tbuckley/cabot-search huggingface dataset:
Phase I study of pemetrexed and sorafenib in advanced solid tumors.
Authors: Andrew Stewart Poklepovic, Danielle A. Shafer, John D. Roberts, Charles E. Geyer, Paul Dent, Richard Moran, Mary Beth Tombes, Ellen Shrader, Kathryn Strickler, Wen Wan
Journal: Journal of Clinical Oncology (2015)

2586 Background: Pemetrexed (Pem) blocks thymidylate synthase, activates AMPK, and inactivates mTOR, increasing autophagy. Sorafenib (Sor) also stimulates autophagy through down-regulation of GRP78/BiP and ER stress signaling. Preclinical data demonstrated the combination of Pem and Sor caused synergistic cell death through a form of toxic autophagy. A phase I trial evaluating the combination of Pem and Sor in advanced solid tumors was initiated. Methods: An open-label, dose escalation study was conducted in patients (pts) with advanced malignancies. Standard 3+3 dose escalation design was used, with escalating doses of Pem (500 mg/m2-1000 mg/m2 IV) every 2 weeks with Sor (200-400 mg PO BID) continuously (cohort A). The initial 4-week period (Cycle 1) was used for dose-limiting toxicity (DLT) assessment. After treatment of 24 pts on cohort A, it was determined that continuous dosing of Sor with any dose of Pem was associated with unacceptable cumulative constitutional symptoms beyond Cycle 1. The protocol was amended to evaluate intermittent Sor (BID dosing days 1-5 of each Pem dose) (cohort B). Radiographic assessments were conducted every 8 weeks using RECIST 1.1. Results: Thirty-seven pts were enrolled and 36 treated, 24 on cohort A and 12 on cohort B. The MTD in cohort A was defined as Pem 500 mg/m2 and Sor 200 mg PO BID on a continuous schedule. Dose reductions for cumulative toxicity became necessary in the majority of patients in cohort A. Intermittent dosing was more tolerable, with 0/12 cohort B pts experiencing DLTs, treated at both 500 mg/m2 and 750 mg/m2 of Pem every 2 weeks with intermittent Sor at 200-400 mg. Of the 36 treated pts, best responses to date are 1 CR, 4 PR, 10 SD, 15 PD, 2 NE, and 4 TETE. Five pts with progressive breast cancer were identified as responders. One PR and the CR had durations of response approximating 1 year. All responding pts were heavily pretreated, with a median of 6 prior lines of therapy. Cutaneous, nodal, and visceral metastases were all observed to respond to treatment. Conclusions: The RP2D for the combination is Pem 750 mg/m2 IV every 2 weeks with Sor 400 mg PO BID days 1-5 with each dose of Pem. A phase II study in breast cancer is planned. Clinical trial information: NCT01450384. Clinical trial information: NCT01450384.
Epidemiology of Brain Death in Pediatric Intensive Care Units in the United States
Authors: Matthew P. Kirschen, Conall Francoeur, Marie Murphy, Danielle Traynor, Bingqing Zhang, Janell L. Mensinger, Rebecca Ichord, Alexis Topjian, Robert A. Berg, Akira Nishisaki, Wynne Morrison
Journal: JAMA Pediatrics (2019)

Guidelines for declaration of brain death in children were revised in 2011 by the Society of Critical Care Medicine, American Academy of Pediatrics, and Child Neurology Society. Despite widespread medical, legal, and ethical acceptance, ongoing controversies exist with regard to the concept of brain death and the procedures for its determination.To determine the epidemiology and clinical characteristics of pediatric patients declared brain dead in the United States.This study involved the abstraction of all patient deaths from the Virtual Pediatric Systems national multicenter database between January 1, 2012, and June 30, 2017. All patients who died in pediatric intensive care units (PICUs) were included.Patient demographics, preillness developmental status, severity of illness, cause of death, PICU medical and physical length of stay, and organ donation status, as well as comparison between patients who were declared brain dead vs those who sustained cardiovascular or cardiopulmonary death.Of the 15 344 patients who died, 3170 (20.7%) were declared brain dead; 1861 of these patients (58.7%) were male, and 1401 (44.2%) were between 2 and 12 years of age. There was a linear association between PICU size and number of patients declared brain dead per year, with an increase of 4.27 patients (95% CI, 3.46-5.08) per 1000-patient increase in discharges (P < .001). The median (interquartile range) of patients declared brain dead per year ranged from 1 (0-3) in smaller PICUs (defined as those with <500 discharges per year) to 10 (7-15) for larger PICUs (those with 2000-4000 discharges per year). The most common causative mechanisms of brain death were hypoxic-ischemic injury owing to cardiac arrest (1672 of 3170 [52.7%]), shock and/or respiratory arrest without cardiac arrest (399 of 3170 [12.6%]), and traumatic brain injury (634 of 3170 [20.0%]). Most patients declared brain dead (681 of 807 [84.4%]) did not have preexisting neurological dysfunction. Patients who were organ donors (1568 of 3144 [49.9%]) remained in the PICU longer after declaration of brain death compared with those who were not donors (median [interquartile range], 29 [6-41] hours vs 4 [1-8] hours; P < .001).Brain death occurred in one-fifth of PICU deaths. Most children declared brain dead had no preexisting neurological dysfunction and had an acute hypoxic-ischemic or traumatic brain injury. Brain death determinations are infrequent, even in large PICUs, emphasizing the importance of ongoing education for medical professionals and standardization of protocols to ensure diagnostic accuracy and consistency.
Neutrophil-lymphocite ratio in stage II-III testicular germ cell tumors before initiating chemotherapy: Correlation with survival.
Authors: Alvaro Pinto, Pilar Zamora, Andres Redondo, Beatriz Castelo, Beatriz Martinez, Enrique Espinosa
Journal: Journal of Clinical Oncology (2015)

e15564 Background: The role of neutrophil-lymphocite ratio (NLR) has been suggested in several malignancies, both as a prognostic factor but also as a predictive factor for response to some therapies. However, this parameter has not been studied yet in germ cell tumors. Methods: This retrospective review included every patient with stage II-III testicular germ cell tumors (both seminoma and non-seminoma) treated from 1997 to 2012. Patients were scheduled to receive at least three cycles of chemotherapy with BEP (bleomycin, etoposide, cisplatin). Data about progression-free survival (PFS) and overall survival (OS) were collected. Results: With a median follow up of 8.2 years, a total of 31 patients were included in the analysis. The characteristics of these patients are summarized in Table 1. Regarding NLR, patients with a pre-treatment NLR > 4 had a significantly worse PFS (median not reached, mean 58 vs 166 months, p = 0.037). NLR > 4 remianed significant in the multivariate analysis (HR 4.1, p = 0.041), together with prognostic group (HR 3.8, p = 0.049). There were few events for OS analysis to derive any conclusion. Conclusions: In our group of patients, pre-treatment NLR was correlated with PFS under standard chemotherapy with BEP. This correlation remained significant in the multivariate analysis. If validated prospectively, this finding could help us to better estimate the outcome of patients with advanced germ cell tumors. Patients’ characteristics. Histology Seminoma Non-seminoma 12 (38.7%) 19 (61.3%) IGCCCG Prognostic Group Good Intermediate Poor 12 (38.7%) 15 (48.4%) 4 (12.9%) ECOG Performance Status 0 1 2 24 (77.4%) 5 (16.1%) 2 (6.5%) NLR > 4 ≤ 4 12 (38.7%) 19 (61.3%)
Morphology-predicted, large-scale transition (LST) number in circulating tumor cells (CTC) as a biomarker of chromosomal instability (CIN) to assess early resistance to standard of care (SOC) drugs in mCRPC.
Authors: Howard I. Scher, Joseph Schonhoft, Melanie Hullings, Emily Carbone, Ethan Barnett, Ramsay Sutton, Adam Jendrisak, Mark Andrew Landers, Yipeng Wang, Ryan Dittamore
Journal: Journal of Clinical Oncology (2019)

225 Background: CIN is a mechanism by which tumor cells evolve, adapt, and evade therapeutic insults. We explored the relationship between the presence of LST as a biomarker of CIN through distinct CTC phenotypes, and sensitivity of tumors with the biomarker to standard of care (SOC) drugs. Methods: CTCs from 634 mCRPC blood samples were morphologically characterized by the Epic Sciences platform [Cytokeratin, CD45, DAPI, Androgen Receptor (AR) staining]. Training: 20 digital single cell image features were extracted from 608 CTC images from 26 patients (Pts) and single cell sequenced to determine the number of genomic LSTs. An image feature based algorithm to predict whether the number of LSTs was above the normal range defined by analysis of leukocytes was trained using this cohort (pLST) and parameters were locked. Analytical Validation (AV): the pLST algorithm was applied to a separate cohort of 570 CTCs from 54 Pts that were also sequenced to test single cell analytical performance. Clinical Validation: The pLST algorithm was then applied to CTC detected in 554 Pt samples obtained at prior to (BL, n= 324) and matched on-therapy (OnTx, n= 230) ~1 mo after starting SOC [including AR directed Tx and taxane]. A pre-defined patient scoring of &gt; 3 pLST+ CTC/mL was related to PSA kinetics, time on drug, and overall survival (OS). Results: pLST identifies CTCs with a high number of genomic LSTs. Pts with pLST+ at BL or OnTx had poor survival (see table): 12/13 pts receiving ARSi’s and 17/18 pts receiving taxanes who were pLST+ On-Tx required a change of Tx in a median of 1.3 mo (0.9 to 2.1) or died within 6 mo. Conclusions: CTC morphology can be used to predict CIN as defined by high LSTs. CTC pLST is a strong marker of resistance to SOC Tx in mCRPC pts and treatment failure requiring a change in Tx earlier than standard criteria.[Table: see text]
Abstract P081: Applying Precision Public Health Tools to Address Health Disparities Among African-Americans in Alachua County, Florida
Authors: Andrew S Cistola
Journal: Circulation (2019)

Precision Public Health (PPH) is the application of public health tools to population subsets with tailored interventions resulting in quantitative improvements in overall population health. The goal of PPH is to move from general impact to specific impact with interventions while maintaining a population focus in our outcomes. Precision Public Health at the University of Florida (PPH@UF) is a multi-disciplinary workgroup established in 2017 for the purpose of pursuing PPH practices. The primary product of the workgroup is the PPH@UF Libguide: a PPH focused tool designed to be a single place for public health workers to find necessary resources they need to understand their community and create effective interventions. Using the resources in this tool can help existing or new public health workers and researchers move from general population analysis towards precision in their interpretation of the data. This poster has two goals: 1) To show how the resources from the PPH@UF Libguide can be used to address health disparities among African-Americans in Alachua County and 2) To provide an example of how a PPH tool can increase the precision in population analysis aimed toward recommending interventions. The study utilized the PPH@UF Libguide to investigate a commonly known disparity between African-American and Caucasian diabetes deaths in Alachua County. By translating demographic data and investigating diabetes hospitalization, prevalence of diabetes by age over time, and population characteristics of relevant census tracts in Alachua County, we identified two specific census tracts that have significantly higher density of these individuals at risk. Using data from the Centers for Disease Control and presented by the Robert Wood Johnson Foundation, we were also able to observe that these tracts had very high rates of annual doctor visits but very low insurance rates and few locally available core preventative services. This indicates that interventions focusing on preventative care outside of doctor’s offices and connecting individuals to currently available community resources may be most helpful. The PPH@UF Libguide includes many different community partners who would be able to supply these types of resources and can serve not only as a research tool but also as a way to sort community health providers. Any intervention would include training individuals to access information on the PPH@UF Libguide for the needs of community members. By identifying a major community issue and providing a more precise geographic scope, supportive and integrated data, and a practical focus, the PPH@UF Libguide shows its ability to make efforts to address disparities among African-Americans in our community more effective. In conclusion, community health workers and advocates can utilize PPH tools similar to the PPH@UF Libguide to increase the impact and value of their community interventions.
Transcriptomic and protein expression analysis of helicase antigen (HAGE) in triple negative breast cancer (TNBC) as a novel prognostic and predictive biomarker.
Authors: Tarek M. A. Abdel-Fatah, Stephanie McArdle, Devika Agarwal, Paul M Moseley, Andrew R. Green, Graham Ball, A Graham Pockley, Ian O. Ellis, Robert Rees, Steve Y.T. Chan
Journal: Journal of Clinical Oncology (2015)

1093 Background: We recently provided evidences that HAGE is immunogenic. In current study, the expression of HAGE as a prognostic and predictive tool was assessed in 1079 TNBC patients. Methods: HAGE protein and mRNA expressions were investigated in two cohorts of BC who received adjuvant chemotherapy (CT) with 10 year median follow up: (1) early primary TNBC (EP TNBC; n = 520) and (2) the METABRIC TNBC (n = 317) cohorts, respectively. The relationship between HAGE protein and mRNA expressions and response to CT was explored in two TNBC cohorts in whom pathological complete response (pCR) was the endpoint: (3) the multicentre phase II clinical trial cohort (NCT00455533; n = 132) received doxorubicin/cyclophosphamide neoadjuvant-CT (Neo-ACT), followed by 1:1 randomisation to ixabepilone (n = 68) or paclitaxel (n = 64) and (4) a locally advanced primary TNBC cohort (LAP TNBC, n = 110) received anthracycline-based Neo-ACT (AC-Neo-ACT), respectively. To investigate HAGE interactome in TNBC, a non-linear, artificial neural network (ANN) modelling based, data mining approach was applied. Results: In CT naïve EP TNBC, high (+) HAGE protein expression had a higher risk of death compared to low (-) HAGE expression (HR (95% CI) = 1.4 (1.2-1.7, p = 0.0000004). While in EP TNBC patients who received adjuvant CT, HAGE mRNA+ level exhibited lower risk of death compared to HAGE mRNA- (HR (95% CI) = 0.56 (0.36-0.86), p = 0.0.008). In LAP TNBC received AC-Neo-ACT, pre CT HAGE+ expression was: linked to tumour infiltration lymphocytes (TILs, p < 0.001), found to be independent predictor for pCR [OR (95%CI) = 5.1 (1.2-22.4), p = 0.03] and significantly associated with prolonged survival (HR (95% CI) = 0.54 (0.41-0.85), p = 0.0.005). Following AC-Neo-ACT, loss of HAGE protein expression was found (p = 0.002) and patients with HAGE+ residual disease exhibited no TILs and had two fold increase in the risk of death (HR (95% CI) = 1.66 (1.10-2.52), p = 0.0.018) compared to HAGE- residual tumours. HAGE interactome included genes that involved in protein degradation and antigen presentation Conclusions: The expression of HAGE is a potential prognostic marker and a predictor of response to AC CT in TNBC.
Role of CD44 and Lewis Y antigen in chemo-resistance of locally advanced cervical squamous cell carcinoma (LACSCC) patients.
Authors: Julieta Leone, Juan Eduardo Perez, Maria Ester Dominguez, Julian Iturbe, Jose Pablo Leone, Maria Mac Donnell, Gabriel Grosman, Carlos Teodoro Vallejo, Bernardo Amadeo Leone, Ariel Osvaldo Zwenger
Journal: Journal of Clinical Oncology (2015)

e16590 Background: Several mechanisms are involved in the development of resistance to therapy in LACSCC. Studies have shown that CD44 and Lewis Y antigen (LeY) form a complex that is associated with chemoresistance, tumor invasion and metastasis. We assessed the role of CD44 and LeY in the outcome of LACSCC patients (pts) treated with different chemotherapy regimens. Methods: A total of 126 LACSCC pts FIGO stages IIB-IVA were selected from GOCS databases: 74 pts included in three different prospective phase II trials in the neoadjuvant setting (vinorelbine, docetaxel, ifosfamide-vinorelbine-cisplatin) and 52 pts treated with standard radio-chemotherapy based in cisplatin (RCBC). CD44 and LeY expressions were detected in pre-treated biopsy by immunohistochemistry. Clinical data at baseline, disease free survival (DFS) and overall survival (OS) were recorded. Univariate and multivariate Cox models were used to analyze variables of interest. Results: Median age was 45.6 years (range: 24.9 - 80.5). Sixty-three and 47 tumors were CD44+ and LeY+, respectively. Expansive growth tumors showed a higher grade (p= .0024), mitotic index (p= .0505), tumoral necrosis (p= .0191), LeY+ (p= .0034) and CD44+/LeY+ co-expression (p= .0334). CD44+ cells were present in 81.3% of tumors with viral cytopathic effect and in 91.3% of those with local recurrence (p= .0317). Advanced stage was associated with LeY+ (p= .0057) and CD44+/LeY+ (p= .081). In the univariate analysis, low pre-treatment hemoglobin level, expansive growth pattern, advanced FIGO stage and poor response to therapy were associated with shorter DFS and OS. Pts treated with RCBC had worse DFS and OS when their tumors expressed LeY antigen (p= .0083 and p= .0137, respectively). Pre-treatment hemoglobin level, FIGO stage and tumor response remained the most significant prognostic factors in Cox regression. Conclusions: In our cohort of LACSCC pts, the co-expression of CD44/LeY was not associated with worse outcome. However, in the subgroup of pts receiving RCBC, LeY expression was correlated with shorter DFS and OS.
Comparison of retroperitoneal and transperitoneal robotic partial nephrectomy by pentafecta perioperative and renal functional outcomes.
Authors: Chang Il Choi, Seong Il Seo
Journal: Journal of Clinical Oncology (2019)

602 Background: To compare and analyze surgical, oncological and functional outcomes of transperitoneal (TRPN) and retroperitoneal robotic partial nephrectomy (RRPN). Methods: Out of 566 consecutive patients who underwent RAPN by a single surgeon from December 2008 to July 2017, this study included 523 patients (TRPN 310, RRPN 213) who evaluated preoperative and 1-year postoperative estimated glomerular filtration rate (eGFR). Our primary endpoint was to compare the perioperative and postoperative outcomes of both approaches by the measure of Pentafecta (negative surgical margin, no 30-day complication, warm ischemic time (WIT) ≤25 minutes, return of estimated glomerular filtration rate (eGFR) to &gt; 90% from baseline and no upstaging of chronic kidney disease). Secondary endpoint was to find the factors associated with Pentafecta by multivariate regression analysis. Results: No significant difference was found in terms of age, BMI, laterality, history of hypertension or diabetes, ASA grade, tumor size and RENAL nephrometry score. These outcomes were lower in the RRPN group: operative time [median (IQR) 244 (202-295) vs. 273 (230-314); p &lt; 0.001], WIT [median (IQR) 19 (15-25) vs. 21 (16-27); p &lt; 0.008] and estimated blood loss (EBL) [median (IQR) 100 (60-200) vs. 150 (100-200); p &lt; 0.003]. Hospital stay, baseline eGFR, 1-year postoperative eGFR, the rate of Pentafecta achievement, recurrence and complications were not different. The rate of WIT ≤ 25 minutes was solely significantly different (TRPN 69.7% vs. RRPN 77.9%, p = 0.045) in the Pentafecta criteria. Multivariate analysis revealed tumor size [OR (95% CI) 0.641 (0.536-0.767), p &lt; 0.001) and hospital stays (OR 0.639, p &lt; 0.001) as predictive for lack of Pentafecta. Conclusions: RRPN demonstrated less operative time, WIT and EBL than TPRN. Pentafecta achievements were equivalent in both approaches. Tumor size and hospital stays were found as predictive factors of Pentafecta.
Abstract 3184: A secondary mutation inBRAFconfers resistance to RAF inhibition in aBRAFV600E-mutant brain tumor
Authors: Jiawan Wang, Zhan Yao, Philip Jonsson, Amy Allen, Alice Can Ran Qin, Sharmeen Uddin, Ira J. Dunkel, Mary Petriccione, Katia Manova, Sofia Haque, Marc Rosenblum, David J. Pisapia, Neal Rosen, Barry S. Taylor, Christine A. Pratilas
Journal: Cancer Research (2018)

Abstract BRAF V600E hyperactivates ERK and signals as an RAF inhibitor-sensitive monomer. While RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAF V600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAF L514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAF V600E L514V induces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. A novel class of RAF dimer inhibitors and an ERK inhibitor are effective against BRAF L514V-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence. Citation Format: Jiawan Wang, Zhan Yao, Philip Jonsson, Amy Allen, Alice Can Ran Qin, Sharmeen Uddin, Ira J. Dunkel, Mary Petriccione, Katia Manova, Sofia Haque, Marc Rosenblum, David J. Pisapia, Neal Rosen, Barry S. Taylor, Christine A. Pratilas. A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAF V600E-mutant brain tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3184.
Problem behavior in autism spectrum disorders: A paradigmatic self-organized perspective of network structures
Authors: Lucio Tonello, Luca Giacobbi, Alberto Pettenon, Alessandro Scuotto, Massimo Cocchi, Fabio Gabrielli, Glenda Cappello
Journal: Behavioral and Brain Sciences (2019)

Abstract Autism spectrum disorder (ASD) subjects can present temporary behaviors of acute agitation and aggressiveness, named problem behaviors . They have been shown to be consistent with the self-organized criticality (SOC), a model wherein occasionally occurring “catastrophic events” are necessary in order to maintain a self-organized “critical equilibrium.” The SOC can represent the psychopathology network structures and additionally suggests that they can be considered as self-organized systems.