tbuckley/cabot-search huggingface dataset:
Interferon (IFN)-based chemoradiation (CRT) in localized biliary cancer (LBC): A 10-year (yr) experience.
Authors: V. J. Picozzi, G. Song
Journal: Journal of Clinical Oncology (2010)

e14501 Background: LBC has poor median (6-24 mo) and long-term (0%-40% 5-yr) overall survival (OS). A prior report (Picozzi et al. Proc ASCO 2005) on 23 patients (pts) with locally advanced (LA)BC using IFN-based CRT showed promising results. We sought to extend observations using this approach to LBC at our center. Methods: From 2000-2009, all pts with biopsy-proven, previously untreated LBC, either gallbladder (GBCA) or cholangiocarcinoma (CHCA), both resected (res) and LA were analyzed. All pts received 4,500-5,040 cGy XRT/25-28 fractions with 5-FU 200 mg/m2 IVCI and IFNα 3,000,000 mU SQ tiw throughout XRT . Pts with proximal (prox) LBC received mitomycin C 10 mg/m2 IV day 1. Pts with distal (dis) LBC received cisplatin 30 mg/m2 IV weekly during XRT. Results: 47 pts (median age 64 yrs) were identified. 12 pts had GBCA (6 res, 6 LA), 35 pts had CHCA (21 res,14 LA, 25 prox,10 dis). 70% (19/27) res pts were node and/or margin positive. All pts received intended XRT dose; 42/47 pts (89%) received ≥ 85% calculated 5-FU dose. 38/47 pts (81%) received additional chemotherapy (gemcitabine and/or a fluorpyrimidine) for 4-6 months post CRT. 53% (25/47 pts) experienced ≥ grade 3 toxicity during CRT, including neutropenia (17%), mucositis (13%),wt loss (11%), fever, nausea/vomiting, and diarrhea (all 9%).No toxic deaths occurred during CRT, although 1 pt died with possibly treatment-related cirrhosis > 6 yrs from diagnosis. With median f/u > 20 mo, 15/47(32%) pts recurred, all but 1 within 18 mo of dx. Local/systemic recurrences were 11% (5/47 pts) /23% (11/47 pts, 5 peritoneum. 5 liver, lymph node). All-cause mortality at time of last f/u was 38% (18/47 pts, 13 disease progression,3 infection, 2 unknown) .For all 47 pts (median OS > 20 mo), 1,2,3 and 5-yr OS is 87%, 60%,48%, and 25%, respectively. 2/5-yr OS were 70%/44% GBCA, 55%/13% CHCA, 71%/33% all res LBC, 47%/17% all LABC, 58%/24% all prox LBC, 67%/33% dis CHCA (Kaplan-Meier). Conclusions: 1) IFN-based CRT in LBC has moderate toxicity, with therapy delivered as intended. 2) This approach offers excellent (∼90%) local disease control in LBC and produces competitive OS and potential long-term survival for both res and LABC pts.3) IFN-based CRT provides a platform for future clinical trials in LBC. No significant financial relationships to disclose.
Effect of early detection of occult brain metastases in HER2-positive breast cancer patients on survival
Authors: A. Niwinska, M. Tacikowska, I. Lemanska, T. Pienkowski, M. Murawska
Journal: Journal of Clinical Oncology (2007)

1015 Aim: The aim of the study was to compare disease free survivals (DFS), survivals from the detection of brain metastases, overall survivals (OS) and the causes of death between two patient groups: group I with disseminated HER2-positive breast cancer and occult brain metastases and group II with symptomatic brain metastases. Material and Methods: MRI screening of the brain was performed in 80 HER2-positive breast cancer pts treated with trastuzumab and cytostatics for visceral metastases. In 29 pts (34%) in whom occult brain metastases were detected, whole brain radiotherapy (WBR) to the brain (30 Gy in 10 fractions) was performed (Group I). They were compared with 48 pts with symptomatic brain metastases treated at the same clinic during the same time period (Group II). Both groups were comparable regarding the site of distant metastases and the type of treatment. All pts in both groups had distant metastases to the lung and/or liver. Results: Median DFS in group I was 17 months and in Group II- 19.9 months (p=0.61). Median survival from dissemination of the disease (visceral metastases) to the detection of occult and symptomatic brain metastases was 9 and 15 months, respectively (p=0.21). Median survival calculated from the detection of brain metastases was 9 and 9.3 months, respectively (p=0.76). Median OS of pts with occult and symptomatic brain metastases was 53.8 and 52 months, respectively (p=0.79). In the group with occult brain metastases 15% of pts died because of progression in the brain and in the group of symptomatic brain metastases the rate of cerebral death was 48%. Conclusions: WBR performed during the asymptomatic period decreased the rate of cerebral deaths, but did not prolong overall survival. Screened MRI of the brain during the asymptomatic period did not improve the outcome of pts with HER2-positive breast cancer and with visceral metastases. No significant financial relationships to disclose.
A Test of the Transdiagnostic Dopamine Hypothesis of Psychosis Using Positron Emission Tomographic Imaging in Bipolar Affective Disorder and Schizophrenia
Authors: Sameer Jauhar, Matthew M. Nour, Mattia Veronese, Maria Rogdaki, Ilaria Bonoldi, Matilda Azis, Federico Turkheimer, Philip McGuire, Allan H. Young, Oliver D. Howes
Journal: JAMA Psychiatry (2017)

The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis.
Polypeptide growth factor signaling, stromal-epithelial interactions and the emergence of the neuroendocrine phenotype in novel transgenic mouse models of prostate cancer
Authors: Andreas I. Evangelou, Barbara A. Foster, Paula J. Kaplan-Lefko, Norman M. Greenberg
Journal: Cancer Research (2004)

4298   Accumulation of the cyclin-dependent kinase (cdk) inhibitor, p27, is prognostic for patient outcome in prostate cancer. In order to determine how p27 loss influences tumor progression, we studied the rate and frequency of tumor progression in sibling pairs of  p27 +/+   or  p27 −/−   transgenic mice that are predisposed to prostate tumor development by prostate-specific expression of the SV40 Large T Antigen (LT). Transgenic mice expressing intact LT, but lacking both copies of p27, developed prostate tumors earlier than  p27 +/+   mice (T½ = 29 weeks for  p27  −/−  mice, 48 weeks for  p27  +/+  mice). Epithelial cell proliferation rates were 38% higher in  p27 −/−   mice at 12 weeks, and 78% higher at 26 weeks of age, even when areas of tumor were excluded from counting. On the other hand, apoptotic rates were similar at all time points. We took advantage of the androgen-responsive transgenic promoter to control the onset of oncogene-driven proliferation by castrating sexually immature animals for 21 days, followed by testosterone supplementation. We found that proliferation and cdk2 kinase activity were equally suppressed in castrate p27+/+ and p27−/− animals, and that there was no detectable expression of the LT transgene. However, 5 days after testosterone supplementation, with similar high level induction of LT expression and high proliferation rates in both genotypes, cdk2 activity was significantly higher in the p27−/− prostates. We are performing similar analyses in older mice to clarify whether elevated cdk2 kinase activity is a consistent feature of LT-expressing p27−/− mice and whether this property underlies the more rapid proliferation and tumor progression seen in p27 deficient animals. In order to test whether loss of p27 alone can substitute for the proliferative contribution LT makes by inactivating Rb family members (Rb, p107, and p130), we generated sibling pairs of  p27 +/+   and  p27 −/−   mice that over-express an analogous transgene, differing by a 3 amino acid substitution disrupting the conserved Rb binding site, and which is unable to inactivate the Rb pathway, but which inactivates the p53 pathway. Mice from this mutant line have high levels of transgene expression, but proliferation rates were only minimally increased above that seen in non-transgenic prostates. Tumors did not arise within 52 weeks of observation, regardless of p27 status. In summary, we find that p27 loss collaborates with oncogene-induced tumor development in the prostate, but that loss of p27 does not provide the proliferative impetus sufficient for oncogenesis. Serial analyses are planned to study the relationship between cyclin-dependent kinase activity, proliferation, and tumor progression in this model .
Toxicity associated with ipilimumab and nivolumab (Ipi+Nivo) combination therapy in melanoma patients (pts) treated at a single-institution under an expanded-access program (EAP).
Authors: Claire Frances Friedman, Pedram Navid-Azarbaijani, Alexander Noor Shoushtari, Shonnette C. Campbell, Margaret K. Callahan, Parisa Momtaz, Nana A. Prempeh-Keteku, Michael Andrew Postow, Yelena Shames, Jedd D. Wolchok, Paul B. Chapman
Journal: Journal of Clinical Oncology (2016)

9519 Background: Ipi+Nivo is now FDA approved in the US to treat pts with melanoma. We report our clinical experience of toxicity in pts enrolled in the Ipi+Nivo EAP. Methods: 64 pts were treated on the Ipi+Nivo EAP from Dec. 2014 through Jan. 2016 at MSKCC. Ipi (3mg/kg) and nivo (1mg/kg) were administered q3 weeks for 4 doses. Afterwards, pts were offered Nivo (3mg/kg) q2wks or off-protocol pembrolizumab (2 mg/kg) q3wks until unacceptable toxicity, disease progression (POD), or complete response. Clinically significant immune-related adverse events (irAEs) were defined as CTCAE v4.0 grade ≥ 2 or grade 1 events requiring systemic steroids. Results: 15 pts (39.1%) received all 4 doses of Ipi+Nivo; 11 pts (17.2%) received 3 doses, 20 pts (31.3%) received 2 doses, and 8 pts (12.5%) received 1 dose. Minimum follow up after last Ipi+Nivo treatment was 1 month. 31 pts (79.5%) stopped early for toxicity, 7 (18.0%) for POD and 1 (2.6%) for death due to other causes. The median number of anti-PD-1 doses administered was 1 (range 0-16); 31 pts (48.4%) did not receive any anti-PD-1 therapy after ipi/nivo. 58/64 pts (90.6%) had ≥ 1 clinically significant irAE (median = 2, range 0-6) and 46/64 pts (71.9%) required ≥ 1 course of systemic steroids. 14/64 pts (21.9%) required infliximab for steroid-refractory diarrhea and 2 pts (3.1%) required mycophenolate for treatment of steroid-refractory transaminitis. 40 pts (62.5%) had ≥ 1 emergency room (ER) visit while on study (range 0-5); 30 pts (47.6%) had ≥ 1 admission to the hospital. The majority of both ER visits (61%) and hospital admissions (70%) were related to irAEs. Clinically significant irAEs on anti-PD-1 monotherapy were uncommon. 8/33 pts (24%) had an asymptomatic grade ≥ 2 increase in lipase and 5 pts (15%) had endocrine dysfunction. Conclusions: Treatment with Ipi+Nivowas associated with a high rate of clinically significant irAEs, ER visits, and systemic immunosuppression to treat irAEs. Only 39% of pts were able to receive all 4 doses of Ipi+Nivo, with the majority stopping early for toxicity. Patients and oncologists should be aware of need for careful monitoring and the likelihood of irAEs requiring therapy. Clinical trial information: NCT02186249.
Final analysis of time to subsequent disease progression/death in patients with metastatic enteropancreatic neuroendocrine tumours progressing under placebo and switched to lanreotide autogel/depot 120mg in the CLARINET open-label extension
Authors: J.B. Cwikla, E.M. Wolin, M. Pavel, A.T. Phan, M. Raderer, E. Sedláčková, G. Cadiot, J. Capdevila, G. Rindi, C. Lombard-Bohas, N. Liyanage, X-M. Truong Thanh, P. Ruszniewski, M. Caplin
Journal: Annals of Oncology (2017)
Impact of time to surgery in the outcome of patients with liver resection for BCLC 0-A stage hepatocellular carcinoma
Authors: Chetana Lim, Prashant Bhangui, Chady Salloum, Concepción Gómez-Gavara, Eylon Lahat, Alain Luciani, Philippe Compagnon, Julien Calderaro, Cyrille Feray, Daniel Azoulay
Journal: Journal of Hepatology (2017)
Subgroup analyses from KEYNOTE-045: Pembrolizumab (pembro) versus individual investigator’s choice of chemotherapy (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer (uc)
Authors: D. Petrylak, N.J. Vogelzang, Y. Fradet, D. Bajorin, R. de Wit, D.J. Vaughn, J-L. Lee, L. Fong, M.A. Climent, A. Necchi, W.R. Gerritsen, H. Gurney, D.I. Quinn, S. Culine, C.N. Sternberg, E. Jensen, M. Puhlmann, R. Perini, J. Bellmunt, T.K. Choueiri
Journal: Annals of Oncology (2017)
Mechanistic studies on the formation and metabolism of nitrosamines
Authors: Richard Loeppky
Journal: Cancer Research (2007)

SS05-03  Despite 50 years of research, human exposure to potent carcinogenic nitrosamines is still common. Mechanistic analysis and investigation of both their routes of formation and their metabolic pathways of activation are important in cancer prevention. Two examples from our research will be presented to illustrate these points. In the first case the mechanism of metabolic activation of N-nitrosodiethanolamine (NDELA), an environmentally ubiquitous nitrosamine, will be discussed. NDELA and structurally related β-hydroxynitrosamines are bident carcinogens because two fragments from the same molecule, glyoxal and a diazonium derived alkylating agent, bind DNA. The metabolism of NDELA involves competitive oxidation of the 2-hydroxyethyl side chain at both the α-, and β-positions. The latter process gives N-nitroso-2-hydroxymorpholine (NHMOR) through intramolecular hemiacetal formation from the immediately produced aldehyde. In vitro metabolism studies reveal competitive P450 2E1 mediated oxidation of NDELA to give NHMOR or the unstable 2-hydroxyethyldiazonium ion and glycoladehyde, which is further metabolized to glyoxal. Glyoxal and the diazonium ion are also metabolites of NHMOR. The α-acetate of NDELA, and the two α-acetates of NHMOR have been prepared and their mechanisms of decomposition determined as models of the enzymatic α-oxidation process. Extensive molecular rearrangement and “chemical detoxification” of the 5-acetoxy-NHMOR occurs. NDELA produces both glyoxal-guanine and O6-hydroxyethylguanine adducts in rat liver DNA following oral administration.  Reports of the occurrence of O6-carboxyethyguanine residues in DNA prompted our explorations of the mechanisms by which this glycine derived adduct could arise. α-Amino acids reversibly form imines (Schiff bases) with dietary aldehydes. Nitrosation of the imine (C=N-) bond in these compounds under gastric conditions leads to the formation of an unexplored group of heterocyclic nitrosamines, N-nitroso-1,3-oxazolidin-5-ones (NOZ), through ring closure via the carboxyl group. These nitrosamino lactones, also independently synthesized, generate reactive diazonium ion alkylating agents upon hydrolysis. Decomposition rates very markedly with structure and pH. N-Nitroso-1,3-oxazolidin-5-one (5-NOZ), derived from glycine, formaldehyde, and nitrite, has a t½ of 9.1 min at pH 7, 37 °C, but ring substitution increases stability. 5-NOZ exhibits activity similar to a direct mutagen in the Comet and related assays. In the case of cysteine, serine and threonine, aldehyde-nitrite NOZ formation competes with the formation of N-nitroso-1,3-thiazolidine- or N-nitroso-1,3-oxazolidine-4-carboxylic acids, respectively. The heating of these compounds under conditions of cooking leads to the vinylation of acids. Under similar conditions, N-nitrosoproline, a common non-carcinogenic food contaminant, produces a set of complex hydrazine derivatives of possible toxicological significance. The nitrosation of other C=N containing compounds will also be discussed.
Genetic Interaction Network as an Important Determinant of Gene Order in Genome Evolution
Authors: Yu-Fei Yang, Wenqing Cao, Shaohuan Wu, Wenfeng Qian
Journal: Molecular Biology and Evolution (2017)

Although it is generally accepted that eukaryotic gene order is not random, the basic principles of gene arrangement on a chromosome remain poorly understood. Here, we extended existing population genetics theories that were based on two-locus models and proposed a hypothesis that genetic interaction networks drive the evolution of eukaryotic gene order. We predicted that genes with positive epistasis would move toward each other in evolution, during which a negative correlation between epistasis and gene distance formed. We tested and confirmed our prediction with computational simulations and empirical data analyses. Importantly, we demonstrated that gene order in the budding yeast could be successfully predicted from the genetic interaction network. Taken together, our study reveals the role of the genetic interaction network in the evolution of gene order, extends our understanding of the encoding principles in genomes, and potentially offers new strategies to improve synthetic biology.
Abstract 19368: Improving Hypertension Control Through the Million Hearts Learning Collaborative
Authors: Letitia Presley-Cantrell, Michael Sells, Camillia Easley
Journal: Circulation (2016)

Introduction:  The CDC Division for Heart Disease and Stroke Prevention through a cooperative agreement with the Association of State and Territorial Health Officials selected state health agencies to participate in a Million Hearts State Learning Collaborative (MHSLC). The MHSLC works to achieve the goals of Million Hearts by supporting state and local agencies in integrating healthcare and community partners by implementing evidence-based strategies to identify, control, and improve blood pressure.   Purpose:  A comprehensive overview of the MHSLC strategies, interventions, outcomes, and lessons learned will be provided. Several state examples will be offered demonstrating how the MHSLC successfully helped states to develop viable partnerships to standardize hypertension measures; adopt treatment protocols; identify, control and improve blood pressure; and increase use of home blood pressure monitoring with clinical support.   Results:  Sixteen states were selected: ten the first year (2014) and six the second year (2015). The states implemented the Edward Deming Plan, Do, Study, Act (PDSA), a quality improvement process, to test strategies across 4 sectors (Data-driven action; financing and policy; community-clinical linkages; and standardizing clinical practice). For the first 2 years of the collaborative, 16 states had an estimated reach of 3.3 million individuals in health care system. During this time period more than 430 PDSA pilot cycles were conducted and more than 290 partners and stakeholders were convened. In Years One and Two of the learning collaborative state teams: 1) Identified 992,893 individuals in target populations; 2) Screened 57,475 individuals for hypertension who had been previously undiagnosed; 3) Identified 15,553 individuals with hypertension; 4) Referred 7,327 individuals with hypertension to clinical, public health, community, and self-management services and 5) Helped 3,167 individuals bring their blood pressure under control.   Conclusion:  Key findings from the MHSLC demonstrate that collaborations among public health, health care systems, and the community through implementation of quality improvement processes can improve hypertension control.
GW28-e0662 Comparison of cryoballoon ablation for atrial fibrillation guided by real-time transesophageal echocardiography versus contrast agent injections
Authors: Yuanjun Sun, Xiaomeng Yin, Xianjie Xiao, Dong Chang, Yingxue Dong, Yunlong Xia, Lianjun Gao, Yanzong Yang, Xiaomeng Yin
Journal: Journal of the American College of Cardiology (2017)
Microenvironment-Driven Shift of Cohesion/Detachment Balance within Tumors Induces a Switch toward Metastasis in Neuroblastoma
Authors: Céline Delloye-Bourgeois, Lorette Bertin, Karine Thoinet, Loraine Jarrosson, Karine Kindbeiter, Thomas Buffet, Servane Tauszig-Delamasure, Muriel Bozon, Aurélien Marabelle, Valérie Combaret, Christophe Bergeron, Edmund Derrington, Valérie Castellani
Journal: Cancer Cell (2017)
Efficacy and immune activation with PEGylated human IL-10 (AM0010) in combination with an anti-PD1 in advanced NSCLC: Update
Authors: D.J. Wong, J.G. Schneider, R. Aljumaily, M.W. Korn, K. Autio, J.R. Infante, M.R. Patel, K. Papadopoulos, A. Naing, N. Gabrail, P. Munster, J. Goldman, P. Van Vlasselaer, A. Hung, G. Brown, M. Oft, E.B. Garon
Journal: Annals of Oncology (2017)
Vitamin D as a prognostic factor in triple negative early breast cancer
Authors: S. Morales, A. Gasol Cudos, A. Novell Alvarez, F. Vilardell Villellas, M.J. Panades Siurana, C. Canosa Morales, J. Mele Olive, E. Iglesias Martinez
Journal: Annals of Oncology (2017)
Gene expression changes responsible for lapatinib acquired resistance in HER2 positive gastric cancer cell lines: a microarray analysis
Authors: V. Gambardella, J. Castillo, F. Gimeno-Valiente, N. Tarazona, M. Huerta, D. Roda, T. Fleitas, G. Ribas, S. Rosello, E. Serna, A. Cervantes
Journal: Annals of Oncology (2017)
Decreased tumorigenicity of lung cancer cells by minimal Fhit expression
Authors: Joshua P. Cantor, Atul S. Rao, Teresa Druck, Phyllis Wachsberger, Joseph S. Friedberg, Kay Huebner
Journal: Cancer Research (2005)

2887   Purpose: Most lung cancers have lost expression of the Fhit tumor suppressor. Stable over expression of Fhit suppresses tumorigenicity in nude mice, although  in vitro  growth is unaffected. To clarify the relationship between Fhit expression and  in vivo  lung cancer cell growth, we have examined the tumorigenicity of lung cancer cell line H1299 carrying an inducible FHIT gene (H1299D1). Methods: Five groups of 4 female nu/nu mice 6-8 weeks old were inoculated subcutaneously with 5x10 6  of the following cells: control 1) H1299; control 2) H1299/pVgRXR, the D1 parental cell carrying the ponasterone A inducible RXR gene but no FHIT gene; 3) H1299D1 cells expressing a basal level of Fhit; 4) H1299 cells transiently induced  in vitro  to express >10-fold increased Fhit before inoculation; 5) H1299D1 cells inoculated and 2 weeks later exposed  in vivo  to 125 μg of the inducer, ponasterone A, injected into the inoculation site once weekly for 4 weeks. Tumor diameters were measured 2-3 times per week and volumes calculated using the equation V (mm3) = a x b 2 /2, where a is the largest diameter and b is the perpendicular diameter. Mice were sacrificed when total tumor volume reached or exceeded 400 mm 3 . Summary: Tumors of control group 1 (H1299) reached 400 mm 3  mean volume by day 30 and all 4 mice exhibited 400 mm 3  tumors by day 32. Control group 2 cells (H1299/pVgRXR) reached mean tumor volume of 400 mm 3  by day 32 with all mice showing 400 mm 3  tumors by day 35. Tumors of group 3, inoculated with H1299D1 cells (basal level of Fhit), reached 400 mm 3  mean volume by day 61 with one mouse remaining tumor free. Tumors of mice inoculated with  in vitro  transiently induced H1299D1 cells reached 400 mm 3  mean volume by day 70, with one mouse tumor free. Tumors of group 5, in which H1299D1 cells were inoculated and  in vivo  Fhit induction begun 2 weeks later, reached 400 mm 3  mean volume by day 81, with 2 mice remaining tumor free. H1299D1 cells express a basal level of Fhit which is barely detectable by immunoblot, and yet tumorigenicity of these cells was decreased 2-fold. The transiently induced H1299D1 cells, expressing maximal Fhit at the time of inoculation, showed a 2.3-fold reduction in tumor growth. Tumor growth after inoculation of H1299D1 cells, followed 2 weeks later by sustained  in vivo  induction of Fhit expression, was reduced 2.7-fold with two mice remaining tumor free at endpoint. Conclusion: A very low level of Fhit expression significantly reduced tumorigenicity of H1299 lung cancer cells. This suggests that minimal reexpression of epigenetically silenced Fhit, or induction of expression of thus far unidentified Fhit effector proteins, could have a significant effect on human lung cancer growth.
Electrolyte Disturbances in Patients with Chronic Alcohol-Use Disorder
Authors: Biff F. Palmer, Deborah J. Clegg
Journal: New England Journal of Medicine (2017)

Electrolyte disturbances are common among patients with chronic alcohol-use disorder. This review discusses these disturbances and focuses on the interrelationship between the physiological features of the relevant electrolyte disorders and approaches to therapy.