tbuckley/cabot-search huggingface dataset:
P05.44 Single-cell transcriptomic analysis of microglia/macrophages in Glioblastoma
Authors: A Michelucci, A Golebiewska, Y Pires-Afonso, S K Poovathingal, A Oudin, R Balling, A Skupin, S P Niclou
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is characterized by prominent genetic and histopathological heterogeneity. A major contributing factor to GBM development and progression is its ability to evade the immune system. Neoplastic cells are known to release factors that recruit resident microglia, macrophages and other peripheral immune cells and transform them into tumour-supportive cells. It remains unclear how and when the tumour-promoting characteristics of the microglia/macrophage population (MM) are established and how they differ in different regions of the tumour, e.g. infiltrative areas versus tumour core. MM behaviour was analysed in established patient-derived orthotopic xenografts (PDOX) that represent different stages of tumour progression and recapitulate inter- and intra-tumour heterogeneity observed in patients. ‘Invasive’ tumours present an apparent normal brain vasculature while ‘angiogenic’ phenotypes are more circumscribed, display necrotic areas and microvascular proliferation. We applied multicolour flow cytometry combined with immunohistochemistry and single cell RNA-Seq using the DropSeq method to study MM characteristics. We found that MMs display different morphologies and activation states depending on the histopathological features of GBM, with a prominent accumulation in and around the tumour core. Taking advantage of high-throughput single-cell sequencing, we elucidated specific MM transcriptional profiles associated with invasive and angiogenic tumours, thus revealing high immune cell heterogeneity related to specific tumour compartments. Single cell-Seq allows for an unbiased, surface marker-free approach to decipher MM transcriptional signatures at the single-cell level and enabled the elucidation of MM subtypes correlating to temporal and spatial heterogeneity in GBM. These analyses provide a better understanding of pro- and anti-tumourigenic MM phenotypes which may pave the way for therapeutic exploitation.
A pilot, non-randomized evaluation of the safety of anakinra plus FOLFIRINOX in metastatic pancreatic ductal adenocarcinoma patients.
Authors: Andrew Whiteley, Carlos Becerra, David McCollum, Andrew Scott Paulson, Ajay Goel
Journal: Journal of Clinical Oncology (2016)

e15750 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with a dense fibroinflammatory stroma which has been shown to confer resistance to therapy. Data suggest IL-1 serves as a key driver for this inflammatory cascade, and, therefore, is a rational therapeutic target. We investigated the safety of anakinra, an IL-1 receptor antagonist, given concurrently with FOLFIRINOX in patients with metastatic pancreatic cancer. Methods: Patients self-administered anakinra 100mg subcutaneously every other day for 8 weeks beginning with day 1 of modified FOLFIRINOX given every 2 weeks. Patients continued on FOLIFIRINOX until disease progression or toxicity. The primary endpoint was safety, with secondary endpoints of progression free survival, overall survival and tumor response by CT or PET along with CA 19-9 measurements. Serial blood samples were collected for biomarker analysis. Results: Fifteen patients were treated on study, 12 of whom completed at least 3 cycles of FOLFIRINOX. Two patients withdrew after the first cycle of chemotherapy due to poor tolerability and the third patient had disease progression after 2 cycles with transition to hospice. All patients were ECOG 1 with median age 63yo (48-76) and median CA 19-9 of 7,068 U/mL (13-929,950). The most common adverse reactions were nausea/vomiting (73%), fatigue (67%) pain at the injection site (53%) and diarrhea (47%). Grade 3/4 toxicities included neutropenia (13%), diarrhea (13%) and neutropenic sepsis (7%). Toxicities during anakinra administration and subsequent cycles of FOLFIRINOX alone were similar. 9/11(82%) patients with an initially elevated CA 19-9 experienced a > 70% reduction of CA19-9 while on treatment. The ORR is not confirmed and will be updated at the meeting. The median PFS was 5 months. Median OS has not been reached at a median follow up of 15mo (3mo-25mo) with a 1-year OS of 75%. Conclusions: Anakinra in combination with FOLFIRINOX in patients with metastatic pancreatic cancer is safe and feasible, with adverse events consistent with that expected from FOLFIRINOX except for pain at the injection site. The clinical benefit is encouraging. Biomarker analysis will be presented at the meeting. Clinical trial information: NCT02021422.
Kidney cancer mobile application: Comparison of treatment choice of online and offline medical oncologists.
Authors: Ilya Tsimafeyeu, Andrey Vetluzhskiy
Journal: Journal of Clinical Oncology (2017)

e18240 Background: There are online tools aimed at helping professionals assess the risks of getting therapy after surgery . Our kidney cancer mobile application (KCMA) has been designed for oncologists to help them decide on the ideal course of treatment of metastatic renal cell carcinoma (mRCC). Here, we present results of comparison of treatment choice of oncologists used KCMA and oncologists made choice based on their knowledge. Methods: KCMA has been developed in 2016. It is strictly built on NCCN guidelines (ver. 3.2016). In our study 122 medical oncologists participated at the RCC meetings were involved. Three clinical cases were proposed. First clinical case described non-treated mRCC patient with favorable MSKCC prognosis (0 unfavorable factors) and clear-cell RCC. Second case described non-treated mRCC patient with poor prognosis (3 factors) and non-clear-cell RCC. Third case characterized patient treated with sunitinib in first-line with progression. 60 and 62 oncologists made treatment choice with (online) or without (offline) mobile application, respectively. Results: Comparison of choice is listed in Table. 100% oncologists used KCMA recommended sunitinib, pazopanib, bevacizumab+IFN or temsirolimus in first-line treatment. 6%, 6% and 12% of offline doctors chose sorafenib, everolimus and axitinib in first-line treatment of clear-cell mRCC. 98.3% of oncologists correctly used application for administration of second-line. 21 of 62 (34%) offline doctors recommended axitinib or everolimus as second-line and 66% prescribed bevacizumab+IFN (31%), sorafenib (15%), pazopanib (4%), temsirolimus (8%) or even continued sunitinib (8%) in patient with disease progression on sunitinib. Conclusions: Online tools based on guidelines could educate and support oncologists to score prognosis and to select best systemic therapy in daily practice. [Table: see text]
Racial disparities in ovarian cancer survival in New York state.
Authors: Sarah Madhu Temkin, Zhaomin Xu, Carla Francesca Justiniano, Adan Z Becerra, Christopher Thomas Aquina, Francis P. Boscoe, Maria J. Schymura, Fergal J. Fleming, Larissa K. F. Temple, Lori M. Minasian, Gary R. Morrow
Journal: Journal of Clinical Oncology (2017)

5579 Background: Disparities between black and white patients are well documented in gynecologic cancers but information on the contributions of social factors and medical comorbidities is sparse. We examined differences in outcomes amongst black and white women with ovarian cancer in New York State. Methods: Patients with incident ovarian cancer in the New York State Cancer Registry and the Statewide Planning and Research Cooperative System from 2006-2013 were included. Differences in social and demographic factors, comorbidities and tumor characteristics between black and white women were examined with bivariate analysis. Multivariable analyses were used to examine factors associated with specific treatments and survival. Results: Of 5969 patients, 87% were white and 13% black. Age, Hispanic ethnicity and median income were similar between groups. Black women were less likely to be married (27 vs 48%, p &lt; 0.01); and less likely to be privately insured (20 vs 50%, p &lt; 0.01). More black women had comorbidities by Charlson Comorbidity Index (CCI) (63 vs 51%, p &lt; 0.01). Black women were more likely to have Stage IV disease and non-serous histology (p &lt; 0.01). More black women were treated at academic medical centers (67 vs 50%, p &lt; 0.01). Marital status, insurance, CCI, stage, histology and treatment site correlated to the type of treatment received (p &lt; 0.01). Black women received different treatment and had higher odds of receiving no treatment 1.63 (1.24, 2.14); chemotherapy without surgery 1.26 (1.00, 1.59); lower odds of undergoing primary surgical management 0.71 (0.58, 0.86) or chemotherapy following surgery 0.79 (0.66, 0.96; and similar rates of neoadjuvant chemotherapy. The risk of 5 year mortality was 1.14 (1.02, 1.27) times higher for black women compared with whites. Marital status, CCI, stage and histology correlated with overall and disease specific survival among both black and white women (p &lt; 0.01). Conclusions: Multiple factors, including race, are associated with receipt of treatment and survival in ovarian cancer. Treatment for ovarian cancer was significantly different amongst black women than white in New York State. Understanding modifiable influences on racial disparities is imperative to reducing race based differences in outcomes.
A Chemical Time Machine for Mucosal Healing
Authors: Jonathan Braun
Journal: Cell Host & Microbe (2018)

Mucosal healing regenerates the mucosal complex upon injury. Mucosal repair requires sequential biologic steps paradoxically enabled or blocked by prostaglandin E2. In this issue of Cell Host & Microbe, Jain et al. (2018) find that the microbial metabolite, deoxycholate, regulates prostaglandin E2 and thus coordinates the steps of mucosal healing.
Bone density screening in postmenopausal women with early-stage breast cancer on aromatase inhibitors.
Authors: Jamie Stratton, Xin Hu, Pamela R. Soulos, Amy J. Davidoff, Lajos Pusztai, Cary Philip Gross, Sarah Schellhorn Mougalian
Journal: Journal of Clinical Oncology (2016)

6599 Background: In postmenopausal females with breast cancer on aromatase inhibitors (AIs), most expert panels advise baseline bone mineral density (BMD) testing with a dual-energy X-ray absorptiometry scan (DXA) repeated every 1 to 2 years. It is unclear how often these recommendations are followed. Methods: We performed a retrospective cohort study of women with stage I-III breast cancer initiating AI therapy from 1/1/08 – 12/31/10, with follow-up through 12/31/12, using the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. Selection criteria also included: surgical treatment of breast cancer within 1 year prior to starting AI; continuous AI use for ≥ 6 months; and no prior or new diagnosis of osteoporosis or recent use of a bisphosphonate. We used multivariate logistic regression to investigate associations between patient characteristics and receipt of baseline DXA (12 months prior up to 6 months after AI initiation). In patients who had a baseline DXA the time to follow-up DXA was assessed. Results: In a sample of 2,628 patients (median age 74), 51.0% of beneficiaries received a baseline DXA. Another 15.3% of women obtained their initial DXA 6 to 24 months after starting an AI. Older women were less likely to have a baseline DXA than younger women (p < .001). Demographic and clinical characteristics associated with absence of a baseline DXA were African American race (v. white; OR 0.71; 95% CI 0.50 – 1.00), having ≥ 3 comorbidities (v. 0 comorbidities; OR 0.56; 95% CI 0.43 – 0.73), and poor functional status (OR 0.54; 95% CI 0.39 – 0.74). Of patients who underwent a baseline DXA and continued their AI past two years (n = 935), 27.8% had a repeat DXA during 2 years of follow-up. Conclusions: Approximately half of postmenopausal females on AIs are receiving the recommended baseline BMD testing. Among patients who receive baseline screening, follow-up testing during the recommended time interval is uncommon.
Long-term oncologic outcomes of fertility-sparing surgery in young women with stage IB1 cervical cancer.
Authors: Jill Tseng, Yukio Sonoda, Ginger J. Gardner, Oliver Zivanovic, Nadeem Abu-Rustum, Mario M. Leitao
Journal: Journal of Clinical Oncology (2016)

e17010 Background: Our objective was to evaluate the associated factors and oncologic outcomes of women with stage IB1 cervical cancer treated with fertility-sparing surgery (FSS, defined as conization or trachelectomy) compared with non-fertility sparing surgery (non-FSS, defined as hysterectomy of any type). Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify women younger than age 45 diagnosed with FIGO stage IB1 squamous cell, adenocarcinoma, or adenosquamous cervical cancer between 1998 and 2012. Associated factors and outcomes of FSS vs non-FSS were analyzed. Appropriate univariate and multivariate statistical testing was performed. Results: Of 3001 women identified, 197 underwent FSS (conization 53%, trachelectomy 47%) and 2804 underwent non-FSS (simple hysterectomy 30%, modified radical/radical hysterectomy 64%, unspecified hysterectomy 6%). For FSS vs non-FSS, median age was 34 (range, 19-44) vs 37 (range, 17-44) (p = < .001), 71% vs 54% of women had tumor size < 2 cm (p < .001) and 64% vs 92% underwent regional lymphadenectomy (p < .001). Race, histology, and lymph node positivity were similar between the two groups. Those treated with FSS were more likely to be younger (OR 0.91, 95% CI 0.89-0.94) and less likely to be married (OR 0.67, 95% CI 0.48-0.94), have grade 3 disease (OR 0.52, 95% CI 0.30-0.88) or tumor size > 2 cm (OR 0.51, 95% CI 0.36-0.72) than those treated with non-FSS. Factors independently associated with disease-specific survival (DSS) included adenosquamous histology (HR 2.06, 95% CI 1.38-3.08), grade 3 disease (HR 2.84, 95% CI 1.26-6.39), tumor size > 2 cm (HR 2.15, 95% CI 1.54-3.00), and lymph node positivity (HR 2.16, 95% CI 1.54-3.02). Median follow-up was 79 months (range, 0-179), and 10-year DSS for FSS vs non-FSS was 92.7% vs 92.1% (SE ± 2.1, 0.6; p = .86). When stratified by tumor size, DSS for FSS vs non-FSS was as follows: tumor size < 2 cm, 95.0% vs 95.5% (n = 140, 1525; SE ± 2.2, 0.6; p = .75); and tumor size > 2 cm, 86.5% vs 87.7% (n = 52, 1235; SE ± 5.2, 1.1; p = .37). Conclusions: Fertility-sparing surgery does not appear to compromise DSS in young women with stage IB1 cervical cancer.
Immunological evaluation of peptides in pediatric medulloblastomas and diffuse intrinsic pontine glioma (DIPG).
Authors: Juan Pablo Marquez-Manriquez, Julio CESAR Villegas-Pineda, Alfredo TOLEDO Leyva, Lorena Montijo Fernandez, Geobanni TORRES Montano, Mario ALBERTO Perez-Astorga, Alejandro Camacho-Hernandez, Salvador Icedo-Zamora, Pedro ALEJANDRO Lucero-Diaz, Diana Ayon-Figueroa, jose Antonio Matute
Journal: Journal of Clinical Oncology (2018)

e14066 Background: Little is known about the immunogenicity of pediatric medulloblastomas and DIPG in order to rationally develop immunotherapies. We performed a systematic review of putative biologically and clinically relevant proteins in these tumors. We found 14 potential proteins using multivariate analysis studies and clinical studies. We predicted and prepared 40 peptides by immunological algorithms derived from those proteins and tested them in PBMC and sera of repository samples. Both tumors were immunogenic for most of the peptides by ELISPOT and antigen-specific ELISA. Methods: Medulloblastoma (n = 15) and DIPG (n = 15) repository PBMC samples were analyzed by granzyme, interferon-gamma ELISPOT and direct ELISA. Also, we analyzed by IHC the expression of 14 proteins and the immune infiltration of adaptive T cells such as CD8 and Th1 in paraffin blocks. Statistical analyses were done by prism graph pad. Results: Medulloblastoma and DIPG were immunogenic by granzyme ELISPOT against 27/40 predicted immunogenic peptides using immunological algorithms and 11/14 proteins. This includes but is not limited to H3.1, RCAS1, PRL-3, alpha-FAP, Beclin-1, FOXQ1, DLL4, MMP-7, Fascin-1, survivin and Ape-1. We found 85% of the medulloblastoma samples were positive for CD8 and 77% were positive for Th1 cells by IHC. Moreover, in DIPG 4 peptides from fascin-1 (p = 0.005), 5 peptides from Ape-1 (p = 0.0001), 2 peptides from RCAS1 (P = 0.001), 3 peptides from survivin (p = 0.003) and 2 peptides from H3.1 (p-0.001) had significant correlation with OS, CD8 immune infiltration and antigen specific antibodies IgG +IgM +IgA. Conclusions: Both medulloblastomas and DIPG are understudied pediatric brain tumors immunologically speaking. The importance of CD8, Th1 and antibodies in the prognosis of both tumors indicated that we could treat them clinically using a multipeptide immunotherapy in combination with the standard of care treatment to improve the clinical outcomes that are urgently needed in these pediatric brain tumors.
Validation of a new model for estimating glomerular filtration rate in patients with cancer.
Authors: Edward Williams, Reed Stratton Geisler, Ian Beh, Gianfilippo Bertelli, Richard Cathomas, Michael Joseph Dooley, Helena Margaret Earl, Martin Fehr, Daniel Giglio, Paul D Lewis, Patrick Mark, Joanita Ocen, Susan Gaye Poole, Scott Thomas Colville Shepherd, Amy Quinton, Jamie Weaver, Jeff D. White, Simon Tavaré, Duncan Ian Jodrell, Tobias Janowitz
Journal: Journal of Clinical Oncology (2018)

2565 Background: Estimation of glomerular filtration rate (GFR) is essential for carboplatin chemotherapy dosing. However, the most accurate method to estimate GFR in patients with cancer is unknown. Using data from 2471 patients with cancer, we developed a new model that improves estimation of GFR (eGFR) and carboplatin dose calculations when compared to BSA adjusted CKD-EPI, the next most accurate model for determination of eGFR in patients with cancer. [1] Here we present a multi-centre validation study of this work. Methods: Data on age, sex, height, weight, serum creatinine, and results for GFR from 51Cr-EDTA excretion measurements (51Cr-EDTA GFR) were obtained from Caucasian patients aged 18 years or older with histologically confirmed cancer diagnoses from one Swedish and six UK centres. We validated the new multivariate linear model for GFR using statistical analysis. 51Cr-EDTA GFR was compared with the estimated GFR (eGFR) from seven published models and the new model using root-mean-squared-error (RMSE) and median residuals. A comparison of carboplatin dosing accuracy based on an absolute percentage error more than 20% (APE > 20%) was undertaken. Results: Data from 3869 patients were obtained. In a pooled analysis, the new model improved the eGFR accuracy (RMSE 16.58ml/min (95% CI 16.21 to 16.95)) compared with all other published models. Body surface area (BSA) adjusted CKD-EPI remained the second most accurate model for eGFR (RMSE 17.58ml/min (95% CI 17.20 to17.99)). The new model was also the least biased model (Residual Median 0.33 (95% CI -9.56 to 10.69)). Importantly, the new model reduced the fraction of patients with a carboplatin dose APE > 20% (16.93% compared with 19.07% for the next best model). The new model was the most accurate model for patients with seminoma (n = 642), ovarian cancer (n = 553), and bladder cancer (n = 253). A further 2000-2500 patients will be included before completion of the study. Conclusions: In a very large multicentre data set of patients with cancer, we confirm that our new model improves eGFR and carboplatin dose calculations when compared with commonly used, published models. [1] Janowitz T and Williams EH et al., J Clin Oncol. 2017 Aug 20;35(24):2798-2805. doi: 10.1200/JCO.2017.72.7578
Phase II trial of dasatinib (DAS) in pediatric patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP).
Authors: Lia Gore, Pamela Kearns, Maria Lucia Lee, Carmino Antonio De Souza, Yves Bertrand, Nobuko Hijiya, Linda C. Stork, Nack-Gyun Chung, Rocio Cardenas-Cardos, Tapan Saikia, Franca Fagioli, Jong-Jin Seo, Judith Landman-Parker, Donna Lancaster, Andrew E. Place, Karen R. Rabin, Mariana Sacchi, Rene Swanink, Michel Zwaan
Journal: Journal of Clinical Oncology (2017)

10511 Background: Safe and effective treatment options for newly diagnosed (ND) or imatinib (IM) resistant/intolerant (R/I) pediatric CML pts are limited, and a large prospective study is needed. DAS has proven safety and efficacy in adults with ND or IM-R/I CML and is now being evaluated in a phase II trial of pediatric pts. Methods: CA180-226/NCT00777036 is an open-label nonrandomized prospective study of pts aged &lt;18 y in 3 cohorts: (1) CML-CP R/I to IM treated with DAS tablets 60 mg/m 2 QD, (2) IM-R/I CML-AP/BP or Ph+ ALL (enrollment closed early due to poor response), and (3) ND CML-CP treated with DAS tablets 60 mg/m 2 or DAS 72 mg/m 2 powder for oral suspension (PFOS) QD. Primary objectives were major cytogenetic response (MCyR) for CML-CP R/I to IM and complete cytogenetic response (CCyR) for ND CML-CP (MCyR &gt;30% and CCyR &gt;55% considered of clinical interest). Results: 113 pediatric CML-CP pts were treated. Cumulative rate of MCyR &gt;30% was reached as early as 3 mo (55%; [95% CI 36, 74]) for IM-R/I CML-CP. Cumulative rate of CCyR &gt;55% was reached as early as 6 mo (64% [95% CI 53, 74] for ND CML-CP; 61% [95% CI 46, 74] for pts on tablets and 70% [95% CI 51, 84] for pts on PFOS). Estimated PFS by 48 mo was &gt;75% for CML-CP R/I to IM and &gt;90% for ND CML-CP. One CML-CP pt R/I to IM died 1 y after stopping DAS from gastrointestinal bleeding. AEs were consistent with those observed in adults, except no DAS-related pleural/pericardial effusion or pulmonary arterial hypertension (PAH) were reported here. Conclusions: In the largest prospective trial of pediatric pts with CML-CP, target responses were met early and increased over time with DAS treatment. The efficacy and safety of DAS were consistent with previous reports in adults, except no cases of pleural/pericardial effusion or PAH were observed. These results suggest DAS is safe and highly effective in the first- or second-line treatment of pediatric CML-CP. Clinical trial information: NCT00777036. [Table: see text]
Individual variations in cardiovascular-disease-related protein levels are driven by genetics and gut microbiome
Authors: Daria V. Zhernakova, Trang H. Le, Alexander Kurilshikov, Biljana Atanasovska, Marc Jan Bonder, Serena Sanna, Annique Claringbould, Urmo Võsa, Patrick Deelen, Lude Franke, Rudolf A. de Boer, Folkert Kuipers, Mihai G. Netea, Marten H. Hofker, Cisca Wijmenga, Alexandra Zhernakova, Jingyuan Fu
Journal: Nature Genetics (2018)
High Expression of Legumain in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia Is Associated with Central Nervous System Involvement
Authors: Maria Jeppesen, Mette Levinsen, Nicolas Rapin, Line Groth-Pedersen, Kristina Aluzaite, Birgitte Klug Albertsen, Rehannah Borup, Thomas Leth Frandsen, Hans O Madsen, Hanne Vibeke Marquart, Steen Rosthøj, Bibi F. S. S. Scharff, Peder S. Wehner, Bo Porse, Kjeld Schmiegelow
Journal: Blood (2017)