tbuckley/cabot-search huggingface dataset:
Factors affecting epirubicin pharmacokinetics and toxicity: evidence against using body-surface area for dose calculation.
Authors: H P Gurney, S Ackland, V Gebski, G Farrell
Journal: Journal of Clinical Oncology (1998)

An exploratory study to test whether body-surface area (BSA) should be used for the calculation of epirubicin dose.The relationship between pretreatment characteristics and the effects of epirubicin were investigated in 20 chemotherapy-naive patients. Measurements of body size, renal and hepatic function, and other factors were correlated with epirubicin pharmacokinetics (PK) and epirubicin-induced neutropenia. All patients received 150 mg of epirubicin infused continuously over 120 hours, regardless of body size. Factors were analyzed by univariate and multivariate linear regression.There were no correlations between BSA or weight with any PK parameter or with the degree of neutropenia. In multivariate analysis, indicators of liver function were the only factors that correlated with neutropenia and epirubicin PK. Thus, correlations for neutropenia were seen with antipyrine clearance (P = .003), activated partial thromboplastin time (APTT) (P = .005) and serum transferrin (P = .01). Further, the area under the concentration-time curve (AUC) for epirubicin correlated with prothrombin index (P < .01), antipyrine clearance (P < .01), and serum bile salt concentration (P = .03), and there were similar correlations for epirubicin steady-state concentration (CpSS). Epirubicin clearance correlated with antipyrine clearance (P = .02). PK parameters for dihydroepirubicin correlated with prothombin index, serum transferrin, and bile salt concentrations (P < .001 for all correlations). Because of the number of statistical examinations performed, some of these correlations may be spurious. However, some are likely to be real, since the same variables repeatedly correlated with different epirubicin-associated outcomes. There were no correlations between epirubicin PK indices or neutropenia and serum aminotransferase levels or other biochemical liver function tests, creatinine, or any of the clinical factors examined.These results led us to question the use of BSA for epirubicin dose calculation. In contrast, quantitative liver function tests may give a better indication of drug handling and toxicity and may be useful to determine more accurate methods for dose calculation of epirubicin.
Host Genetic Control of Spontaneous and Induced Immunity to Friend Murine Retrovirus Infection
Authors: B Chesebro, M Miyazawa, W J Britt
Journal: Annual Review of Immunology (1990)

Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector functions, high and sustained inhibitory receptor expression, ...Read More
The combined neurosurgical-thoracic management of superior sulcus tumors.
Authors: N Sundaresan, B S Hilaris, N Martini
Journal: Journal of Clinical Oncology (1987)

Thirty patients with superior sulcus carcinoma were prospectively evaluated over an 18-month period. All patients underwent complete neuroradiological evaluation by computed tomography (CT) and myelography. Prior to operation, brachial plexopathy was noted in 20 patients (67%), and invasion of the spine in eight (27%). Using a team approach, gross total resection of tumor was achieved in 17 of 26 patients (65%) undergoing thoracotomy. There was no operative mortality. The use of a team approach allows extended surgical resection, especially when the spine is involved. In patients presenting with brachial plexopathy or cord compression, de novo surgery before radiation may provide better long-term palliation and pain relief.
Intravenous mercaptopurine: life begins at 40.
Authors: D Pinkel
Journal: Journal of Clinical Oncology (1993)

This review is intended to provide a concise portrayal of the background, rationale, and current use of intravenous infusions of mercaptopurine (6MP) in patients with acute leukemia.After a brief description of the mode of action of 6MP and the formulation, pharmacokinetics, and history of its intravenous administration, the rationale for current use of intravenous 6MP infusion is explained. Subsequently, the review summarizes and discusses clinical experience with intravenous 6MP alone and in combination with intravenous methotrexate (Mtx) and cytarabine (Ara-C).Although still an investigative drug, intravenous 6MP has been used for 40 years and currently is being administered extensively to children with previously untreated acute lymphoid leukemia (ALL) in frontline protocol studies. The reasons are the better and more consistent bioavailability of intravenous versus oral MP, higher blood and CSF levels, compliance, and preliminary evidence suggesting superior remission experience for intravenous Mtx and 6MP than for Mtx alone. The apparent lack of late adverse sequelae with 6MP as compared with other antileukemia drugs adds to this interest.The new life of intravenous 6MP at age 40 years illustrates the need for continued investigation of significant anticancer drugs as insights and technology progress.
A reassessment of the role of second-look laparotomy in advanced ovarian cancer.
Authors: A G Ho, U Beller, J L Speyer, N Colombo, J Wernz, E M Beckman
Journal: Journal of Clinical Oncology (1987)

Thirty-nine patients with stage III and IV epithelial ovarian cancer who underwent second-look laparotomy (SLL) at New York University Medical Center and 11 eligible patients who did not undergo reexploration were retrospectively studied with follow-up from 24 to 105 months after diagnosis. Sixteen patients (41%) were found to have macroscopic disease, six (15%) microscopic tumor, and 17 (44%) no disease at SLL. Five of 22 patients who received further therapy based on positive SLL findings have remained without clinical evidence of disease 17 to 65 months after SLL. Nine of 17 patients with negative SLL, in whom treatment was stopped, recurred 8 to 52 months after SLL, five in extraperitoneal sites only. Five of 11 patients not undergoing SLL recurred 16 to 39 months after diagnosis, four intraperitoneally. There was no significant difference in survival between the second-look and no second-look groups for the period of study. Clinical trials are needed to determine if SLL influences longer-term survival and if continued treatment is indicated in a high-risk subgroup despite negative SLL. The value of SLL is limited by the efficacy of second line therapy. The role of routine SLL outside an investigational setting is questioned.
5-aza-deoxycytidine (5-Aza-dC) restores interferon-stimulated gene (ISG) expression and IFN-induced anti-proliferative effects in melanoma cells
Authors: Yan wu, Barbara S Jacobs, Ernest C Borden
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

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Anti-tumor effects of IFNs are mediated by a set of IFN-stimulated genes (ISGs). Suppression of expression of ISGs or IFN-pathway products may underlie resistance to IFNs. We have previously identified aberrant methylation of RASSF1A, XAF1, and TRAIL-R1 as blunting apoptosis induction by IFNs (Borden E, Cytokine Growth Factor Revs 18:491, 2007). To identify other ISGs which might be methylation silenced, real-time RT-PCR was undertaken to assess relative expression levels of selected ISGs. Ten melanoma cell lines A375, SKMEL-1, SKMEL-3, SKMEL-28, WM164, WM3211, C32TG, FEMX, MEWO and LUC451 were treated with 0.2 µM of 5-Aza-dC daily for 4 days, total RNA isolated, and relative gene expression quantified compared to untreated control. ISGs augmented >6x in two or more cell lines were IRF5, IRF7, IRF8, fas, fasL, MyD88, BST2, and IFIT2. Particularly marked (>12x) were increases in the potential tumor suppressor BST2 in 6/10 and fasL in 3/6 cell lines. In contrast, the ISGs IRF1, HLA-A, and IFITM1 were not increased in any of the melanoma cell lines. MAGEA1, whose T cell recognition could be enhanced by IFNs, was confirmed as increased >20x in 6/10 cell lines. These studies provide a basis for assessment of reversal of DNA methylation by quantitative RT-PCR and expanded association of induction of apoptosis with other ISGs. The data also further support reversal of methylation as an approach to enhance clinical effects of IFN-α2 in melanoma.
Effects of Ranolazine on Angina and Quality of Life After Percutaneous Coronary Intervention With Incomplete Revascularization
Authors: Karen P. Alexander, Giora Weisz, Kristi Prather, Stefan James, Daniel B. Mark, Kevin J. Anstrom, Linda Davidson-Ray, Adam Witkowski, Angel J. Mulkay, Anna Osmukhina, Ramin Farzaneh-Far, Ori Ben-Yehuda, Gregg W. Stone, E. Magnus Ohman
Journal: Circulation (2015)

Background— Angina often persists or returns in populations following percutaneous coronary intervention (PCI). We hypothesized that ranolazine would be effective in reducing angina and improving quality of life (QOL) in incomplete revascularization (ICR) post-PCI patients. Methods and Results— In RIVER-PCI, 2604 patients with a history of chronic angina who had ICR post-PCI were randomized 1:1 to oral ranolazine versus placebo; QOL analyses included 2389 randomized subjects. Angina and QOL questionnaires were collected at baseline and months 1, 6, and 12. Ranolazine patients were more likely than placebo to discontinue study drug by month 6 (20.4% versus 14.1%, P &lt;0.001) and 12 (27.2% versus 21.3%, P &lt;0.001). Following qualifying index PCI, the primary QOL outcome (Seattle Angina Questionnaire [SAQ] angina frequency score) improved markedly, but similarly, in the ranolazine and placebo groups, respectively, from baseline (67.3±24.5 versus 69.7±24.0, P =0.01) to month 1 (86.6±18.1 versus 85.8±18.5, P =0.27) and month 12 (88.4±17.8 versus 88.5±17.8, P =0.94). SAQ angina frequency repeated measures did not differ in adjusted analysis between groups post baseline (mean difference 1.0; 95% CI -0.2, 2.2; P =0.11). Improvement in SAQ angina frequency was observed with ranolazine at month 6 among diabetics (mean difference 3.3; 95% CI 0.6, 6.1; P =0.02) and those with more angina (baseline SAQ angina frequency ≤60; mean difference 3.4; 95% CI 0.6, 6.2; P =0.02), but was not maintained at month 12. Conclusions— Despite ICR following PCI, there was no incremental benefit in angina or QOL measures by adding ranolazine in this angiographically-identified population. These measures markedly improved within 1 month of PCI and persisted up to 1 year in both treatment arms. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01442038.
Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen
Authors: Tian-Ying Zhang, Quan Yuan, Jing-Hua Zhao, Ya-Li Zhang, Lun-Zhi Yuan, Ying Lan, Yu-Chieh Lo, Cheng-Pu Sun, Chang-Ru Wu, Jun-Fang Zhang, Ying Zhang, Jia-Li Cao, Xue-Ran Guo, Xuan Liu, Xiao-Bing Mo, Wen-Xin Luo, Tong Cheng, Yi-Xin Chen, Mi-Hua Tao, James WK Shih, Qin-Jian Zhao, Jun Zhang, Pei-Jer Chen, Y Adam Yuan, Ning-Shao Xia
Journal: Gut (2015)

<h3>Objective</h3> This study aimed to investigate the therapeutic potential of monoclonal antibody (mAb) against HBV as a novel treatment approach to chronic hepatitis B (CHB) in mouse models. <h3>Methods</h3> Therapeutic effects of mAbs against various epitopes on viral surface protein were evaluated in mice mimicking persistent HBV infection. The immunological mechanisms of mAb-mediated viral clearance were systematically investigated. <h3>Results</h3> Among 11 tested mAbs, a novel mAb E6F6 exhibited the most striking therapeutic effects in several HBV-persistent mice. Single-dose administration of E6F6 could profoundly suppress the levels of hepatitis B surface antigen (HBsAg) and HBV DNA for several weeks in HBV-transgenic mice. E6F6 regimen efficiently prevented initial HBV infection, and reduced viral dissemination from infected hepatocytes in human-liver-chimeric mice. E6F6-based immunotherapy facilitated the restoration of anti-HBV T-cell response in hydrodynamic injection (HDI)-based HBV carrier mice. Immunological analyses suggested that the Fcγ receptor-dependent phagocytosis plays a predominant role in E6F6-mediated viral suppression. Molecular analyses suggested that E6F6 recognises an evolutionarily conserved epitope (GPCK(R)TCT) and only forms a smaller antibody–viral particle immune complex with limited interparticle crosslinking when it binds to viral particles. This unique binding characteristic of E6F6 to HBV was possibly associated with its effective in vivo opsonophagocytosis for viral clearance. <h3>Conclusions</h3> These results provided new insight into understanding the therapeutic role and mechanism of antibody against persistent viral infection. The E6F6-like mAbs may provide a novel immunotherapeutic agent against human chronic HBV infection.
Abstract 3486: Synergistic effect of quinacrine in combination with decitabine for the treatment of acute myeloid leukemia cells <i>in vitro</i>: implication for treatment of AML in the elderly
Authors: Wenge Wang, David T. Dicker, David F. Claxton, Hong-Gang Wang, Wafik S. El-Deiry
Journal: Cancer Research (2015)

Abstract Demethylating agents remain one of the few options for treatment of AML in the elderly; however, the response rate is limited. In searching for p53 pathway activating agents for cancer therapy, we found that quinacrine is a potent p53 stimulator and induces tumor cell death. Quinacrine also induces expression of Death Receptor 5 (DR5), reduces expression of anti-apoptotic Mcl-1, and suppresses NFkB activity in tumor cells. Because of its acceptable toxicity profile, history of use in humans, and relevance of the target pathways modulated by quinacrine we explored whether it may serve as a potent anti-leukemia drug as most leukemia cells carry a wild-type p53. We tested the cytotoxic effects of quinacrine on malignant hematopoietic cell lines derived from patients with myeloid leukemia, including HL-60, MOLM-13, and MV4-11. We found that quinacrine induces massive cell death in the cell lines tested, at concentrations from as less as 1 microM to 5 microM, 2-10 times lower than required to induce solid tumor cell death. Most interestingly, quinacrine facilitates cell death in decitabine pre-treated leukemia cells in a synergistic manner. Further mechanistic studies showed that quinacrine stabilizes p53, induces Mcl-1 degradation, and PARP cleavage in treated cells. Our work supports translational efforts to advance the use of quinacrine from the bench to the clinic and provides a preliminary rationale for its combination with decitabine for the treatment of AML. Citation Format: Wenge Wang, David T. Dicker, David F. Claxton, Hong-Gang Wang, Wafik S. El-Deiry. Synergistic effect of quinacrine in combination with decitabine for the treatment of acute myeloid leukemia cells in vitro: implication for treatment of AML in the elderly. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3486. doi:10.1158/1538-7445.AM2015-3486
Incidence of Suicide Among Persons Who Had a Parent Who Died During Their Childhood
Authors: Mai-Britt Guldin, Jiong Li, Henrik Søndergaard Pedersen, Carsten Obel, Esben Agerbo, Mika Gissler, Sven Cnattingius, Jørn Olsen, Mogens Vestergaard
Journal: JAMA Psychiatry (2015)

Parental death from suicide is associated with increased risk of suicide in the bereaved child, but little is known about the long-term risks of suicide after parental death from other causes. A better understanding of this association may improve suicide prevention efforts.To examine the long-term risks of suicide after parental death and how the risk trajectories differed by cause of parental death while accounting for major potential confounding variables.A population-based matched cohort study was performed using information from nationwide registers (data from 1968 to 2008) in 3 Scandinavian countries (for a total of 7,302,033 persons). We identified 189,094 children (2.6%) who had a parent who died before the child reached 18 years of age (ie, the bereaved cohort). Each bereaved child was matched by sex and age to 10 children who did not have a parent who died before they reached 18 years of age (for a total of 1,890,940 children) (ie, the reference cohort). Both cohorts were followed for up to 40 years. Poisson regression was used to calculate the incidence rate ratio (IRR), while accounting for age at parental death, sex, time since bereavement, maternal/paternal death, birth order, family history of psychiatric illness, and socioeconomic status. Data analyses were finalized June 24, 2015.The main exposure was death of a parent within the first 18 years of life.Incidence of suicide among persons who had a parent who died during their childhood.During follow-up, 265 bereaved persons (0.14%) and 1342 nonbereaved persons (0.07%) died of suicide (IRR = 2.02 [95% CI, 1.75-2.34]); IRR = 3.44 (95% CI, 2.61-4.52) for children who had a parent who died of suicide, and IRR = 1.76 (95% CI, 1.49-2.09) for children who had a parent who died of other causes. The IRR tended to be higher for children who had a parent who died before they reached 6 years of age, and the IRR remained high for at least 25 years. During 25 years of follow-up, the absolute risk of suicide was 4 in 1000 persons for boys who experienced parental death and 2 in 1000 persons for girls who experienced parental death.Parental death in childhood is, irrespective of cause, associated with an increased long-term risk of suicide. The consequences of parental death in childhood are far-reaching, and suicide risk trajectories may be influenced by early-life conditions. Future public health efforts should consider helping highly distressed children to cope with bereavement.
Localized extremity soft tissue sarcoma: an analysis of factors affecting survival.
Authors: C Collin, J Godbold, S Hajdu, M Brennan
Journal: Journal of Clinical Oncology (1987)

The management of extremity soft tissue sarcoma is undergoing rapid change as new techniques of adjuvant treatment are developed. Critical assessment of these advances requires a fundamental understanding of the natural course of this disease. In an effort to define important prognostic factors, this review of 423 adults with localized extremity soft tissue sarcomas, treated at one institution (1968 to 1978), was undertaken. The effect of the following variables on survival was examined: patient factors, ie, age, sex, symptoms, and status at presentation; tumor factors, ie, site, size, depth, bone or neurovascular invasion, histogenesis, grade, and nodal status; and treatment factors, ie, biopsy technique, type of operation, surgical margins, adjuvant treatment, and subsequent local treatment failure. Patient factors with an adverse impact on survival included age greater than 53 and the presence of local symptoms. High tumor grade, positive regional nodes, histology other than liposarcoma, fibrosarcoma or malignant fibrohistiocytoma, invasion of vital structures, proximal site, deep location, and size greater than 10 cm were also poor prognosticators. Treatment factors correlating with optimal survival included limb sparing surgery, adequate margins, biopsy with delayed definitive resection, and absence of subsequent local failure. Patients treated by amputation had a greater proportion of risk factors than patients treated with limb-sparing surgery (LSS). When the data were subjected to multivariate analysis, the following variables emerged as independent predictors of poor outcome: local symptoms, age greater than 53, high grade, proximal site, size greater than 10 cm, positive regional nodes, surgery by amputation, and inadequate margins. These factors are now to be evaluated in our prospective study based on 600 patients with soft tissue sarcoma of all sites admitted to our institution in the last 3 years. These factors should be considered as important stratifications in prospective trials.
Observational Cohort Study of 1St Line Bevacizumab Combined with Chemotherapy in Metastatic Colorectal Cancer: Hgcsg0802
Authors: Michio Nakamura, Satoshi Yuki, Kazuaki Harada, Yoshimitsu Kobayashi, Takashi Kato, Minoru Uebayashi, Norikazu Sonoda, Kazunori Eto, Takenori Takahata, Yoshito Komatsu
Journal: Annals of Oncology (2014)
GC-14ENDOCRINOPATHY AFTER INTRACRANIAL GERM CELL TUMOURS (IGCT) IS DISEASE NOT RADIATION- RELATED: TWO DECADES OF SURVEILLANCE IN A LARGE TERTIARY PAEDIATRIC COHORT
Authors: Eftychia Ioanna Dimitrakopoulou, Jasmine Chow, Joana Serra Caetano, Ash Ederies, Sara Stoneham, Helen Spoudeas
Journal: Neuro-Oncology (2016)
Quantitative Dual-Energy Computed Tomography Supports a Vascular Etiology of Smoking-induced Inflammatory Lung Disease
Authors: Krishna S. Iyer, John D. Newell, Dakai Jin, Matthew K. Fuld, Punam K. Saha, Sif Hansdottir, Eric A. Hoffman
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Endothelial dysfunction is of interest in relation to smoking-associated emphysema, a component of chronic obstructive pulmonary disease (COPD). We previously demonstrated that computed tomography (CT)-derived pulmonary blood flow (PBF) heterogeneity is greater in smokers with normal pulmonary function tests (PFTs) but who have visual evidence of centriacinar emphysema (CAE) on CT.We introduced dual-energy CT (DECT) perfused blood volume (PBV) as a PBF surrogate to evaluate whether the CAE-associated increased PBF heterogeneity is reversible with sildenafil.Seventeen PFT-normal current smokers were divided into CAE-susceptible (SS; n = 10) and nonsusceptible (NS; n = 7) smokers, based on the presence or absence of CT-detected CAE. DECT-PBV images were acquired before and 1 hour after administration of 20 mg oral sildenafil. Regional PBV and PBV coefficients of variation (CV), a measure of spatial blood flow heterogeneity, were determined, followed by quantitative assessment of the central arterial tree.After sildenafil administration, regional PBV-CV decreased in SS subjects but did not decrease in NS subjects (P < 0.05), after adjusting for age and pack-years. Quantitative evaluation of the central pulmonary arteries revealed higher arterial volume and greater cross-sectional area (CSA) in the lower lobes of SS smokers, which suggested arterial enlargement in response to increased peripheral resistance. After sildenafil, arterial CSA decreased in SS smokers but did not decrease in NS smokers (P < 0.01).These results demonstrate that sildenafil restores peripheral perfusion and reduces central arterial enlargement in normal SS subjects with little effect in NS subjects, highlighting DECT-PBV as a biomarker of reversible endothelial dysfunction in smokers with CAE.