tbuckley/cabot-search huggingface dataset:
Child Maltreatment and Risk for Psychopathology in Childhood and Adulthood
Authors: Sara R. Jaffee
Journal: Annual Review of Clinical Psychology (2017)

Although rates of child maltreatment are declining, more than 600,000 children in the United States are substantiated victims of abuse or neglect. The focus of this review is on the relationship between maltreatment and mental health problems in childhood and adulthood. Children and adults who are exposed to abuse or neglect in childhood are at risk for a range of poor mental health outcomes, including internalizing and externalizing psychopathology, posttraumatic stress disorder, psychotic symptoms, and personality disorders. I review three potential mechanisms by which maltreatment may increase risk for various forms of psychopathology, (a) hypervigilance to threat, (b) deficits in emotion recognition and understanding, and (c) low responsivity to reward. I also review genetic and psychosocial factors that moderate the relationship between maltreatment and risk for psychopathology. Finally, I discuss methodological limitations of the literature on maltreatment, with an emphasis on the challenges associated with establishing a causal role for maltreatment (and moderators or mediators of maltreatment) in the development of mental health problems and the reliance of many studies on retrospective self-reports.
Phase I and pharmacological study of oral topotecan and the BCRP and P-gp inhibitor elacridar
Authors: J. H. Schellens, I. E. Kuppens, R. C. Jewell, S. A. Radema, E. O. Witteveen, E. M. Paul, S. G. Mangum, H. Rosing, J. H. Beijnen, E. E. Voest
Journal: Journal of Clinical Oncology (2004)

2003 Background: Oral topotecan has a moderate (∼ 40%) and variable bioavailability (F). Complete apparent F can be obtained by combining topotecan with elacridar which inhibits BCRP and P-gp in the gut wall. The OBJECTIVES were 1] to determine the lowest effective dose (LED) of elacridar resulting in complete apparent F of topotecan and the optimal schedule of elacridar and topotecan and 2] to determine the maximal tolerated dose (MTD) and dose-limiting toxicity (DLT) of topotecan in combination with the LED of elacridar at a dailyx5 schedule every 21 days. Methods of part 1: Patients (pts) were randomized to receive 1000, 700, 500, 300 or 100 mg of elacridar (tablets) plus 2 mg topotecan (capsules) after a standard breakfast. Elacridar was administered 60 minutes prior to topotecan or simultaneously with topotecan on day 1 and 8, which was randomized within patients. I.V. topotecan was given on day 15. Pharmacokinetics (PK) of topotecan (total and lactone form) and elacridar were obtained by validated LC/MS/MS on days 1, 8 and 15. Part 2: The LED of elacridar was combined with increasing doses of topotecan in patient cohorts of 3 to determine MTD and DLT of the regimen. Results Part 1: 23 pts with advanced cancer (age range 27–75) were included in part 1. Three pts were not evaluable for PK and were replaced. There was no statistically significant effect of the elacridar dose or administration schedule on the apparent F of topotecan, which was 102 ± 7 % (range 94–111%). Part 2: 15 pts were included with age range 27–71 yrs. Dose levels of topotecan evaluated were 1.0, 1.5, 2.0, and 2.5 mg/day for 5 days. DLTs consisting of CTC Grade 4 leukocytopenia, neutropenia and thrombocytopenia were observed at 2.5 mg/d of topotecan. The MTD (6 pts) was 2.0 mg plus 100 mg elacridar. GI toxicity was minimal and the combination was well tolerated. Conclusions: 100 mg elacridar given simultaneously was sufficient to provide maximal apparent F of topotecan. The recommended oral dose of topotecan in this combination and schedule is 2.0 mg. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline
The implementation of a streamlined process for biomarker testing in medical oncology.
Authors: Laavanya Dharmakulaseelan, Tanya Jorden, Bryan B. Franco, Janice Stewart, Gail Sanders, Patrice Boulianne, Karen Laws, Matthew C. Cheung, Simron Singh, Nadia Ismiil, Maureen E. Trudeau
Journal: Journal of Clinical Oncology (2017)

179 Background: Biomarker testing is increasingly becoming an essential part of standard care. At Sunnybrook Health Sciences Centre (SHSC) in Toronto, Canada, our Department of Molecular Services handles some internal biomarker tests, while some tests are referred to citywide labs. The Odette Cancer Centre (OCC) of SHSC is one of the largest cancer centres in Canada, serving over 12,000 new patients per year, of whom many rely on biomarker tests for personalized treatment. We aimed to describe the work systems at the OCC for biomarker testing and reporting, and to initiate system improvements. Methods: This quality improvement initiative occurred in three phases: qualitative descriptive analysis of the current process of biomarker testing, exploration of future state process using LEAN, and implementation of a streamlined process. In phase one, ten medical oncologists, two administrative assistants, and one pathologist were interviewed. A multidisciplinary team was then assembled to investigate and initiate improvements. Results: Tracking results from external labs was managed by individual physicians and hard copy results were submitted to medical records for filing in patient paper charts, compared to internal tests which are posted on the electronic record, making outside tests harder to retrieve later. The current process involved more than 150 different tests with only 44% of results appearing in the hospital electronic record. In June 2016, a standardized process was implemented where a designated laboratory assistant managed requisition forms, sent corresponding specimens to qualified labs, ensured the receipt of results through various electronic tracking tools and validated the subsequent upload to the electronic medical system. Over a four-month implementation period, there were 364 cases/patients with 467 tests requested; 100% of these test results are stored in the electronic record. Conclusions: The lack of standardization of biomarker testing and reporting can have negative implications on quality of care and patient safety. Therefore, streamlining this process and incorporating electronic tracking tools can improve the accessibility of test results to improve the quality of oncology care.
Refused versus recommended adjuvant chemotherapy in the United States: A reason for concern.
Authors: Elizabeth Butzer Habermann, Anasooya A Abraham, Yanrong Zhu, Abraham Markin, David A. Rothenberger, Karen M Kuntz, Selwyn M. Vickers, Waddah B. Al-Refaie
Journal: Journal of Clinical Oncology (2012)

6016 Background: We designed this study to identify factors driving treatment recommendations and refusal in surgically treated patients with gastrointestinal (GI) cancers eligible for adjuvant chemotherapy. Methods: Using the 2001-2008 California Cancer Registry (CCR), we constructed a cohort of 22,469 patients surgically treated for three GI cancers and eligible for adjuvant chemotherapy (stage III colon cancer in patients &lt; 80 years, Ib-IVM0 gastric cancer, or nonmetastatic resected pancreatic adenocarcinoma). Information on chemotherapy receipt, recommendation, and refusal was utilized to construct our outcome measures. Multivariate logistic regression models identified predictors of recommendation and refusal of adjuvant chemotherapy across three GI cancer sites, adjusting for potential confounders. Results: Of those eligible for adjuvant therapy, only 61.4% were recommended treatment and 54.3% received it. Refusal rate was 3.5%. Persons who were older, black, publicly insured or uninsured, or with gastric cancers were less likely to have adjuvant chemotherapy recommended. Yet, older, Medicaid-insured, and those treated for gastric cancer were more likely to refuse adjuvant therapies. Women were as likely as men to be recommended adjuvant therapies but more likely to refuse them (Table). Conclusions: Many patients eligible for adjuvant chemotherapy after GI cancer surgery have not been so advised. Striking variations exist between recipients of treatment recommendations versus those who refuse them. These results demonstrate a wide implementation gap between the recommendations arising from cancer clinical trials versus actual clinical practice. [Table: see text]
Effect of cancer nurse navigators (CNN) on physician engagement in multidisciplinary discussions prior to head and neck cancer treatment.
Authors: Valerie Werner, Anne Barry-Weers, James Leighton Weese, Martin Corsten
Journal: Journal of Clinical Oncology (2017)

98 Background: Aurora Health Care, a 15 hospital integrated system has recognized a multidisciplinary approach is the best practice for treatment of head and neck (H&amp;N) cancers. We tested whether CNNs and system wide high definition video conferencing facilitates multidisciplinary collaboration in the treatment of H&amp;N cancers. Methods: Baseline data identified the percent of newly diagnosed H&amp;N cancer cases with prospective multidisciplinary discussion prior to initiation of treatment (Phase I). Then, performance improvement initiatives were identified to increase the percent of patients discussed during a multidisciplinary conference (MDC). The initiatives included: weekly review of all H&amp;N cancer cases by a lead CNN found by Cancer Registry through EPATH; electronic communication from the CNN requesting physician presentation of their patients at the MDC; engagement of site-specific CNNs to schedule their provider’s patients for the MDC; collaboration with cancer registrars to place their site-specific patients with H&amp;N cancer on their local or system MDC case list; follow-up with providers on patients not presented at MDC; and timely feedback (&lt; 24 hours) to referring providers on recommendations for patients presented at MDC . After implementation of performance improvement initiatives, comparison data was obtained (Phase II) and analyzed utilizing a chi square test. Results: From January through September 2015 (Phase I) and October 2015 through June 2016 (Phase II), 75 and 102 H&amp;N cancer cases were reviewed, respectively. A significant rise (p=0.005) in the percentage of patients being presented at an MDC occurred between phases I (77%, N=75) and II (93%, N=102). Conclusions: Through a coordinated process by CNNs, providers engaged in multidisciplinary discussions prior to the initiation of treatment. This increased engagement, changed practice patterns with patient assessment, aligned the institution with best practice guidelines and aided in therapy selection for the best possible patient outcomes.
A phase 1 study of AZD6244 in children with recurrent or refractory low-grade gliomas: A Pediatric Brain Tumor Consortium report.
Authors: Anuradha Banerjee, Regina Jakacki, Arzu Onar-Thomas, Shengjie Wu, Theodore Nicolaides, David Turner, Stacye Richardson, Tina Young-Poussaint, Joanna J Phillips, Michael Prados, Roger Packer, Ibrahim A Qaddoumi, Sridharan Gururangan, Stewart Goldman, Ian Pollack, L. Austin Doyle, Clinton F. Stewart, James M. Boyett, Maryam Fouladi
Journal: Journal of Clinical Oncology (2014)

10065 Background: Pathway activating genetic aberrations of the Ras-MAP kinase signaling pathway have been observed in pediatric low grade glioma (LGG), most commonly a fusion gene, BRAF-KIAA1549 or a mutation of BRAFV600E. MEK is a downstream target of BRAF; thus, MEK inhibition may represent a promising treatment strategy for patients with LGGs. Methods: AZD6244 was administered orally BID to children ≥ 3yrs and ≤21 years with refractory or recurrent LGG. The starting dose was 33 mg/m2/day BID and continual reassessment method was used for dose finding. Pre-treatment tissue was assessed for BRAF aberrations by FISH and IHC. Serial PK studies were obtained on day 1 cycle 1. Results: Thirty eight eligible patients were enrolled. Initially, only patients >12 and ≤21 years were eligible. Dose levels 1 and 2 (33 and 43 mg/m2/dose, BID) were deemed intolerable with dose limiting toxicities (DLTs) of headache, rash and mucositis. Following de-escalation to dose level 0 (25mg/m2/dose BID), eligibility was extended to patients <12 years. Among the 24 patients treated at dose level 0, no patient <12 years and 3 of 12 patients ≥12 years experienced DLTs of elevated amylase/lipase, rash and mucositis. The MTD/RP2D for both cohorts was 25 mg/m2/dose BID. Non-compartmental pharmacokinetic analysis in 23 patients at 25 mg/m2/dose BID indicated the median (range) AUC0-∞ and CL/F were 3,855 ng*hr/mL(1,780 to 7,250 ng×hr/mL) and 6.5 L×hr-1×m-2 (3.4 to 14.0 L×hr-1×m-2), respectively. Similar plasma exposures of AZD6244 are known to inhibit ERK phosphorylation in peripheral blood cells. Nineteen patients had sufficient tissue for BRAF studies. Eleven patients had KIAA1549:BRAF fusion products, 3 had BRAF-V600E mutations; and 1 patient had both. ERK1/2 phosphorylation immunohistochemical staining was noted in all 19 cases studied. There were 8/38 sustained responses (1 complete and 7 partial). Of these, 5 had biology data: 3 had BRAF fusion, 1 had BRAFV600E mutation and 1 was negative for both. Conclusions: The RP2D of AZD6244 in children with recurrent LGG is 25 mg/m2/dose BID, with the most common toxicity being rash. This study suggests promising activity in pediatric LGG. A Phase II study is currently ongoing. Clinical trial information: NCT01089101.
Abstract P138: PTEN Mediates Post--Myocardial Infarction Remodeling
Authors: Nirmal Parajuli, Yuan Yuan, Djahida Bedja, Zheqing P Cai
Journal: Circulation Research (2011)

Background- Following myocardial infarction (MI), innate immunity is activated, leading to cytokine production and initiation of inflammation. Interleukin (IL)-10 has been reported to attenuate post-MI remodeling by inhibiting expression of tumor necrosis factor (TNF)-α. The phosphatase and tensin homologue deleted on chromosome ten (PTEN) plays an important role in myocardial ischemia-reperfusion injury. It is not known whether PTEN regulates cytokine production and cardiac remodeling. Here, we have investigated the hypothesis that PTEN mediates post-MI remodeling by inhibiting IL-10. Methods and Results- MI was induced in wildtype (WT) mice and Pten heterozygous (HET) mice. In a separate experiment, Pten adenoviruses or empty viruses were injected into the peri-infarct area of WT mice. Left ventricular (LV) anatomical and functional changes were assessed by echocardiography. Mononuclear cell infiltration was measured by histology. TNF-α, IL-10, matrix metalloproteinase (MMP)-2 and MMP-9 protein levels were analyzed in the peri-infarct area. At the end of the experiments, LV end-diastolic diameter (LVEDD) was decreased and fractional shortening (FS) was increased in HET mice compared with WT mice (LVEDD: 4.13±0.22 vs. 5.42±0.26 mm, p&lt;0.01; FS: 21.9±2.6 vs. 11.5±1.1 %, p&lt;0.001). Moreover, heart weight and infarct size were decreased in HET mice compared with WT mice. However, FS was decreased and LV rupture (LVR) was increased in Pten adenovirus-treated mice compared with empty vector-treated mice [FS: 8.2±1.1 vs. 21.5±3.2 %, p &lt; 0.01; LVR: 100% (16/16) vs. 33% (3/9)]. Mononuclear cell infiltration was attenuated in HET mice and worsened in Pten adenovirus-treated mice. IL-10 protein levels were upregulated and TNF-α, MMP-2, and MMP-9 protein levels were downregulated in HET mice. The opposite effects were found in Pten over-expressing hearts. Conclusions- PTEN downregulation increases IL-10 production and inhibits inflammatory responses and attenuates cardiac remodeling; conversely, PTEN over-expression inhibits IL-10 expression and increases cardiac injury. Therefore, our studies demonstrate that PTEN mediates post-MI remodeling, at least in part, by regulating IL-10 production.
Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma
Authors: Eileen Wedge, Jakob Werner Hansen, Christian Garde, Fazila Asmar, Dorte Tholstrup, Søren Sommer Kristensen, Helga D. Munch‐Petersen, Elisabeth Ralfkiaer, Peter Brown, Kirsten Grønbæk, Lasse Sommer Kristensen
Journal: American Journal of Hematology (2017)

Global hypomethylation has been linked to disease progression in several cancers, but has not been reported for Diffuse Large B Cell Lymphoma (DLBCL). This study aimed to assess global methylation in DLBCL and describe its prognostic value. Mean LINE1 methylation, a validated surrogate measure for global methylation, was measured in DNA from 67 tumor biopsies. Additionally, cell-free circulating DNA (cfDNA) in plasma samples from 74 patients was tested to assess the feasibility of global hypomethylation as a biomarker in liquid biopsies. LINE1 methylation was assessed using a commercially available kit, based on pyrosequencing of PCR amplified bisulfite-treated DNA. Global hypomethylation was detected in a subset of cases and was associated with poor overall survival in both tumor biopsies (P = .001) and cfDNA (P = .009). It was the strongest risk factor in multivariate analysis in both biopsies (HR: 10.65, CI: 2.03-55.81, P = .005) and cfDNA (HR: 11.87, CI: 2.80-50.20, P = .001), outperforming conventional clinical risk factors. Finally, hierarchical cluster analyses were performed for the cfDNA samples using previously published gene-specific methylation data. This analysis shows that global hypomethylation co-occurs with other epigenetic abnormalities, including DAPK1 promoter hypermethylation. In conclusion, we have shown that global hypomethylation is strongly associated with poor survival in DLBCL both when present in tumor biopsy DNA and when detected in plasma cfDNA, and has potential for clinical application as a prognostic biomarker.
The relationship between <i>HIF</i> family gene expression in allogeneic T-cell products and acute graft-versus-host disease.
Authors: Joseph Rimando, Steven Larrick, Nicholas Fowler, Luciano Castiello, Syed Abbas Ali, Marianna Sabatino, Dave Stroncek, Tania Felizardo, Daniel H Fowler
Journal: Journal of Clinical Oncology (2015)

7026 Background: Allogeneic hematopoietic cell transplantation (HCT) provides beneficial graft-versus-tumor effects (GVT) but is limited by graft-versus-host-disease (GVHD). In murine models and clinical trials, our group has shown that ex vivo-manufactured rapamycin-resistant donor T cells (T-rapa cells) provide a favorable balance of GVT and GVHD effects. Recently, T cells cultured in rapamycin for 6 days (TR6) were found to mediate increased GVHD relative to T cells cultured for 12 days (TR12); specifically, TR6 recipients had approximately 40% acute GVHD whereas TR12 recipients had approximately 10% acute GVHD. The HIF gene family allows T cells to survive at hypoxic sites including potential GVHD target sites. We thus hypothesized that the increased GVHD mediated by the TR6 cells relative to the TR12 cells might be due in part to differences in HIF family gene expression. Methods: We used microarray gene expression analysis (Agilent Platform) to find differences in HIF gene family expression (94 genes) between the TR6 and TR12 clinical products (n = 40 products evaluated for each condition). To assess the impact of culture interval and rapamycin on HIF expression, we used western blotting to measure HIF1/2 expression (see Table). Results: On gene expression analysis, the HIF1/2 gene family was greatly upregulated in each TR6 cell product relative to the TR12 cell products. When compared with T cells at culture initiation, T-rapa cells had decreased HIF family gene expression at day 3, increased expression at day 6, and decreased expression again at day 12. These RNA-based results were confirmed at the protein level with western blotting. Conclusions: Relative to TR12 cells, TR6 cells have increased HIF family expression at both the RNA and protein level. Further studies will address our hypothesis that increased HIF expression in the TR6 cells contributes to their increased GVHD potential. Experimental design. Experimental Cohort1 T Cell Culture2 Culture Duration 1 X Initiation 2A/2B X 4 hours 3A/3B X 24 hours 4A/4B X 3 days 5A/B X 6 days 6A/B X 12 days 1Cohorts A and B were without or with rapamycin (1 uM), respectively. 2CD4+ T cells were cultured with anti-CD3/CD28 co-stimulatory beads, IL-2, and IL-4.
Development of a melanoma risk prediction model incorporating MC1R genotype and indoor tanning exposure.
Authors: Lauren A Smith, Meng Qian, Elise Ng, Yongzhao Shao, Marianne Berwick, DeAnn Lazovich, David Polsky
Journal: Journal of Clinical Oncology (2012)

8574 Background: Invasive melanoma is the second most common cancer in young adults, yet they exhibit poor skin-protective behavior. We previously demonstrated a significant association between melanoma risk, melanocortin receptor (MC1R) polymorphisms, and indoor ultraviolet light (UV) exposure. As existing melanoma risk models do not take these factors into account, we investigated whether these variables would improve the predictive ability of a clinical risk model, especially in a younger population. Methods: We determined MC1R genotype and collected self-reported phenotypic and UV (indoor and outdoor) exposure variables from 923 melanoma cases and 813 healthy controls between ages 25 – 59 from the Minnesota Skin Health Study. These data were initially used to develop a clinical melanoma risk model (Model A) with conventional risk factors (i.e. age; gender; hair, skin, and eye color; mole count, freckling, and family melanoma history). We then developed a second model (Model B) combining outdoor UV, indoor UV, and MC1R genotype variables with those in Model A to determine if the model’s predictive ability improved. Finally, we assessed the predictive ability of both models when confined to younger subjects (ages 25-35). Results: The clinical model, combining conventional melanoma risk factors (Model A), yielded an area under the receiver operating characteristic curve (AUC) of 0.72 (95% CI 0.70 – 0.75). Incorporating outdoor UV, indoor UV, and MC1R genotype variables (Model B) increased the AUC to 0.75 (p=0.001, 0.72 – 0.77). Confining the analyses to younger subjects substantially increased the AUC of Model A to 0.78 (0.72 – 0.84) and Model B to 0.83 (p=0.007, 0.78-0.88). Conclusions: This preliminary risk model is the first in melanoma to demonstrate that the addition of genotypic data and indoor UV exposure results in a measurable increase in predictive ability when compared to models comprised only of clinical and outdoor UV exposure variables. The enhanced predictive ability of the model (AUC&gt;0.80) when limited to younger individuals suggests the potential for developing tools to facilitate targeted screening and prevention strategies in melanoma.