tbuckley/cabot-search huggingface dataset:
P01.132 A case of adult anaplastic ganglioglioma of the frontal lobe
Authors: E Fotopoulou, G Soulimioti, A Theodoridou, S Tzorakakis, I Maravelis, K Girlemis, E Athanasiou
Journal: Neuro-Oncology (2018)

Anaplastic gangliogliomas represent less than 1% of all CNS tumors. It affects mainly children and young adults. Diagnosis according to ΜRI imaging is difficult due to a wide range of degree in solid and cystic components, contrast uptake, and calcification patterns. Pathology review of the surgical specimen is often challenging. There is limited data regarding optimum treatment and outcome. We report the case of a 21-year-old female patient who was diagnosed with anaplastic ganglioglioma grade III to the left frontal lobe. She presented initially with firming type headache gradually deteriorating Treatment approach was gross total tumor resection followed by 3D-conformal adjuvant radiotherapy. She was referred to our department June of 2012.Patient was ambulatory without focal neurologic deficits or neurocognitive abnormalities. Radiation therapy was completed on July of 2012 with total dose of 60Gy- 2Gy per fraction. She was under treatment with corticosteroids and anticonvulsants. Mild headache was the only symptom during the course of treatment. Patient had a significant improvement in presenting symptoms after radical treatment. She is under surveillance and a close follow-up of almost six years (April of 2018) with no sign of recurrence in the ΜRI setting and an excellent clinical performance. Our case is totally consistent with the limited documentation from the literature review that adjuvant radiotherapy after complete surgical excision prolongs survival.
Glycolytic enzymes lactate dehydrogenase A (LDHA) and phosphofructokinase P (PFKP) are good biomarkers of survival and potential therapeutic targets in cervical cancer
Authors: L.V. Bolaños, A.M. Espinoza, A. Alfaro, E.V. Barron, E. Juárez, J. Berumen Campos
Journal: Annals of Oncology (2018)

Background: Cervical Cancer (CC) is the fourth most common cancer in women worldwide. Potential biomarkers in cancer can be identified by considering the changes in tumoral glycolysis. In this work, we investigated whether the expression of some glycolytic enzymes is associated with the overall and disease-free survival of patients with CC. Methods: We analyzed the expression of 14 genes related with glycolysis (SLC2A1, ADPGK, ALDOA, EDARADD, ENO1, GAPDH, GPI, HK2, LDHA, PFKP, PGK1, PKM, TPI1P1, SLC9A1) in 67 CC, 10 high-grade cervical intraepithelial neoplasia (HG-CIN) and 17 healthy cervical epitheliums (HCE), as controls, with the Human Gene 1.0 ST Microarray (HG 1.0 ST). Validation of gene expression of LDHA and PFKP was performed by qRT-PCR and immunohistochemistry. The expression of LDHA and PFKP was correlated with 5-year survival of CC patients by the Kaplan-Meier method, and FIGO staging and the gene expression were included as covariates in a Cox proportional hazard model. Results: The amount of the mRNA transcribed from the 14 glycolytic genes was higher in CC tumors than in HG-CIN and HCE. Overexpression of genes TPI1P1, LDHA, PFKP, GAPDH, GPI, PGK1 was associated with poor survival, but only the overexpression of LDHA and PFKP genes was independent of the FIGO stage. The qRT-PCR assays confirmed that the overexpression of LDHA and PFKP were associated with poor overall survival (LDHA p= 0.004, PFKP p = 0.0043, Long-rang test) and disease-free survival (LDHA p = 0.001, PFKP p = 0.013, Long-rang test) in an independent fashion of the FIGO stage (LDHA p = 0.050, PFKP p = 0.029, Cox proportional-hazards regression). Interestingly, only the protein encoded by LDHA gene, analyzed by immunohistochemistry, showed a significant higher expression in recurrent than in non-recurrent tumors. Conclusions: Our results indicate that the expression of LDHA and PFKP at the mRNA and protein levels may be good biomarkers for overall and disease-free survival, independent of FIGO clinical stage, and could be potential therapeutic target for CC. Legal entity responsible for the study: Conacyt, Mexico. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
The efficacy of duvelisib monotherapy following disease progression on ofatumumab monotherapy in patients with relapsed/refractory CLL or SLL in the DUO crossover extension study.
Authors: Bryone J. Kuss, Matthew Steven Davids, Peter Hillmen, James H. Essell, Carol Moreno, Nicole Lamanna, Zsolt Nagy, Constantine Si Lun Tam, Stephan Stilgenbauer, Ulrich Jäger, Paolo Ghia, Julio Delgado, Ngocdiep T. Le, Brenda Jeglinski, Marco Montillo
Journal: Journal of Clinical Oncology (2018)

7533 Background: Duvelisib, an oral dual inhibitor of PI3K-δ,γ, is being developed for the treatment of hematologic malignancies, including relapsed/refractory (RR) CLL/SLL. In the Phase 3 DUO study (NCT02004522) duvelisib monotherapy demonstrated significant improvement compared to ofatumumab monotherapy (PFS 13.3 vs 9.9 mo. p < 0.0001; ORR 74% vs 45% p < 0.0001) with a manageable safety profile (Flinn, ASH 2017). Study IPI-145-12 (NCT02049515) is an open-label, optional, crossover extension study where pts with confirmed progressive disease (PD) on DUO were given the option to receive the opposite treatment. Herein we present data for the 89 pts who voluntarily rolled over following PD on ofatumumab on DUO and received duvelisib on Study IPI-145-12. Methods: Eligible pts were enrolled within 3 months of PD on the DUO study (excluding Richter’s transformation or prolymphocytic leukemia), and maintained adequate renal and hepatic function and an ECOG PS of 0-2. Duvelisib 25 mg BID was administered until PD, intolerance, death, or study withdrawal. Responses were determined by investigators using modified IWCLL/IWG criteria. Results: Median age was 68 yrs (range: 39-89), 63% were male, and 90% Caucasian. Nearly half (49%) had Rai Stage III/IV or Binet Stage C, and 23% had del(17p) and/or TP53 mutation. Median prior anticancer therapies was 3 (range: 2-8). Median exposure to duvelisib was 32 weeks on the extension study. The ORR for pts treated with duvelisib in the crossover was 73% (95% CI: 64, 82) (all PRs) compared to 28% (95% CI: 19, 37) (1% CR, 27% PR) when previously treated with ofatumumab in DUO. The median PFS for duvelisib was 15 mo. (95% CI: 10, 17) compared to 9 mo. (95% CI: 9, 11) for prior ofatumumab. Conclusions: In an extension study, duvelisib monotherapy achieved robust and durable responses in 89 RR CLL/SLL pts with PD following ofatumumab treatment in the DUO study (ORR: duvelisib 73%; prior ofatumumab 28%), with a longer PFS with duvelisib than prior ofatumumab (PFS: duvelisib 15 mo.; prior ofatumumab 9 mo.). These data further support duvelisib monotherapy as an effective oral treatment option for pts with RR CLL/SLL. Clinical trial information: NCT02049515.
Factors affecting the development of irinotecan-associated acute cholinergic syndrome.
Authors: Amrita Singh, Khilna Patel, Lillian Chou, Jiafeng Lin, Gulam Abbas Manji
Journal: Journal of Clinical Oncology (2018)

e14515 Background: Acute cholinergic syndrome is a well-established adverse effect of irinotecan. To date there have been no studies evaluating risk factors for irinotecan-associated acute cholinergic syndrome. This study was designed to evaluate the impact of treatment related factors on the incidence of irinotecan-associated acute cholinergic syndrome. Methods: Retrospective study of adult patients who received irinotecan at NewYork-Presbyterian, Columbia University Irving Medical Center from May 2014 to June 2017. Results: Eighty-four patients received a total of 945 irinotecan doses. Doses were divided into two groups based on the occurrence of acute cholinergic syndrome: no reaction (N = 903 doses) and reaction (N = 42 doses). Age, sex, oncologic diagnosis, total bilirubin ≥1.5 mg/dL, and UGT1A1 gene polymorphisms were comparable in both groups. In the no reaction group 37% of doses were administered as part of FOLFIRINOX regimen versus 69% of doses in the reaction group (p = 0.01). Median irinotecan dose was 150 mg/m2 (IQR 120-150) in the no reaction group versus 150 mg/m2 (IQR 150-175) in the reaction group (p < 0.001). Median irinotecan infusion time was 55 minutes (IQR 30-90) versus 90 minutes (IQR 30 to 90) in the no reaction and reaction groups, respectively (p = 0.04). There was no significant difference in irinotecan infusion rate (mg/m2/min). Atropine pre-medication was administered for 92% of irinotecan doses with more doses in the reaction group receiving 0.4 mg atropine versus the no reaction group (86% versus 55%; p = 0.001). Median irinotecan dose number was 8 (IQR 4-15) in the no reaction group versus 5 (IQR 3-8) in the reaction group (p = 0.001). In the no reaction group, 16% of irinotecan doses were administered to patients who previously developed acute cholinergic syndrome as compared to 48% of doses in the reaction group (p < 0.001). Conclusions: Our data show that chemotherapy regimen, irinotecan dose, irinotecan infusion time, atropine pre-medication dose, irinotecan dose number, and previous occurrence are factors which may impact the development of irinotecan-associated acute cholinergic syndrome.
Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel or eribulin in patients with metastatic breast cancer (MBC).
Authors: Jesus Del Santo Anampa Mesias, Maja H. Oktay, Xiaonan Xue, John Condeelis, Joseph A. Sparano
Journal: Journal of Clinical Oncology (2017)

TPS2611 Background: TMEM (Tumor Microenvironment of Metastasis) are microanatomic structures formed by a Mena-expressing tumor cell, Tie2-expressing macrophage, and endothelial cell in direct content, which serve as the primary portal for tumor cell intravasation into the circulation and subsequent metastasis. Paclitaxel (P) induces the formation of TMEM in the primary tumors of patients treated with neoadjuvant chemotherapy (NAC), and in the primary tumor and distant metastases in the PyMT/PDX models. Tumor cell intravasation is mediated by release of VEGF at TMEM sites from TMEM-associated Tie2 HI /VEGF HI macrophages upon binding of the Tie2 receptor to angiopoietin. The Tie2 inhibitor rebastinib (R) inhibits intravasation at TMEM sites, reduces circulating tumor cell (CTC) burden, prevents distant metastases, and improves survival in breast cancer animal models when added to either P or eribulin (E). We hypothesize that the addition of R to antitubulin therapy in patients with HER2-negative MBC will prevent hematogenous dissemination and distant metastasis by inhibiting TMEM function, reduce CTC burden; and improve clinical outcomes. Methods: Primary objective of this phase Ib study (NCT02824575) is to evaluate safety and tolerability of R in two dose levels (DL) (50mg or 100mg PO BID) combined with IV P 80mg/m2 (day 1, 8 and 15) or E 1.4mg/m2 (day1 and 8) for four 21-day cycles. Key eligibility includes histologically confirmed HER2 negative MBC, ≤ 2 non-taxane chemotherapy regimens for R plus P arm or ≥ 2 chemotherapy regimens (including a taxane) for E plus R arm, ≥2 endocrine therapies ( including CDK4/6 inhibitor) for ER positive patients, ECOG PS 0 or 1; and normal organ and marrow function. Exclusion criteria include significant ocular or cardiac disease. Pharmacodynamic biomarkers to be measured during cycle 1-3 include CTCs, angiopoietin 1/2 levels and Tie-2 expressing monocytes. Tissue biopsy after two treatment cycles in 6 patients will be performed to evaluate TMEM score and function. With two DL of rebastinib, and 3-6 patients at each DL, it is anticipated that 6-12 patients will be required. This trial has enrolled two patients assigned to P arm combined with R 50mg BID. Clinical trial information: NCT02824575.
Development and clinical validation of circulating tumor cell (CTC) biomarkers in clear cell renal cell carcinoma (ccRCC) for the OMNIVORE clinical trial.
Authors: Waddah Arafat, Joshua Desotelle, Tamara Rodems, Rana R. McKay, Jason Abel, Toni K. Choueiri, Joshua Michael Lang
Journal: Journal of Clinical Oncology (2017)

4579 Background: New therapeutic strategies and biomarkers of treatment resistance are needed for metastatic ccRCC patients (pts) progressing on Nivolumab (Nivo). The upcoming OMNIVORE phase II clinical trial will evaluate whether adding Ipilumimab improves rPFS for pts with SD or PD on Nivo alone. We report development and clinical validation of predictive CTC biomarkers that will be evaluated in the OMNIVORE trial. Methods: We tested blood samples from ccRCC pts collected on biomarker trials at Dana Farber and U. of Wisconsin. Carbonic Anhydrase (CA) IX was used to capture CTCs in the VERSA platform to compare protein and gene expression signatures of resistance to Nivo. HLA and PD-L1 expression on CTC was quantified with independent confirmation with multicolor flow cytometry (FC). Results: We identified CTCs in 26/27 pts using RCC-specific CA IX antibody. Staining with CAXII and PAX8 confirmed CTC were of renal origin. The range of captured CK+/CAXII+/CD45- CTCs was 3-279 (median 15) from 18 pts. Multicolor FC found 8/9 pts with triple positive events for renal specific markers CAIX/CAXII/PAX8 [0-14.9%, median 0.32]. PDL1 and HLA staining was validated in cell line and pts samples with high reproducibility. PDL1 was expressed in &lt; 10% of CTCs while HLA expression had high intra- and interpatient heterogeneity. Three pts had CTCs positive for both HLA and PDL1 that correlated with a high frequency of CTCs that were positive for 3 RCC markers (1.3, 5.1 and 14.9% of events) for an R² value of 0.92 (p &lt; 0.0001). In 3 pts with ongoing response to Nivo (9-13 moths) triple positive events were 0, 0.2 and 0.3% (median 0.25%) and absent expression of PDL1/HLA. In 3 pts with early progression on Nivo ( &lt; 5 mo), triple positive CTCs ranged 0.33-14.9% (median 5.05%) with CTCs from 2/3 pts positive for PDL1/HLA. Conclusions: We report the first identification of ccRCC CTCs using CAIX, CAXII and PAX8 as confirmatory markers. CTC frequency and PDL1/HLA expression is lower in Nivo responders versus pts with early progression. High but variable HLA expression suggests variant resistance mechanisms. The utility of theses predictive and pharmacodynamic biomarkers will be tested in the OMNIVORE trial.
LION-PAW: Lymphadenectomy in ovarian neoplasm-pleasure ability of women—Prospective substudy of the randomized multicenter LION study.
Authors: Annette Hasenburg, Jalid Sehouli, Boern Lampe, Alexander Reuss, Barbara Schmalfeldt, Antje Kristina Belau, Michaela Bossart, Sven Mahner, Peter Hillemanns, Karl-Ulrich Petry, Andreas Du Bois, Uwe Herwig, Felix Hilpert, Martina Gropp-Meier, Volker Hanf, Wolfgang Janni, Elfriede Greimel, Uwe A. G. Wagner, Philipp Harter
Journal: Journal of Clinical Oncology (2018)

5575 Background: There is limited information regarding the impact of radical surgery including pelvic and para-aortic lymphadenectomy (LNE) and subsequent chemotherapy on sexuality in patients (pts.) with advanced ovarian cancer (AOC). We addressed this question within the prospectively randomized LION trial, evaluating the role of LNE in AOC. Methods: The Sexual Activity Questionnaire (SAQ) was used to assess sexual function in terms of its subscales activity, pleasure, and discomfort. Additionally we added the "orgasm" subscale from the Female Sexual Function Index. The questionnaire was administered together with the EORTC QLQ-C30 questionnaire at baseline before surgery, after 6, 12 and 24 months. Primary endpoint was changes in sexual function. Results: 495 pts. received the questionnaires. 254 pts. responded at baseline (55 sexually active, 182 sexually inactive,17 data not available (na)), 55 at 6 months, 139 at 12 and 81 at 24 months (22 active, 56 inactive, 3 data na). Median age was 60.5 years (range 21.4 – 75.8 yrs.). Discomfort evaluated as dryness of the vagina and pain during sexual intercourse was significantly worse at 12 months compared to baseline (p < 0.001), however, the surgical variable LNE did not show any impact on this. In contrast, the orgasm subscale showed diverging results with a deterioration from baseline to 12 months in the LNE group, but slightly improving in the no-LNE group. This difference was significant (p = 0.02). None of the other subscales showed significant differences between arms at any time point. Conclusions: A significant difference in pts. with or without LNE after 12 months regarding the ability to get an orgasm was observed in sexually active patients with AOC. This domain should be addressed when sexually active pts. are informed about the potential sequelae of systematic LNE. However, the majority of pts. in this LION substudy were sexually inactive and furthermore the compliance to respond to the sexuality questionnaire was limited. Clinical trial information: NCT00712218.
Hospitalization trends and outcomes for adults with metastatic cancers in the United States: 2004-2013.
Authors: Oladimeji Akinboro, Odunayo Olorunfemi, Daniel Pomerantz, Stephen Jesmajian, Gbolahan Ogunbayo, Deola Saheed, Elizabeth Phillips
Journal: Journal of Clinical Oncology (2017)

e18111 Background: Metastatic cancer accounts for 90% of cancer deaths. However, the impact of metastatic cancer on hospitalization patterns and in-hospital mortality is unknown. We sought to examine trends in hospitalizations and mortality among adults with metastatic cancers in the United States. Methods: We obtained data from the National Inpatient Sample for hospitalized adults, aged ≥18 years, with metastatic cancer listed as a discharge diagnosis from 2004 to 2013. We estimated and trended the following: i) proportion of hospitalized adults with metastatic cancers; ii) leading causes of hospitalization for adults with metastatic cancer; and iii) in-hospital mortality among adults with metastatic cancer. Independent associations of in-hospital mortality with age, gender, race/ethnicity, payment source, and hospital type were examined with multivariable logistic regression. Survey weights were applied in estimating the population-based rates, odds ratios, and confidence intervals (CI). Results: 3.0% (95% CI 2.9-3.1%) and 3.2% (95% CI 3.0-3.3%) of hospitalized adults had metastatic cancers in 2004 and 2013, respectively ( P for trend 0.07). The leading causes of hospitalization from 2004 to 2013 were: maintenance chemotherapy/radiotherapy – 3.5% (95% CI 3.2-3.8%); pneumonia – 3.2% (95% CI 3.1-3.3%); complications of surgery, medical care, devices, and implants – 2.8% (95% CI 2.8-2.9%); fluid/electrolyte abnormalities – 2.4% (95% CI 2.4-2.5%); and heart failure/pulmonary circulation diseases – 2.2% (95% CI 2.1-2.2%). In-hospital mortality for patients with metastatic cancer declined from 10.3% (95% CI 9.9-10.7%) in 2004 to 8.1% (95% CI 7.8-8.3%) in 2013 ( P for trend &lt; 0.01). Higher odds of in-hospital mortality were consistently seen each year with increasing age, non-Hispanic blacks, self-payment, and admissions at hospitals other than urban teaching hospitals. Conclusions: The relative hospitalization rates for adults with metastatic cancer remain stable. Significant declines in in-hospital mortality for these patients are noted but disparities are seen for certain groups. The economic burden and policy implications of these findings for end-of-life care warrant further investigation.
Wnt-signaling pathway in the cancer stem cells of glioblastoma
Authors: I.S. Bryukhovetskiy, V. Shevchenko, Y. Khotimchenko
Journal: Annals of Oncology (2018)

Background: Glioblastoma multiforme (GBM) is an aggressive brain tumor. The median survival time is 14,5 months. GMB resistance to treatment is associated with cellular population of cancer stem cells (CSCs). Wnt-signaling pathway is recognized as a strategically important proliferation mechanism for all stem cells. This study compares the expression levels of Wnt-signaling pathway proteins in CD133+ and CD133- cells in the common pool of GBM. Methods: Research is conducted with CD133+ and CD133- cells of U87MG cell line of human glioblastoma. High-performance liquid chromatography-mass spectrometry was used for proteome analysis. Mass spectrometry data were processed with MaxQuant (version 1.6.1.0) and Perseus (version 1.6.1) software, Max Planck Institute of Biochemistry (Germany). Biological processes, molecular functions, cells locations and protein pathways were annotated with a help of PubMed, PANTHER, Gene Ontology, KEGG and STRING v10 databases. Results: The statistically reliable changes in expression of 8 proteins from Wnt-signaling pathway (CACYBP, CSNK2A2, CSNK2B, CTNNB1, CUL1, RAC2, RHOA, RUVBL1) were discovered in CD133+cells of glioblastoma as opposed to CD133- cells of this glioblastoma cell line. We registered higher expression levels of nine proteins that positively influence the activity of Wnt-cascade. The increase in the expression of the cadherin complex components with underlying upregulation of casein kinases stimulated β-catenin degradation. Yet due to enhanced focal adhesion an increase of the β-catenin production was discovered. This may be either a mechanism of inducing stemness in the gliomaspheres, or one of the ways to incorporate the embryonic mechanisms of pluripotency in the glioblastoma cells. Conclusions: Therefore, proteins of Wnt-signaling cascade are considered as a prospective target for regulating the activity of glioblastoma CSCs. Potentially, the pharmacological suppression of β-catenin would be able to disrupt the mechanisms of tumor cells interaction with extracellular matrix and local microenvironment. That can be an important step in the direction of prolonging the life of patients. Legal entity responsible for the study: Far Eastern Federal University of Russia. Funding: The study was funded by the Ministry of Education and Science of the Russia (grant no. 14.584.21.0027; ID: RFMEFI58417X0027. Disclosure: All authors have declared no conflicts of interest.
Abstract 12263: The Role of Glucagon-Like Peptide-1 in the Immediate Improvement of Endothelial-Protective HDL Functions After Roux-en-Y Gastric Bypass in Obese Patients
Authors: Elena Osto, Petia Doytcheva, Helena Buhmann, Marco Bueter, Sophie Colin, Lucia Rohrer, Ulf Landmesser, Bart Staels, Christian Matter, Thomas A Lutz, Thomas F Luscher
Journal: Circulation (2014)

Introduction: Roux-en-Y gastric bypass (RYGB) reduces body weight (BW) and cardiovascular (CV) mortality in morbidly obese patients (pts). We showed in rats that glucagon-like peptide-1 (GLP-1) contributes to improve endothelial vasorelaxation early after RYGB in a BW loss-independent manner. Hypothesis: Here, we investigated in rats and patients whether obesity-induced HDL dysfunction improves after RYGB by a GLP-1-dependent mechanism. Methods: Diet induced obese male Wistar rats undergoing RYGB received vehicle (RYv); sham-operated ad libitum fed rats received vehicle (ALv) or the GLP-1 analog liraglutide (AL-lira; 0.2 mg/kg BID). HDL was isolated after 8 days. In parallel, HDL was also isolated from 28 healthy subjects and 28 morbidly obese pts (BMI >40) before, 14 days and 12 weeks after RYGB. In endothelial cells stimulated with HDL, we assessed nitric oxide (NO) production by DAF-2 fluorescence and endothelial NO synthase (eNOS) protein dimerization. Moreover, we measured paraoxonase-1 (PON-1) antio...