tbuckley/cabot-search huggingface dataset:
Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed for <i>KRAS</i>-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial.
Authors: Karen Kelly, Julien Mazieres, Natasha B. Leighl, Fabrice Barlesi, Gerard Zalcman, Michael S. Gordon, Karen L. Reckamp, David R. Gandara, Carlos Alberto Gomez-Roca, Jaafar Bennouna, Byoung Chul Cho, Keunchil Park, Jeffrey R. Infante, Donald A. Richards, Yuehui Wu, Daniel J. Schramek, Donna S. Cox, Olivia S. Gardner, Vijay Gopal Reddy Peddareddigari, George R. Blumenschein
Journal: Journal of Clinical Oncology (2013)

8027 Background: Lung cancer patients with mutated KRAS tumors present a treatment challenge. Trametinib + pemetrexed (pem) enhanced growth inhibition and apoptosis compared with either agent alone in lung cancer cell lines with WT or mutated RAS/RAF. Methods: This 2-part, multiarm, phase I/Ib, open-label study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase II dose (RP2D) for trametinib + pem in patients (pts) with advanced solid tumors. In part 2, NSCLC pts were stratified as KRAS WT or mutation unknown (WT) or KRAS-mutant (KRAS) and were treated with trametinib + pem at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Exploratory mutational profiling was done using circulating-free DNA from plasma and available archival tumor tissue. Results: As of January 2013, 42 NSCLC pts (22 WT [82% had ≥ 2 prior therapies], 20 KRAS [55% had ≥ 2 prior therapies]) have been treated at the trametinib + pem RP2D (1.5 mg + 500 mg/m 2 ). Nausea, fatigue, and peripheral edema were the 3 most frequent toxicities. 26% of pts reported grade 3-4 hematologic toxicity. Dose reduction occurred in 15 pts (33%), most often for diarrhea, decreased ejection fraction, and fatigue (all 7%). Preliminary PK suggests no drug-drug interaction. In KRAS pts, the best investigator-assessed response (confirmed + unconfirmed) was 3 partial response (PR; RR = 15%) and 10 stable disease (SD; 50%); additionally, 3 pts had &gt; 20% tumor shrinkage. The disease control rate (DCR) was 65%. Final response and progression-free survival (PFS) data will be reported upon maturity. In WT pts, 3 PR (RR = 14%) and 13 SD (59%) were observed (73% DCR); preliminary median PFS was 5.8 months (95% CI, 2.8-6.7 months). Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are ongoing. Conclusions: MEK inhibition with trametinib + pem demonstrates tolerability and clinical activity in both KRAS-mutant and WT NSCLC, exceeding expectations for each drug alone and warranting further study. Clinical trial information: NCT01192165.
Mebendazole in the treatment of melanoma: The role of Bcl-2 in predicting response and enhancing efficacy.
Authors: N. A. Doudican, R. Pennell, S. Byron, P. Pollock, L. Liebes, I. Osman, S. Orlow
Journal: Journal of Clinical Oncology (2010)

e19021 Background: Mebendazole (MBZ), a microtubule binding agent, is a potent inducer of apoptosis in a panel of melanoma cells, yet largely non-toxic to melanocytes (Mol Cancer Res, Aug 2008). We sought to enhance the clinical potential of MBZ by examining its anti-melanoma growth inhibition in combination with other melanoma chemotherapies (temozolomide (TMZ) and Bcl-2 anti-sense) as well as determine molecular markers of MBZ sensitivity. Methods: MBZ, TMZ and Bcl-2 anti-sense-induced melanoma growth inhibition were analyzed using MTT assay in SKM-173 and A375 metastatic melanoma cells. Drug interaction was analyzed through calculations of the combination index (CI) using Calcusyn software. Bcl-2 expression was determined by immunoblotting. MBZ GI50 values were calculated from dose response curves generated from cellular proliferation assays. Results: Combination MBZ and Bcl-2 antisense treatment resulted in enhanced growth inhibition in A375 and SKM-173 melanoma cell lines with CI values indicative of synergy. The addition of TMZ to MBZ and Bcl-2 antisense treatment further enhanced melanoma growth inhibition in both in A375 and SKM-173 cells. Moreover, MBZ resistance may be associated with reduced Bcl-2 expression as the average MBZ GI50 in melanoma cells with high Bcl-2 expression is 0.63 μ M in contrast to 9.2 μ M for low Bcl-2 expressing melanoma cells. Conclusions: These results impact on future in-vivo trials and suggest that the clinical benefit of MBZ may be best realized when administered in combination with Bcl-2 antisense and/or TMZ to melanoma patients with low levels of Bcl-2 expression. No significant financial relationships to disclose.
miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells
Authors: Eric R. Lechman, Bernhard Gentner, Stanley W.K. Ng, Erwin M. Schoof, Peter van Galen, James A. Kennedy, Silvia Nucera, Fabio Ciceri, Kerstin B. Kaufmann, Naoya Takayama, Stephanie M. Dobson, Aaron Trotman-Grant, Gabriela Krivdova, Janneke Elzinga, Amanda Mitchell, Björn Nilsson, Karin G. Hermans, Kolja Eppert, Rene Marke, Ruth Isserlin, Veronique Voisin, Gary D. Bader, Peter W. Zandstra, Todd R. Golub, Benjamin L. Ebert, Jun Lu, Mark Minden, Jean C.Y. Wang, Luigi Naldini, John E. Dick
Journal: Cancer Cell (2016)

To investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance.
A randomized, double-blind study comparing corticorelin acetate with dexamethasone in patients with primary malignant glioma who require increased dexamethasone doses to control symptoms of peritumoral brain edema
Authors: W. R. Shapiro, L. Mechtler, L. Cher, H. Wheeler, V. Hines, R. Milsted, P. C. O'Connor, R. P. Ryan, L. Recht
Journal: Journal of Clinical Oncology (2009)

2080 Background: Corticorelin acetate (CrA) is a synthetic peptide of corticotropin-releasing factor, undergoing clinical trials as a treatment for peritumoral edema in patients with cerebral tumors. This study compared CrA therapy vs an increase in dexamethasone (dex) dose (+4 mg) for controlling symptoms in primary glioma patients with a subacute exacerbation. Methods: In addition to their prestudy dex dose, patients were randomized to receive CrA 1 mg bid SC or control (+4 mg dex PO) for 8 weeks. Patients were evaluated at baseline and during weeks 1 and 2 for their neurologic status, Karnofsky Performance Score (KPS), and continuing dex requirements. The primary endpoint was response, defined as no post-baseline increase in dex dose &gt;4 mg for &gt;1 day; stable or improved KPS; and ≥25% improvement in 10-item Neurological Examination Score during weeks 1 and 2. Dex therapy requirements were also evaluated. The study aimed to enroll 120 patients, but was terminated with only 37 patients (20 CrA, 17 control) due to slow recruitment. Results: Formal statistical analyses were not undertaken due to the small sample size. The treatment groups had similar demographic and baseline disease characteristics. Despite the small numbers, the data suggest that CrA treatment had similar efficacy to increased dex: (1) The proportions of responders were similar (CrA 3/20; control 3/17); (2) Comparable proportions of patients completed 8 weeks’ treatment (CrA 16/20; control 12/17); (3) After randomization of blinded study drug (CrA or dex 4 mg), dex dosing remained stable for most patients in each arm (CrA 12/20; control 11/17); (4) The mean daily dex dose was 3 mg in the CrA arm and 7 mg in the control arm. There was a lower incidence of cushingoid symptoms in the CrA arm (CrA 1/20, control 3/17). Patients in the CrA arm reported more injection site erythema and flushing vs. the control arm. CrA was well tolerated and no patient withdrew from the trial because of CrA side effects. Conclusions: CrA may be of value in managing patients with cerebral tumors who have subacute exacerbations of their symptoms, without needing to increase their dex dose. [Table: see text]
Normalization of prostate specific antigen (PSA) in patients treated with intensity modulated radiotherapy (IMRT) for clinically localized prostate cancer
Authors: P. Y. Chun, G. D. A. Padula, M. H. Rahbar, J.-P. He, T. Bichay, C. M. Wilkinson, J. M. Kane
Journal: Journal of Clinical Oncology (2005)

4771 Background: In this study, we determined the expected time to Prostate Specific Antigen (PSA) normalization with or without neoadjuvant androgen deprivation therapy (NAAD) after treatment with Intensity Modulated Radiotherapy (IMRT) for patients with clinically localized prostate cancer. Methods: Fifty-five patients with clinical stage T1c to T2b prostate cancer (1997 AJCC staging) treated in a community setting with IMRT between January 2002 and February 2003 were retrospectively reviewed for time to PSA normalization (using PSA<2 ng/mL and PSA<1 ng/mL as criteria). Of these 55 patients, 22 (40%) received NAAD, whereas 33 (60%) did not. In 24 patients (47%), radiotherapy was delivered to a limited pelvic field followed by an IMRT boost; 31 patients (53%) received IMRT alone. Median pretreatment PSA was 7.6 (r=1.95–34). Median radiotherapy dose was 75.6 Gy. Median follow-up was 7.4 months (r=0.5–16). Actuarial times to PSA normalization were calculated using the Kaplan-Meier method. Univariate analyses were performed on hypothesized predictors of PSA normalization using the Cox Proportional Hazards Model. Results: Serum PSA values normalized to <2 in 46 of 54 (85%) patients and <1 in 37 of 55 (67%) patients analyzed. The actuarial mean time to normalization was 4.5 months for PSA<2 and 5.9 months for PSA<1. The mean time to normalization of PSA<2 was 2.1 months for patients receiving NAAD versus 6.1 months for patients not receiving NAAD (p=0.002). Mean time to normalization of PSA<1 was 2.5 months for patients receiving NAAD versus 8.3 months months for those not receiving NAAD (p=0.002). PSAs of patients receiving NAAD were 2.9 times more likely than those not receiving NAAD to become <2 (95% CI: 1.54–5.58), and 3.5 times more likely to become <1 (95% CI: 1.68–7.13). Conclusions: In this study with limited followup, the expected time to normalization of serum PSA after IMRT may be measured in months. Using PSA<1 ng/mL as the criterion for normalization, PSA may take an extensive period of time to achieve normalization after IMRT. NAAD given with IMRT predicts for shortened time to PSA normalization. No significant financial relationships to disclose.
Suicide in the Naval Service
Authors: Marc A. Schuckit, E.K. Eric Gunderson
Journal: American Journal of Psychiatry (1974)

The authors analyzed records of all suicides in the naval service between July 1965 and January 1972 by officer/enlisted-man status. Officer suicides were demographically similar to civilian suicides, but enlisted men were relatively younger. Data on this sample are compared with demographic data on men in the naval service who attempted or threatened suicide and with the general service population. A relatively small proportion of the suicide sample (10 percent) had had in-service psychiatric hospitalizations. The authors discuss their findings in relation to possibilities for increased detection of the potential for suicide.
Abstract 17786: Novel Non-invasive Techniques for Assessing Dynamic Pulmonary Vascular Function: Potential Roles for Dobutamine Stress Echocardiography and Postural Single Photon Emission Computed Tomography
Authors: Edmund M Lau, Elizabeth A Bailey, Shareen K Jaijee, Tamera J Corte, Lisa Simmons, Paul J Torzillo, Dale L Bailey, David S Celermajer
Journal: Circulation (2012)

Current techniques for assessing pulmonary vascular disease (PVD) are mostly performed under resting conditions. Novel methods aimed at evaluating the pulmonary circulation under dynamic conditions may provide additional pathophysiological insights and allow early detection of PVD. Aims: We used (1) Dobutamine Stress Echocardiography (DSE) to generate multipoint pressure-flow (mPAP-CO) relationships; and (2) quantitative Single Photon Emission Computed Tomography (qSPECT) to assess changes in regional lung perfusion related to postural shift. We hypothesized that ino-chronotropic stress might alter mPAP-CO relationships and that the normal gravity-related redistribution of lung perfusion may be impaired, in PVD. Methods: (1) Dobutamine infusion (5mcg/kg/min increments) was given to generate mPAP-CO plots. Subjects underwent exercise testing for peak VO2. (2) Regional pulmonary perfusion in supine and upright postures were obtained using qSPECT. A perfusion redistribution index (PRI) was devised to quantif...
Screening for Depression—A Tale of Two Questions
Authors: Mary A. Whooley
Journal: JAMA Internal Medicine (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Hyperbaric Pressure Effects Measured by Growth of a Transplantable Tumor in the C3H/HeN Mouse&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: B L Herndon, J J Lally
Journal: JNCI Journal of the National Cancer Institute (1984)

Both hypobaric exposure at 0.5 atmospheres absolute (ATA) and hyperbaric pressure exposure at 3.5-8 ATA slowed transplantable tumor growth. These experiments detailed the hyperbaric pressure exposure. C3H/HeN-MTV+ mice, bearing the 16/C transplantable murine mammary adenocarcinoma and exposed to 18 days' treatment by a hyperbaric chamber at 3.5-8 ATA, had tumor weights that averaged 50-75% less than the tumor weights in mice caged at ambient ("sea level") pressure. A series of experiments was run to investigate this response to hyperbaric pressure exposure. After mice underwent continuous exposure to 3.5-8 ATA normoxic (normal oxygen) hyperbaric pressure with use of either argon or nitrogen inert gas, which began 3 days after tumor inoculation, tumors were removed at about 3 weeks' growth from these pressure-exposed mice and measured for growth by weighing. Final tumor weight in pressure-exposed experimental mice was significantly less than tumor weight in paired groups of tumor-bearing controls that received no hyperbaric pressure. Tumor weight was inversely related to pressure "dose," although the small pressure range produced an effect at all pressures used. The number of compression-decompression cycles to which the animals were subjected, however, was related positively to tumor weight at necropsy. Continued tumor growth in mice subjected to frequent pressure change (in conjunction with pressure exposure that otherwise limited tumor size) was unexplained by these experiments. The greatest difference between tumor weights in controls and pressure-exposed animals was seen with 2 weeks' continuous pressure exposure. A limited profile of blood tests was performed, and these reflected only minor, expected change in the pressure-exposed experimental animals. The data at hand did not suggest a mechanism by which chronic normoxic hyperbaric pressure limited tumor size.
DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression
Authors: Michela Borghesan, Caterina Fusilli, Francesca Rappa, Concetta Panebianco, Giovanni Rizzo, Jude A. Oben, Gianluigi Mazzoccoli, Chris Faulkes, Illar Pata, Antonella Agodi, Farhad Rezaee, Shane Minogue, Alessandra Warren, Abigail Peterson, John M. Sedivy, Julien Douet, Marcus Buschbeck, Francesco Cappello, Tommaso Mazza, Valerio Pazienza, Manlio Vinciguerra
Journal: Cancer Research (2016)

Abstract Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear. macroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescent-like phenotype and induced synergistic global DNA hypomethylation. Conversely, macroH2A1 depletion amplified the antiproliferative effects of 5-aza-dC in HCC cells, but failed to enhance senescence. Senescence-associated secretory phenotype and whole-transcriptome analyses implicated the p38 MAPK/IL8 pathway in mediating macroH2A1-dependent escape of HCC cells from chemotherapy-induced senescence. Furthermore, chromatin immunoprecipitation sequencing revealed that this hepatic antisenescence state also required active transcription that could not be attributed to genomic occupancy of these histones. Collectively, our findings reveal a new mechanism by which drug-induced senescence is epigenetically regulated by macroH2A1 and DNA methylation and suggest macroH2A1 as a novel biomarker of hepatic senescence that could potentially predict prognosis and disease progression. Cancer Res; 76(3); 594–606. ©2016 AACR.
Analysis of relationship between baseline body weight and efficacy/safety of yttrium 90 (90Y) ibritumomab tiuxetan radioimmunotherapy in patients (pts) with non-Hodgkin's lymphoma (NHL)
Authors: G. A. Wiseman, C. Emmanouilides, K. Vo, R. J. Schilder, P. Foster, L. I. Gordon, T. E. Witzig, A. Molina
Journal: Journal of Clinical Oncology (2004)

6700 Background: 90Y ibritumomab tiuxetan (Zevalin®) has produced high response rates and durable remissions in pts w/relapsed or refractory low-grade, follicular, or transformed B-cell NHL. Increased stability and favorable pharmacokinetic profile (ie, predictable urinary clearance and absence of dehalogenation) associated w/the 2nd-generation chelator tiuxetan enables simple weight-based dosing and obviates need for determining whole body clearance. Standard dose 90Y ibritumomab tiuxetan is 0.4 mCi/kg in pts w/plts ≥ 150,000/μL, to maximum recommended dose (MRD) 32 mCi. Pts >80 kg, therefore, receive a dose/kg that is less than that received by pts ≤ 80 kg. The objective of this analysis was to determine whether this difference in dose impacts efficacy or safety. Method/Results: Analysis of efficacy and safety data of pts (n=170) who received 90Y ibritumomab tiuxetan 0.4 mCi/kg from 3 registrational trials was performed. 103 pts ≤ 80 kg w/median wt 70 kg (range, 45–80 kg) were compared w/67 pts >80 kg w/median wt 95 kg (range, 81–59 kg). There were no statistical differences in baseline characteristics in the ≤ 80 kg and >80 kg groups w/exception of gender (41% M vs 73% M, respectively; P<.01). Similar efficacy and safety results were achieved in both groups. Conclusion: A solely weight-based dosing regimen (ie, no MRD 32 mCi) would have given 39% of pts doses > 32 mCi. Despite receiving a lower dose/kg, pts > 80kg had similar efficacy and safety results as pts ≤ 80kg. There is no evidence from this analysis that the 32 mCi MRD results in any significant differences in efficacy or safety for pts > 80 kg. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biogen/IDEC Biogen/IDEC Biogen/IDEC Biogen/IDEC
Use of tumor genomic profiling to reveal mechanisms of resistance to the BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL).
Authors: Betty Y Chang, Richard R. Furman, Marc Zapatka, Jacqueline Claudia Barrientos, Daniel Li, Susanne Steggerda, Karl Eckert, Michelle Francesco, Jennifer Ann Woyach, Amy J Johnson, Danelle Frances James, Matthias Versele, John C. Byrd, Stephan Stilgenbauer, Joseph J. Buggy
Journal: Journal of Clinical Oncology (2013)

7014 Background: Ibrutinib interacts covalently with cysteine 481 of Bruton tyrosine kinase (BTK), resulting in targeted inhibition of B cell receptor signaling. Early trials of ibrutinib mono- or combination therapy enrolled 246 CLL patients receiving a median of 14 months of ibrutinib. 20 patients (8%) experienced progressive disease (PD), including 8 patients with Richter's transformation. Here we examine changes to the CLL genome in 3 patients that acquired resistance to ibrutinib. Methods: Ibrutinib resistance was defined as patients achieving partial response (PR) or better lasting ≥ 6 months, then developing PD without Richter’s transformation. RNAseq and whole exome sequencing (WES) followed by comparative genome analysis was performed at baseline and after PD and confirmed by Sanger sequencing. RNAseq and WES data were aligned using TopHat and BWA software. Single nucleotide variations (SNVs) were identified using SAMtools mpileup. Results: Compared to patients who relapsed from conventional chemotherapy, minimal genomic changes were acquired in ibrutinib resistant patients, reflecting relative genomic stability. SNVs were discovered in 3 patients specific to the relapse sample (Table). 2 out of 3 patients had distinct SNVs that each encode a cysteine-to-serine substitution at position 481of BTK (C481S). Homologous cysteine residues in BMX, ITK, TEC and BLK were wild-type (WT). Ibrutinib inhibited recombinant C481S 25 fold less potently than WT, and could not covalently bind C481S expressed in cells. The third patient had WT BTK, but acquired a potential gain-of-function mutation encoding a R665W substitution in PLCg2, a substrate of BTK, consistent with constitutive PLCg2 activation. Conclusions: Although rare, the acquisition of C481S BTK and R665W PLCg2 mutations in the setting of resistance confirms BTK as an important pharmacologic target of ibrutinib, and suggests mechanisms of ibrutinib resistance. [Table: see text]