tbuckley/cabot-search huggingface dataset:
Time trends in the health care burden and mortality of acute on chronic liver failure in the United States
Authors: Alina M. Allen, W. Ray Kim, James P. Moriarty, Nilay D. Shah, Joseph J. Larson, Patrick S. Kamath
Journal: Hepatology (2016)

Acute on chronic liver failure (ACLF) is associated with multisystem organ failure and poor prognosis in hospitalized patients with cirrhosis. We aimed to determine time trends in the epidemiology, economic burden, and mortality of ACLF in the United States. The National Inpatient Sample database was queried between 2001 and 2011. ACLF was defined as two or more extrahepatic organ failures in patients with cirrhosis. The primary outcomes were trends in hospitalizations, hospital costs, and inpatient mortality. The number of hospitalizations for cirrhosis in the United States nearly doubled from 371,000 in 2001 to 659,000 in 2011. The prevalence of ACLF among those hospitalizations increased from 1.5% (n = 5,400) to 5% (n = 32,300). The inpatient costs increased 2-fold for cirrhosis ($4.8 billion to $9.8 billion) and 5-fold ($320 million to $1.7 billion) for ACLF. In 2011, the cost per hospitalization for ACLF was 3.5-fold higher than that for cirrhosis ($53,570 versus $15,193). The in-hospital fatality rates decreased from 65% to 50% for ACLF and from 10% to 7% for cirrhosis. The organ failure trends in ACLF showed an increasing proportion of cardiovascular and cerebral and decreasing proportion of respiratory and renal failure. Age, male sex, and the number and types of organ failure were predictors of death in ACLF.Cirrhosis and ACLF represent a substantial and increasing health and economic burden in the United States; these data highlight an urgent need for research on pathophysiological mechanisms and effective therapy as well as for education of health care providers of its importance in the care of patients with cirrhosis. (Hepatology 2016;64:2165-2172).
A phase II trial of sorafenib (SOR) in patients (pts) with advanced cholangiocarcinoma (CC)
Authors: C. Dealis, F. Bertolini, N. Malavasi, S. Zironi, C. Boni, M. Banzi, E. Aitini, G. Cavazzini, G. Luppi, P. F. Conte
Journal: Journal of Clinical Oncology (2008)

4590 Background: There is no standard chemotherapy for advanced CC. Gemcitabine and fluoropyrimidine-based chemotherapy (CT) results in < 20% partial response rate. The Raf/MEK/ERK kinase pathway is disrupted in the majority of CCs. We have therefore evaluated the activity of SOR in advanced CC. Methods: Pts with measurable histologically confirmed CC, adequate organ function, ECOG PS ≤2 were admitted; prior systemic chemotherapy (CT) was allowed. Primary objective: 1) disease control (DC, defined as non Progressive Disease) at 12 weeks (RECIST); secondary objectives: time to progression (TTP), overall survival (OS) and toxicity (TOX). The following biomarkers were also assessed at baseline by IHC: VEGFr, pRaf-1, pMEK, pERK. SOR was administered at the dose of 400 mg PO, BID, continuously. Results: From August 2006 to December 2007, 46 pts were enrolled: (M/F=20/26). Median age: 65 yrs (range 37–80). At 12 weeks, a DC was obtained in 13/41 (31.7%) pts (4 pts too early, 1 pt consent withdrawal). Tumor response was assessed in 24 pts (52%): 1 PR (4%), 12 SD (50%), 11 PD (46%); no CR were reported. According to Intention to treat analysis median Progression free survival (PFS) was 76 days. 42 pts (91%) were evaluated for TOX. Grade ¾ drug-related toxicities were reported in 21 pts (50%): 7 (33%) skin rash, 1 (5%) thrombocytopenia, 3 (14%) SGOT/SGPT increase, 2 (9%) hand-foot syndrome, 1 (5%) creatininemia increase, 2 (9%) hyperbilirubinemia, 1 (5%) alopecia, 2 (9%) fatigue, 2 (9%)diarrhea. Six pts discontinued treatment because of TOX while SOR dose was reduced in 6 pts. Conclusions: A DC was reported in 31.7% of pts; 54% of the pts treated for at least 12 weeks achieved a SD or PR. Treatment was generally well tolerated, however 35%of the pts with ECOG=2 at study entry had to stop the treatment early. Biomarker expression in relation to treatment outcome will be available for the meeting. No significant financial relationships to disclose.
Expression of CALR mutants causes mpl-dependent thrombocytosis in zebrafish
Authors: K-H Lim, Y-C Chang, Y-H Chiang, H-C Lin, C-Y Chang, C-S Lin, L Huang, W-T Wang, C Gon-Shen Chen, W-C Chou, Y-Y Kuo
Journal: Blood Cancer Journal (2016)

CALR mutations are identified in about 30% of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET) and primary myelofibrosis. Although the molecular pathogenesis of CALR mutations leading to MPNs has been studied using in vitro cell lines models, how mutant CALR may affect developmental hematopoiesis remains unknown. Here we took advantage of the zebrafish model to examine the effects of mutant CALR on early hematopoiesis and model human CALR-mutated MPNs. We identified three zebrafish genes orthologous to human CALR, referred to as calr, calr3a and calr3b. The expression of CALR-del52 and CALR-ins5 mutants caused an increase in the hematopoietic stem/progenitor cells followed by thrombocytosis without affecting normal angiogenesis. The expression of CALR mutants also perturbed early developmental hematopoiesis in zebrafish. Importantly, morpholino knockdown of mpl but not epor or csf3r could significantly attenuate the effects of mutant CALR. Furthermore, the expression of mutant CALR caused jak-stat signaling activation in zebrafish that could be blocked by JAK inhibitors (ruxolitinib and fedratinib). These findings showed that mutant CALR activates jak-stat signaling through an mpl-dependent mechanism to mediate pathogenic thrombopoiesis in zebrafish, and illustrated that the signaling machinery related to mutant CALR tumorigenesis are conserved between human and zebrafish.
Active and passive tobacco exposure: a serious pediatric health problem. A statement from the Committee on Atherosclerosis and Hypertension in Children, Council on Cardiovascular Disease in the Young, American Heart Association.
Authors: Samuel Gidding, Wayne Morgan, Cheryl Perry, Josephine Isabel-Jones, J Bricker, Rae-Ellen Kavey, Stephen Bricker, Richard Daniels, Edward Deckelbaum, Samuel Fisher, Josephine Gidding, Gerald Isabel-Jones, Douglas Marx, Jack Teske, Mary Wilmore
Journal: Circulation (1994)

This review defines the substantial pediatric morbidity from tobacco use, including health effects on the cardiovascular system, the respiratory system, the fetus and newborn, and risk-taking behaviors of adolescents. More recent research suggests effects may extend to other areas, including reports that cigarette smoking decreases breast milk production in mothers, byproducts of tobacco use are transmitted in breast milk, exposure to passive smoking may alter children's intelligence and behavior, and passive smoke exposure in childhood may be a risk factor for developing lung cancer as an adult. Primary prevention is the most effective strategy to decrease the prevalence of smoking. Those who never smoke never become addicted to nicotine and never have to quit. Secondary prevention must also be emphasized, because children whose parents smoke are exposed to health risks and are themselves more likely to smoke in the future. Parental health can be improved by smoking cessation. To accomplish the goals of primary and secondary prevention, the aggressive public health strategy directed at both parents and children should be expanded. This strategy requires the strong support of physicians, with emphasis on prevention in practice, support of public health initiatives, medical and public policy, and the conduct of high-quality research.
Three decades of evolving treatment for melanoma: No improvement in survival?
Authors: S. E. Young, A. E. Giuliano, D. L. Morton
Journal: Journal of Clinical Oncology (2005)

7511 Background: Despite tremendous effort towards the development of novel treatments for advanced melanoma, a significant survival benefit has not been clearly documented. The objective of the current study is to determine whether the survival of AJCC stage III melanoma has improved over the past 30 years. Methods: A prospective database of >12,000 melanoma patients was used to identify patients evaluated and treated at our institution within 4 months of an AJCC stage III diagnosis. After exclusion of subjects receiving active specific immunotherapy, patients were assigned to 3 chronologic groups (Table). A computer program matched patients from each group by known prognostic variables (non-palpable/micrometastases vs. palpable/macrometastases nodes, number of metastatic nodes, and pT stage) to randomly create sets of patients. Results: From a cohort of 1,422 patients, 882 were matched into 294 sets. No significant inter-group differences in 5- or 10-year survival were observed (p=0.99). There were no survival differences in 232 matched sets with palpable nodes (P=0.58) or in 62 matched sets with non-palpable nodes (P=0.18) (Table). However, among patients matched by non-palpable nodes, those in the most recent group (III) tended towards better survival than those in the earlier groups (I/II) (68% vs. 54%, p=0.08). Conclusions: No overall survival advantage has been achieved in AJCC stage III melanoma patients over three decades. The accuracy of staging clinically negative disease has improved, however, with the advent of lymphatic mapping and sentinel lymphadenectomy (SLND), which was primarily utilized for patients in the most recent group (III). The trend towards improved survival in this group likely reflects stage migration from more accurately detected micrometastases. Modern imaging techniques probably have not significantly contributed to this increase in staging accuracy as there is no survival difference noted in patients with palpable nodal involvement. No significant financial relationships to disclose.
A Dose Finding Phase II Trial of Isatuximab (SAR650984, Anti-CD38 mAb) As a Single Agent in Relapsed/Refractory Multiple Myeloma
Authors: Thomas Martin, Joshua Richter, Ravi Vij, Craig Cole, Djordje Atanackovic, Jeffrey Zonder, Jonathan L. Kaufman, William Bensinger, Meletios A. Dimopoulos, Jesús San Miguel, Todd Zimmerman, Nikoletta Lendvai, Parameswaran Hari, Enrique M. Ocio, Cristina Gasparetto, Shaji Kumar, Karl Hsu, Eric Charpentier, Stephen A. Strickland, Joseph Mikhael
Journal: Blood (2015)
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck
Authors: Robert L. Ferris, George Blumenschein, Jerome Fayette, Joel Guigay, A. Dimitrios Colevas, Lisa Licitra, Kevin Harrington, Stefan Kasper, Everett E. Vokes, Caroline Even, Francis Worden, Nabil F. Saba, Lara C. Iglesias Docampo, Robert Haddad, Tamara Rordorf, Naomi Kiyota, Makoto Tahara, Manish Monga, Mark Lynch, William J. Geese, Justin Kopit, James W. Shaw, Maura L. Gillison
Journal: New England Journal of Medicine (2016)

Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition.In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life.The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group.Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).
Vaccination Coverage Among Children Aged 19–35 Months — United States, 2015
Authors: Holly A. Hill, Laurie D. Elam-Evans, David Yankey, James A. Singleton, Vance Dietz
Journal: MMWR Morbidity and Mortality Weekly Report (2016)

Sustained high coverage with recommended vaccinations among children has kept many vaccine-preventable diseases at low levels in the United States (1). To assess coverage with vaccinations recommended for children by age 2 years in the United States (2), CDC analyzed data collected by the 2015 National Immunization Survey (NIS) for children aged 19-35 months (born January 2012-May 2014). Overall, coverage did not change during 2014-2015. Coverage in 2015 was highest for ≥3 doses of poliovirus vaccine (93.7%), ≥3 doses of hepatitis B vaccine (HepB) (92.6%), ≥1 dose of measles, mumps, and rubella vaccine (MMR) (91.9%), and ≥1 dose of varicella vaccine (91.8%). The data were also examined for potential vaccination coverage differences by race/ethnicity, poverty status, and urbanicity. Although disparities were noted for each of these factors, the most striking differences were seen for poverty status. Children living below the federal poverty level* had lower coverage with most of the vaccinations assessed compared with children living at or above the poverty level; the largest disparities were for rotavirus vaccine (66.8% versus 76.8%), ≥4 doses of pneumococcal conjugate vaccine (PCV) (78.9% versus 87.2%), the full series of Haemophilus influenzae type b vaccine (Hib) (78.1% versus 85.5%), and ≥4 doses of diphtheria, tetanus, and acellular pertussis vaccine (DTaP) (80.2% versus 87.1%). Although coverage was high in some groups, opportunities exist to continue to address disparities. Implementation of evidence-based interventions, including strategies to enhance access to vaccination services and systems strategies that can reduce missed opportunities, has the potential to increase vaccination coverage for children living below the poverty level and in rural areas (3).
Sensitivity analyses for progression-free survival (PFS) and radiographic PFS (rPFS) from the phase II STRIVE trial comparing enzalutamide (ENZA) with bicalutamide (BIC) in men with castration-resistant prostate cancer (CRPC).
Authors: David F. Penson, Andrew J. Armstrong, Raoul S. Concepcion, Kenneth Wu, Fong Wang, Andrew P. Krivoshik, De Phung, Celestia S. Higano
Journal: Journal of Clinical Oncology (2016)

169 Background: STRIVE was arandomized, double-blind, phase 2 trial comparing ENZA vs BIC in nonmetastatic (M0) or metastatic (M1) CRPC. In this study, ENZA significantly reduced the risk of prostate cancer progression or death compared with BIC in patients with M0 or M1 CRPC. Methods: 396 men with M0 (n = 139) or M1 (n = 257) CRPC were randomized to ENZA 160 mg/day or BIC 50 mg/day. The primary endpoint of PFS was defined as the time from randomization to radiographic progression, PSA progression, or death from any cause, whichever occurred first. rPFS was defined as the time from randomization to death or the first objective evidence of radiographic disease progression in soft-tissue disease per RECIST v1.1 or in bone per PCWG2 guidelines. Sensitivity analyses were prespecified to assess the impact of alternative definitions for PFS in all patients and were performed post hoc for the key secondary endpoint of rPFS in patients with M1 disease only (table). Results: Consistent with the primary analyses of PFS and rPFS, the results from all sensitivity analyses favored ENZA over BIC (table). Conclusions: PFS and rPFS sensitivity analyses in STRIVE demonstrated a consistent and robust treatment benefit with ENZA compared with BIC by any variation of the original definition of PFS. Clinical trial information: NCT01664923. [Table: see text]
Zinc Deficiency In Patients Adults Undergoing To Hematopoietic Stem Cell Post-Transplantation
Authors: Andrea Z Pereira, Silva Bernardo Juliana, Silvia MF Pivocari, Marcia Tanaka, Barrere N Ana Paula, Fabiana Lucio, Claudio Galvão Castro, Andreza Alice Feitosa Ribeiro, Nelson Hamerschlak
Journal: Blood (2013)
POL5551, a Novel and Potent CXCR4 Antagonist, Enhances Sensitivity to Chemotherapy in an in Vivo Model of High-Risk (HR) Pediatric Acute Lymphoblastic Leukemia (ALL)
Authors: Edward Allan R. Sison, Daniel Magoon, Li Li, Barbara Romagnoli, Garry Douglas, Gerald Tuffin, Johann Zimmermann, Patrick Brown
Journal: Blood (2014)
Prognostic Relevance of Cytometric Quantitative Assessment in Patients with Myelodysplastic Syndromes.
Authors: B. Pollio, M.M. Ciriello, A. Fruttero, M. Geuna, A. Iavarone, P. Omede’, M. Pautasso, A.M. Pollono, A. Santagostino, G. Garbaccio Ioria, A. Stacchini, D. Gioia, D. Ferrero, F. Marmont, A. Gallamini, G. Saglio, Alessandro Levis, M. Girotto
Journal: Blood (2006)
mTORC2 Signaling Drives the Development and Progression of Pancreatic Cancer
Authors: David R. Driscoll, Saadia A Karim, Makoto Sano, David M. Gay, Wright Jacob, Jun Yu, Yusuke Mizukami, Aarthi Gopinathan, Duncan I. Jodrell, T.R. Jeffry Evans, Nabeel Bardeesy, Michael N. Hall, Brian J. Quattrochi, David S. Klimstra, Simon T. Barry, Owen J. Sansom, Brian C. Lewis, Jennifer P. Morton
Journal: Cancer Research (2016)

Abstract mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor deletion resulted in profoundly delayed tumorigenesis. Whereas previous studies showed most pancreatic tumors were insensitive to rapamycin, treatment with a dual mTORC1/2 inhibitor strongly suppressed tumorigenesis. In late-stage tumor-bearing mice, combined mTORC1/2 and PI3K inhibition significantly increased survival. Thus, targeting mTOR may be a potential therapeutic strategy in pancreatic cancer. Cancer Res; 76(23); 6911–23. ©2016 AACR.
Tunneling nanotubes and intercellular communication: Differences between platinum-resistant and platinum-sensitive ovarian cancer.
Authors: Elizabeth Louise Dickson, Venugopal Thayanithy, Rachel Isaksson Vogel, Peter Argenta, Melissa Ann Geller, Subbaya Subramanian, Emil Lou
Journal: Journal of Clinical Oncology (2013)

e22007 Background: Preliminary evidence suggests that cell-to-cell communication may be responsible for the development of chemotherapy resistance in ovarian cancer. We propose tunneling nanotubes (TnTs) – long, thin actin-based cell extensions – as novel candidates to explain direct communication between treatment-refractory malignant ovarian cells. The purpose of this study was to investigate TnT formation between ovarian cancer cells in vitro. Methods: Using platinum-sensitive (A2780) and resistant (C200 and SKOV3, as well as ES2) ovarian cancer cell lines, we tested various conditions to assess factors affecting TnT formation. Scratch assays were utilized as a 2-dimensional simulation of ovarian cancer invasion. To assess TnTs as a conduit for transmission of therapeutic drugs between connected cells, we used doxorubicin, which auto-fluoresces in cell culture. Results: We determined that a hyperglycemic, low-serum, acidic medium stimulated TnT formation between all ovarian cancer cells studied, and more significantly, formed direct connections between A2780 to both C200 and SKOV3 cell lines. Conversely, Everolimus or Metformin decreased TnT formation in all cell lines with continuous exposure up to 96 hours; most prominently for the platinum-sensitive cell line. Time-lapse microscopy was used to assess chronologic formation of TnTs at the advancing front of the scratch wound. Cell proliferation assays were performed and confirmed the decrease in TnTs was not due to decreased cell proliferation. We directly observed fluorescing doxorubicin within the TnTs, suggesting TnTs act as a transport mechanism for cellular communication. Conclusions: TnT formation is stimulated in conditions of cellular stress similar to those experienced in vivo and results in direct connections between cells. Our data suggests that these conduits are a potential means of cellular exchange between platinum-sensitive and resistant ovarian cancer cells. Using currently available agents to target TnTs and disrupt this communication provides a novel approach to understanding and treating the problem of platinum resistance in ovarian cancer.
Multicenter open label study of epoetin beta prevention and treatment for anaemia in non-small cell lung cancer patients treated with chemotherapy prone to induce anaemia
Authors: J. Yang, Y. Wu, D. Yu, C. Huang, C. Zhou, Y. Cheng, G. Chen, S. Lu, B. Han, Y. Lin, J. Wang
Journal: Journal of Clinical Oncology (2008)

20743 Background: To determine the efficacy and safety of epoetin beta in the prevention and treatment of anaemia in non-small cell lung cancer (NSCLC) patients treated with chemotherapy. Methods: It is a multicenter, open-label, single-arm study. All eligible patients receive treatment of epoetin beta subcutaneously 3 times weekly at the initial dose of 150 IU/kg for 16 weeks. Primary efficacy parameter is the percentage of patients with increase in haemoglobin values by ≥ 2 g/dl compared to baseline without blood transfusion in previous 6 weeks (defined as response rate). Secondary efficacy parameters are increase in haemoglobin,number and volume of blood transfusion per patient and red cell count. Safety includes blood pressure, adverse events and serious adverse event. Median progression-free survival (mPFS) is calculated only for the advanced NSCLC patients in the first line setting.Statistical computations are performed with SPSS13.0. Results: 26 male and 24 female NSCLC patients treated with chemotherapywere enrolled in this study from October 12, 2006 to December 8, 2006. Response rate of epoetin beta is 74% for intent-to-treatment (ITT) analysis population but 86% for Per-Protocol (PP) analysis population; haemoglobin has increased significantly since the 4th week and is significantly different among different duration of epoetin beta treatment, and change of red cell count is similar to that of haemoglobin. Fewer patients (4%, 2/50) need blood transfusion. After epoetin beta treatment, blood pressure shows no significant difference compared to the baseline. Safety of epoetin beta is good. Grade 3/4 adverse events: neutropenia 14%, diarrhea 2%, vomitting 2%, palpitation 2%, anemia 2%, oral ulcers 2% and arrhythmia (serious adverse events) 2%, all of which were not related to epoetin beta. When epoetin beta is used, mPFS was 152.0 days, 95% CI (115.9∼188.1) for those in the first line setting. Conclusions: Epoetin beta may prevent and treat anaemia in non-small cell lung cancer (NSCLC) patients treated with chemotherapy. No significant financial relationships to disclose.