tbuckley/cabot-search huggingface dataset:
P05.30 Intracranial meningiomas: a systematic analysis of prognostic factors for recurrence in a large surgical series
Authors: F Pessina, P Navarria, G Carta, E Clerici, M Conti Nibali, R Soffietti, R Rudà, M Scorsetti, L Bello
Journal: Neuro-Oncology (2018)

Meningioma is the most common primary intracranial tumor, accounting for approximately 15–30% of primary brain tumors. About 80% are benign slow-growing meningiomas (grade I), 20% are atypical grade II meningiomas, and less than 5% are anaplastic, aggressive, grade III meningiomas. Surgical resection is the first choice of treatment. The amount of surgical resection represents a crucial factor influencing the risk of recurrence. The role of adjuvant radiotherapy (RT) is still unclear and evidence is lacking. The aim of the present study was to evaluate prognostic factors influencing the local recurrence rate in a large series of grade I-II meningiomas. Newly diagnosed WHO grade I-II intracranial meningiomas underwent surgery, were included. Three different groups were defined in relation to tumor location: convexity, parasagittal, and skull base. The extent of surgical resection (EOR) was defined according to Simpson criteria, and were dichotomized as gross total resection (GTR) and subtotal resection (STR). Adjuvant RT was considered in case of STR. Clinical outcome was evaluated by neurological examination and brain MRI performed every 6 months for the first year and yearly thereafter. The 30-days postoperative morbidity and mortality were recorded. From January 2000 to December 2015, 296 patients were analyzed. The majority were female (65.9%), with a KPS ≥80(94.6%), grade I meningioma(79.4%), and symptoms at diagnosis(91.5%). STR was performed in 58%, followed by adjuvant RT in 10%. Improvement or stability of neurological status was obtained in 90.4% of patients. The median follow-up time was 79 months (range 24–214 months). Local recurrence occurred in 87 (29.4%) patients at a median time of 56 months (range 6–214 months). No patients who underwent surgery plus adjuvant RT had local relapse. The median PFS was172 months(95%CI 168–188 months), and the 2,5,10-year PFS were 91.1%(±1.7%), 80.7%(±2.5%) and 67.2%(±3.6%), respectively. On univariate and multivariate analysis factors identified as significantly impacting PFS were the meningioma grade, the EOR, and adjuvant RT in case of STR, regardless of meningioma grade. Overall, our findings suggest that recurrence rates are influenced by WHO meningiomas grade, the extent of surgical resection, and the employ of adjuvant RT in not completely resected meningioma, regardless of tumor grade.
Abstract 11176: SGLT-2-inhibition With Dapagliflozin Reduces Tissue Sodium Content
Authors: Roland Schmieder, Christian Ott, Peter Linz, Agnes Jumar, Stefanie Friedrich, Jens Titze, Matthias Hammon, Michael Uder, Iris Kistner
Journal: Circulation (2016)

Introduction: Sodium tissue content by 23 Na magnetic resonance imaging (Na-MRI) has been validated in experimental and human studies. SGLT-2 inhibition blocks the reabsorption of glucose and, in parallel, of sodium in the proximal tubular cells in a 1:1 fashion. We hypothesized that SGLT-2 inhibition in patients with type 2 diabetes leads to decreased tissue sodium content due to its pharmacological action. Methods: In a prospective, double blind, placebo controlled, cross-over trial 59 patients (61±7.6 years) with type 2 diabetes were randomized to dapagliflozin 10 mg o.d. and placebo for 6 weeks each. In addition to metabolic parameters and ambulatory blood pressure (BP) we analyzed the sodium content in the skin and muscles of the lower leg by the Na-MRI at baseline, after the first and second treatment phase of 6 weeks. Results: Compared to baseline 6 weeks treatment with the SGLT-2 inhibitor dapagliflozin decreased fasting (132±28 vs. 114±19mg/dl, p&lt;0.001), postprandial blood glucose (178±66 mg/dl vs. 153±46mg/dl, p&lt;0.001), body weight (87.6 vs. 86.6 kg, p&lt;0.001) and systolic (129±12 vs. 126±11, p=0.010) and diastolic (77.4±9 vs. 75.6±8 mmHg, p=0.024) 24-hour ambulatory BP. Tissue sodium content in the skin was reduced after 6 weeks treatment with dapagliflozin compared to baseline (24.1±6.6 vs.22.7±6.4 mmol/L; p=0.013). No significant reduction of tissue sodium content was observed in the muscle (M. triceps surae: 20.5±3.5 vs. 20.4± 3.7 mmol/L, p=0.801). No clear significant difference in tissue water content of muscle and skin was observed after 6 weeks of treatment with dapagliflozin, compared to baseline. Conclusions: SGLT-2 inhibition with dapagliflozin resulted in a significant decrease in sodium tissue content of the skin after 6 weeks. This observation point to a decrease of total sodium content in patients with type 2 diabetes known to be salt sensitive and prone to cardiovascular complications, that might be mitigated by SGLT-2 inhibition.The Study was supported by AstraZeneca.
Eosinophils increase airway sensory nerve density in mice and in human asthma
Authors: Matthew G. Drake, Gregory D. Scott, Emily D. Blum, Katherine M. Lebold, Zhenying Nie, James J. Lee, Allison D. Fryer, Richard W. Costello, David B. Jacoby
Journal: Science Translational Medicine (2018)

In asthma, airway nerve dysfunction leads to excessive bronchoconstriction and cough. It is well established that eosinophils alter nerve function and that airway eosinophilia is present in 50 to 60% of asthmatics. However, the effects of eosinophils on airway nerve structure have not been established. We tested whether eosinophils alter airway nerve structure and measured the physiological consequences of those changes. Our results in humans with and without eosinophilic asthma showed that airway innervation and substance P expression were increased in moderate persistent asthmatics compared to mild intermittent asthmatics and healthy subjects. Increased innervation was associated with a lack of bronchodilator responsiveness and increased irritant sensitivity. In a mouse model of eosinophilic airway inflammation, the increase in nerve density and airway hyperresponsiveness were mediated by eosinophils. Our results implicate airway nerve remodeling as a key mechanism for increased irritant sensitivity and exaggerated airway responsiveness in eosinophilic asthma.
P01.150 hypermutations in glioblastoma are associated with increased response to immunotherapy
Authors: E Anghileri, J Zhao, M Eoli, T Langella, B Pollo, S Indraccolo, S Pellegatta, A Iavarone, R Rabadan, G Finocchiaro
Journal: Neuro-Oncology (2018)

Glioblastomas (GBM) exhibit a hyper mutable phenotype only in a restricted subset harboring somatic or germinal mutations of mismatch-repair (MMR) genes. Immunotherapy (IT), including dendritic cell (DC) vaccination and inhibition of immune checkpoints, are actively pursued in GBM patients. We report on two recurrent GBM (rGBM) treated with DC or the anti-PD1 nivolumab. Whole exome sequencing (WES) was performed on total DNA obtained from peripheral blood and FFPE samples. MMR gene expression evaluated by immunohistochemistry (IHC). Patient MA had first surgery for a grade II astrocytoma when 26. Six years later she had a second surgery diagnosed as methylated MGMT, IDH1-mutated GBM. After six years rGBM was removed and IT with DC loaded with whole tumor lysate was started. 25 months later, MA died for further rGBM. Patient FR, with family history of gastric and uterine cancers in first-degree relatives, was diagnosed with GBM when 33 and treated as standard of care. Sixteen months later, she had second surgery for rGBM, and was treated with nivolumab, still ongoing after 42 months, with no sign of progression. During the treatment she had surgery for a colon adenoma with high-grade dysplasia. We performed WES on peripheral blood and on rGBM tissue of these patients. In MA 6,900 somatic mutations were detected on rGBM, including two mutations causing sequence changes in the MMR genes MLH3 (T942I) and PMS2 (T485K), described as benign on Polyphen-2. Mutation T942I was reported as germline in a patient with endometrial cancer that had loss of heterozygosity of the other allele on 14q23, a region of LOH also in gliomas. In FR the first and second GBM shared 12,431 sequence changes, 113 specific of the first GBM and 1,683 of the second, including missense mutations on MSH2 (R359S) and MSH6 (G39E and Q1155R) genes. Loss of MSH6 was confirmed by IHC and Polyphen-2 prediction indicated the mutation MSH6 Q1155R, but not the other two, as pathogenic. We identified a hypermutator phenotype associated to somatic and germinal mutations of MMR genes in one secondary and one primary GBM, respectively. These patients showed clinical response to IT with prolonged survival. These observations support the idea that in gliomas an increased mutational burden is associated to response to IT and encourage the identification of markers to identify these responsive patients.
Abstract 17842: Blood Pressure Control That Reduces Mortality and Cardiovascular Events From 2000 to 2014 for Patients in the Veterans Administration Healthcare System
Authors: Ross D Fletcher, Richard L Amdur, Raya Kheirbek, Ali Ahmed, Farrokh Alemi, David Maron, Charles Faselis, Ronald E Jones, Vasilios Papademetriou
Journal: Circulation (2016)

Background: The Veterans Affairs (VA) Electronic Health Record (EHR) contains blood pressure (BP) measurements over many years and can examine what level of BP control affects mortality and adverse...
Correlates of response to anti-PD-1 immune checkpoint blockade (ICB) in mismatch repair proficient (MMRp) and deficient (MMRd) patients (pts) with metastatic castration resistant prostate cancer (mCRPC).
Authors: Minke Smits, Harm Westdorp, Mark A.J. Gorris, Thomas van Ee, Tjitske Duiveman-de Boer, Kiek Verrijp, Jennifer C Jones, Inge M. van Oort, Michiel Sedelaar, Antoine Van Der Heijden, Alfred Witjes, Astrid Eijkelenboom, Marjolijn Ligtenberg, Katrien Grunberg, Johannes C Textor, Jack A. Schalken, James L. Gulley, Winald R. Gerritsen, Jolanda De Vries, Niven Mehra
Journal: Journal of Clinical Oncology (2018)

5036 Background: Predictive biomarkers are needed to improve the proportion of pts with mCRPC that may benefit from anti-PD-1/PD-L1 ICB. A comprehensive characterization of both genomic alterations as the immunological landscape during ICB may prove fundamental. Methods: We investigated correlates of response and progression in pts with mCRPC treated with anti-PD-1 ICB. Pts were selected by PD-L1 > 1% and/or MMRd. Optional pre-treatment and post-progression biopsies were collected for whole-genome sequencing and multiplex IHC. 8-color flow cytometry was performed on frozen mononuclear cells at baseline and on treatment (Tx) using 6 immune-panels. MMR status was evaluated in exosome subsets using nested amplification PCR. Response was evaluated per PCWG3 criteria and Tx was continued until radiological progression with lack of clinical benefit or due to ICB-toxicity. Results: At present 13 CRPC pts started Tx with median follow-up of 5.3 months. 10/13 pts had PD-L1 expression > 1%, 6/13 pts were MMRd. Tx is ongoing in 4/13 pts. In evaluable pts with MMRp and MMRd, range of mutational burden (TMB) was 2-8 and 25-74 mutations per megabase, respectively (resp); objective responses were only seen in MMRd pts; PSA > 50% declines were seen in 75% and 13%, resp; median progression-free survival was 3.7 vs 7.8 months, resp (p = 0.007). No relationship was seen between PD-L1, TMB and CD3+tumour infiltrating lymphocytes (TILs); TILs were increased in MMRd vs MMRp pts (p = 0.06). During Tx, significant changes were seen in circulating T cell populations, including CD4+PD-1+, CD4+CD28+PD-1+, CD8+PD-1+, CD4+ICOS+and CD8+ICOS+ subsets, with on Tx CD4+PD-1+ cells differing between responders and non-responders (p = 0.03). Additional results on genomic and immune correlates will be presented in more detail. Conclusions: Deep and durable responses to anti-PD-1 ICB were seen in pts with mCRPC, particular those with MMRd. Circulating T cell subsets are associated with response to ICB. An integrative biomarker suite to predict for responsive mCRPC pts to anti-PD-1 ICB is key and these and other correlates should be further investigated.
Incidental meningiomas: Validation of a novel scoring system to stratify risk for progression.
Authors: David Olayinka Kamson, Carlen Yuen, Laura Castillo, Samuel-Adams Tideman, Andrew Wilmington, Matthew Walker, Ryan Thomas Merrell
Journal: Journal of Clinical Oncology (2018)

e14024 Background: Meningiomas are common incidental findings on brain imaging. Although most are indolent, some exhibit rapid growth posing a clinical dilemma for monitoring growth in the absence of robust predictive data. Recently proposed Asan Intracranial Meningioma Scoring System (AIMSS) [1] attempts to stratify growth risk based on imaging features. It scores tumor diameter (i) ( < 25mm, 25mm-39mm, or ≥40mm as 0, 3 or 6 respectively), absence vs. presence of hypointense T2 signal (ii), peritumoral edema (iii) and calcification (iv) (0 vs. 2, 0 vs. 1, and 0 vs. 2, respectively). Scores 0-2 suggest low risk vs. scores 3-11 represent intermediate-to-high risk for rapid tumor growth. The current study’s aim is to assess the relationship between AIMSS and meningioma growth rate (GR), and validate it in a North-American population using the RANO progression free survival (PFS) criteria[2]. Methods: We retrospectively enrolled 92 patients with incidental meningiomas (mean±SD age 62±14y; 73F) with at least 2 contrast-enhanced MRIs acquired in a treatment-naïve state ≥0.5y apart (mean: 4.3 MRIs/patient; mean follow-up time 4.5±3.8y). The largest 2D diameters were measured manually and the AIMSS was calculated using the 1st scan (81 patients had data for all subscores). Average GR (mm2/mo) was estimated and PFS was established as per the RANO criteria, defining progression as ≥25% increase in size. Results: The total AIMSS score had a positive correlation with GR (R = 0.37, p = 0.06). Multivariate analysis of the ASAN subscores showed diameter and edema to be independent factors of GR (B = 17.0 p = 0.005, and B = 162.1, p = 0.07, respectively). Those stratified as low risk (AIMSS 0-2, n = 31) had a mean PFS of 81.4 months vs. 50.4 months in the mid-to-high risk (3-11, n = 50) group (log-rank p < 0.05). Cox-regression analysis of the subscores showed absnce of calcification and presence of edema to be independent predictors of shorter PFS (B 1.53 and 7.40, p = 0.02 and 0.0007, respectively). Conclusions: The AIMSS is a reliable and readily available tool to predict PFS in incidental meningiomas. [1] Lee, EJ, et al. Journal of neurosurgery 127.5 (2017): 971-980. [2] Wen, PY, et al. Journal of clinical oncology 28.11 (2010): 1963-1972.
ESOPEC: A prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy to neoadjuvant chemoradiation in patients with adenocarcinoma of the esophagus (NCT02509286).
Authors: Jens Hoeppner, Florian Lordick, Thomas B. Brunner, Torben Glatz, Claudia Schmoor, Dietmar Lorenz, Christian Ell, Joerg Ruediger Siewert, Ulrich Theodor Hopt
Journal: Journal of Clinical Oncology (2016)

TPS4131 Background: Large randomized controlled trials (RCT) comparing neoadjuvant chemoradiation (neoCRT) (CROSS trial) or perioperative chemotherapy (periCTX) (MAGIC/FFCD 9703 trials) plus surgery with surgery alone have been carried out in non-metastasized esophageal adenocarcinoma. These RCT showed significant survival benefits for combined modality treatment. As prospective head-to-head comparisons of neoCRT versus periCTX applying contemporary treatment regimens are lacking, the present trial was started to define a future standard of care. Methods: This investigator-initiated multicenter prospective two-arm RCT is comparing the efficacy of neoCRT (CROSS regimen) followed by surgery versus periCTX and surgery (FLOT regimen) for the treatment of localized esophageal and junctional adenocarcinoma. Eligibility for the trial is given in cT1 cN+ cM0 and cT2-4a cNx cM0 tumors. The trial will include 438 participants who are 1:1 randomized to one of the two study arms and stratified by N-stage and study site. Patients enrolled in the neoCRT study arm will receive preoperative radiation therapy (41.4Gy in 23 fractions of 1,8Gy: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31) and concurrent carboplatin (2mg/ml/min) and paclitaxel (50mg/m2) on day 1, 8, 15, 22, 29. Patients in the periCTX study arm will receive 4 preoperative cycles and 4 postoperative cycles of 5-FU 2600 mg/m² (24h), d1 leucovorin 200 mg/m², d1 oxaliplatin 85 mg/m², d1 docetaxel 50mg/m2, d1 every two weeks (q2w). The primary endpoint of the trial is overall survival. Secondary endpoints are progression-free survival, recurrence-free survival, site of failure, postoperative morbidity and mortality, duration of hospitalization and quality of life. Biological substudies on biomarkers of esophageal adenocarcinoma are included. Current status: The trial was approved by the competent ethics committee and the German Federal Institute for Drugs and Medicine Devices. Patient recruitment has begun in Feburary 2016. Overall 18 German sites will commence recruitment in 2016. Clinical trial information: NCT02509286.
Treatment at safety-net hospital to influence the rate of pathologic complete response after neoadjuvant chemotherapy.
Authors: Rachel Warren, Lisa Winton, Caitlin Hester, Virginia Bailey, Xiaohan Xu, Hong Zhu, James F. Huth, Deborah Farr, Rachel D. Wooldridge, A. Marilyn Leitch
Journal: Journal of Clinical Oncology (2018)

e18678 Background: The use of neoadjuvant chemotherapy (NAC) has allowed pathologic complete response (pCR) to become a predictive measure for breast cancer recurrence-free survival and overall survival. The purpose of this study was to analyze if disparities exist in treatment outcomes of breast cancer patients treated with NAC at a safety-net hospital when compared to a private hospital (PH). Methods: 819 women who received NAC for newly diagnosed breast cancer from 2010 to 2017 were identified from institutional tumor registries at a private hospital and a safety-net hospital. Patients at both hospitals are managed by medical school faculty. Demographic, clinicopathologic features, and tumor subtypes were compared using univariate and multivariate analysis. Results: pCR was achieved in 239 women overall (29%). Patients at a safety-net hospital were less likely to have pCR when compared to private hospital (24 vs 32 %, p = .01). There are significantly more Hispanic patients at safety-net hospital compared to private hospital (52 vs 19% (PH), p < 0.01). Patients in safety-net hospital were more likely to be uninsured (54 vs 8 % (PH) p < .01), and to have stage 3 disease and grade 3 tumors (43 vs 34 % (PH), p = .03; 67 vs 49% (PH), p = < .01). Hormone positive and HER2 + tumor subtypes had no significant difference in rates of pCR when comparing hospitals. However, rate of pCR was lower in triple negative (TNBC) tumor subtype at safety-net hospital (24 vs 40% (PH), p = .007). Hispanic patient had the lowest pCR for TNBC: 27% vs 38% for Blacks and 40% for Whites. Conclusions: Similar pCR rates were achieved between the two hospital environments with all tumor subtypes, with the exception of the triple negative. There was a lower pCR for TNBC in the Hispanic population, constitutes the majority of the safety-net hospital. This may account for the lower rate of pCR at the safety-net hospital. Focused investigation for underlying causes of lower TNBC pCR at our safety-net hospital, such as treatment delay and compliance, may lead to improved outcomes.
Does the long noncoding RNA HULC act as a sponge or as a downstream target for miR-186 in hepatocellular carcinoma?
Authors: D.A. Habashy, K.A. Hosny, G. Esmat, A.I. Abdelaziz
Journal: Annals of Oncology (2018)

Background: The long noncoding RNA (lncRNA) highly up-regulated in liver cancer (HULC) was identified as an oncogenic noncoding RNA that contributed to hepatocellular carcinoma (HCC) progression. Generally, lncRNAs have been shown to act as a sponge for microRNAs, hindering them from performing their actions. Recent study has shown that HULC sequester miR-186, meanwhile its expression was repressed by it. Our bioinformatics revealed that miR-186 targets HULC and the insulin-like growth factor 2-mRNA-binding protein-1 (IGF2BP1) which was shown to degrade HULC and to stabilize IGF1R in HCC. Therefore, we aimed at investigating the impact of miR-186 on IGF2BP1 and hence on HULC in liver cancer in attempt to unravel the underlying mechanism by which HULC enhances hepatocarcinogenesis. Methods: A total of 18 HCC and 13 healthy liver biopsies were used. Screening and correlation analysis were done. miR-186 expression was forced in Huh-7 cell lines. miR-186, HULC and IGF2BP1 were quantified by qRT-PCR. Binding confirmation and functional analysis experiments were performed. Results: The expression level of HULC was positively correlated with IGF2BP1 expression in HCC tissues, where both were highly elevated compared to healthy controls. However, miR-186 was significantly downregulated in HCC tissues and negatively correlated with IGF2BP1 expression. Furthermore, miR-186 had shown considerable tumor suppressor activity in HCC. Upon forcing miR-186 expression in HCC cell lines, IGF2BP1 expression was repressed, while in contrast to what was previously mentioned by Wang Y et.al, HULC expression showed no change. In addition, miR-186 showed direct binding on IGF2BP1, meanwhile it was bound to HULC on one of its two predicted binding sites. Thus, the binding of miR-186 to HULC without altering its expression may indicate that HULC act as a sponge for miR-186, thereby relieving IGF2BP1 and promoting hepatocarcinogenesis. Conclusions: HULC mediates its oncogenic action through sequestering the tumor suppressor miR-186, relieving its inhibitory effect on IGF2BP1 and thus promoting HCC progression. Finally, we suggest a novel lncRNA-microRNA-mRNA interaction to act as a novel target for halting HCC progression. Legal entity responsible for the study: German University in Cairo. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.