treating teams), followed by a 12-week active period, when patients in the intervention wards received proactive care (by an …
QOLP-30. FEAR OF CANCER RECURRENCE IN PRIMARY BRAIN TUMOR PATIENTS: DO DISEASE-RELATED CHARACTERISTICS MATTER?
Authors: Sarah Braun, Farah Aslanzadeh, Leroy Thacker, Ashlee Loughan
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND/PURPOSE Fear of cancer recurrence (FCR) is associated with disease-related variables including cancer stage and time since diagnosis in non-CNS cancer patients. However, no studies have investigated these relationships in primary brain tumor patients (PBT), with most research on FCR excluding this population purposefully. Given that a diagnosis of PBT is diverse in terms of prognosis, treatment, and disease trajectory, FCR in neuro-oncology may be different from other cancer populations and warrants investigation. METHODS PBT patients receiving care at an NCI-designated cancer center completed the FCR-7, a validated questionnaire assessing FCR. Disease-related variables, including tumor grade, tumor hemisphere, and time since diagnosis were obtained via medical records and investigated as correlates of FCR using t-test, non-parametric Kruskal-Wallis test, and Pearson correlation, respectively. RESULTS Eighty PBT patients (58% female; M age=50.83, range=20-86) agreed to participate. Average patient FCR7 was 17.15 (SD=8.93). The 60th percentile of patient FCR7 was 17.00 and the 90th percentile was 31.90. There was no difference in FCR between low and high tumor grades (p = 0.50). There was no difference in FCR between left, right, and bilateral tumor hemispheres (p = 0.67). Similarly, time since diagnosis was unrelated to FCR (p = 0.54). CONCLUSION Inconsistent with findings in non-CNS cancer, FCR was not related to disease-related variables in PBT patients. Given the certainty of tumor recurrence in this population, FCR may be a more robust experience in PBT patients, such that disease characteristics do not buffer this cancer-specific distress. These results emphasize the need for inclusion of PBT in psycho-oncology research, particularly investigations of psychotherapy targeting FCR across disease-related variables such as tumor grade, tumor hemisphere, and time since diagnosis. The lack of generalizability of non-CNS cancer findings and the further exclusion of this population will prevent efforts to provide patient-centered end-of-life care within neuro-oncology.