tbuckley/cabot-search huggingface dataset:
Polypharmacy in oncology patients.
Authors: Ernesto Gil Deza, Eduardo L. Morgenfeld, Edgardo G. J. Rivarola, Gaston Martin Reinas, Nelson Kohen, Gabriel Lebersztein, Monica Montiel, Felipe G. Gercovich
Journal: Journal of Clinical Oncology (2014)

e17582 Background: Cancer is a disease that primarily affects older people who have been taking numerous drugs for the treatment of multimorbidities or for primary or secondary prevention before cancer diagnosis. The aim of this study is to investigate the medication used by our patients (Pt) before the diagnosis of cancer and the reasons for their use. Methods: All new Pt assisted between September 26th, 2012 and December 10th, 2013 completed a Past Medical History Form (PMHF) and registered the medication used regularly: trade name, drug or active principle and the reason for usage. Active ingredients were classified and the frequency distributions were studied. Results: Three thousand and thirty two cancer Pt filled the PMHF,and 2223Pt (73%) took medications regularly and are the subject of this study. Characteristics of the population (n=2,223 Pt) Sex F/M: 1,116/1,057. The most common tumours were breast 583 (26.2%), prostate 299 ( 13.5 %), colon 191 ( 8.6%) and lung 162 (7.3%). Median age 62 y (range 17-97). Six thousand nine hundred and seventy four non-cancer drugs were registered, as were 381 active ingredients prescribed to treat 97 pathological conditions related to cardiovascular system (34%), pain relief (19%), CNS modulating drugs (12%), gastrointestinal (9%), endocrine (9%), urological disorders (3%), infection (3% ), anemia (2% ), asthma (2% ), osteopenia (1.8% ), metabolic or nutritional disorders ( 1.8%), rheumatological problems ( 0, 7 % ), glaucoma ( 0.4 % ), allergy ( 0.4%), others ( 0.5 % ) the median number of drugs per patient was 4 ( range 1-15 ) and it increased with age and worsening of PS . Conclusions: (a) Polypharmacy in cancer patients is common, occurring in three out of four patients. (b) The median number of drugs per patient was four (c) A third of the drugs were prescribed to treat or prevent cardiovascular problems (d) Drug interactions with oncologic therapies are numerous and can be severe. (e) A significant number of these drugs may be futile, costly and toxic in patients with advanced cancer. (f) Hitherto, no international guidelines about polypharmacy in cancer patients have been developed, and these ought to be done urgently.
A phase II study of sirolimus and erlotinib in recurrent/refractory germ cell tumors.
Authors: Theodore Willis Laetsch, Kirthi Kumar, Dinesh Rakheja, Jonathan E. Wickiser, Carlos Rodriguez-Galindo, A. Lindsay Frazier, James Amatruda
Journal: Journal of Clinical Oncology (2014)

TPS2638 Background: Germ cell tumors (GCTs) affect children and young adults, with testicular germ cell tumor the most common cancer in young men. While platinum-based treatment has been successful for many GCTs, patients whose tumors are platinum-refractory have a poor prognosis. We have previously shown that non-seminomatous germ cell tumor cell lines are dependent on EGFR and mTOR signaling for survival and that the combined inhibition of these two targets in the same pathway results in >1000-fold sensitization to drug in vitro (Rakheja, AACR Peds Cancer 2013). The combination of the EGFR inhibitor erlotinib and the mTOR inhibitor sirolimus has been studied in other tumors, but never in germ cell tumors. Previous studies have not included assessment of pharmacodynamic inhibition of the targets in patients. Recently, flow cytometry based methods for detection of intracellular phosphorylated forms of S6 (downstream of mTOR), and ERK and AKT (downstream of EFGR) in peripheral blood mononuclear cells (PBMC) have been developed. This is the first pediatric trial to determine target inhibition in patients treated with the combination of EGFR and mTOR inhibitors. Methods: Eligible patients are those aged 1-50 years with relapsed or refractory germ cell tumors who have failed at least two prior platinum containing regimens. Patients with CNS disease are excluded. Patients receive daily sirolimus adjusted to a trough of 10-15 ng/mL and daily erlotinib at a starting dose of 120 mg/m2. As the development of rash may be a biomarker of response to erlotinib, patients who don’t develop grade II or worse rash during cycle 1 receive 150mg/m2 for subsequent cycles. Pharmacokinetics and target inhibition in PBMCs using phospho-flow cytometry are measured during cycles 1 and 2 and correlated with response. The primary endpoint is progression free response (PFR) after 16 weeks of therapy. Using a Simon 2-stage design, 11 patients will be enrolled in the first cohort and an additional 16 patients in the second if 2 or more of the initial 11 patients have PFR. This regimen will be considered beneficial if greater than or equal to 6 of the 27 evaluable patients have PFR (response rate of 20%). This study began enrollment in January 2014 and no results are yet available. Clinical trial information: NCT01962896.
Abstract 12295: Adipose Derived Stem Cells Enhance Cardiac Function Preservation of a Biodegradable Cardiac Patch and Increase Vascularization in Rats With Subacute Myocardial Infarction
Authors: Noriyuki Kashiyama, Robert L Kormos, Yasumoto Matsumura, Shin-ichi Higuchi, Lindemberg M Silveira-Filho, Garrett Coyan, Jiang Hong Bin, Antonio D’Amore, William R Wagner
Journal: Circulation (2018)

Introduction: Although bioengineered cardiac patches provide not only mechanical support for ventricles but also induction of cardiac regenerative cells in the failing heart, the overall regenerati...
Corrigendum to “Impaired brain glymphatic flow in experimental hepatic encephalopathy” [J Hepatol 69 (2019) 40–49]
Authors: Anna Hadjihambi, Ian F. Harrison, Marta Costas-Rodríguez, Frank Vanhaecke, Natalia Arias, Rocío Gallego-Durán, Svetlana Mastitskaya, Patrick S. Hosford, Steven W.M. Olde Damink, Nathan Davies, Abeba Habtesion, Mark F. Lythgoe, Alexander V. Gourine, Rajiv Jalan
Journal: Journal of Hepatology (2019)
Biochemotherapy with interleukin-2 for metastatic melanoma: Long-term results in 100 patients.
Authors: David R. Minor, Mohammed Kashani-Sabet
Journal: Journal of Clinical Oncology (2014)

9047 Background: As the limitations of new melanoma treatments are seen, we felt an evaluation of long-term results of biochemotherapy (BC) for metastatic melanoma (MM) would be useful. Methods: Retrospective single-institution review of 100 consecutive patients (pts) who began therapy between 9/30/2002 and 6/20/2006. Median follow-up is 9 years. Staging: IIIC-1; M1A-17; M1B-35; M1C-47. Patients were treated with the O’Day regimen which is similar to ECOG BC except Temozolomide 150mg/m2 used for DTIC; 6 cycles of BC given, not 4; decrescendo IL-2 dosing 36-18-9-9 miu/day dosing not based on BSA; and patients received maintenance inpatient “pulse IL-2” 108miu/42 hrs monthly for 6-18 months after BC. Results: 28 pts are still alive, all without evidence of melanoma (NED). One patient died NED due to a pulmonary embolus, one died from sepsis during BC, and 70 died from MM. 17 pts achieved CR with BC and never relapsed. Two patients achieved PR, had surgery for solitary sites of residual disease, and are NED. 6 pts progressed soon after BC, received ipilimumab (ipi) on various schedules, and are now NED. Two patients had late relapses over 3 years after BC. The first received ipi and is now NED off therapy. The second responded to ipi, progressed, and is now NED on therapy with anti-PD-1. One patient received BC in 2005, relapsed in 2007 and is NED after multiple continuous treatments over 7 years with chemo, RT, surgery, ipi, and vemurafenib. Of the 28 patients alive, only the last two are currently receiving therapy. Conclusions: First-line decrescendo BC can give durable remissions in many patients; late relapses are uncommon. Durable responses to ipilimumab may follow progression with BC. Biochemotherapy should now be systematically studied as second line or consolidation therapy.
Prognostic utility of the preoperative neutrophil/lymphocyte ratio combined with BRAF and MMR status in colorectal cancer patients.
Authors: Connie Irene Diakos, Joseph Chan, Lucy Jankova, Christopher Toon, Anthony Gill, Stephen John Clarke
Journal: Journal of Clinical Oncology (2014)

e14529 Background: Accurate, simple and inexpensive biomarkers will enable better use of cancer treatments. The neutrophil to lymphocyte ratio (NLR) is prognostic in advanced colorectal cancer (CRC). BRAF and mismatch repair (MMR) status also have prognostic utility and can be identified using immunohistochemical (IHC) analyses of surgical samples. We investigated the prognostic significance of the preoperative NLR in combination with BRAF and MMR status on CRC survival in patients with stages I-IV CRC. Methods: 899 consecutive patients admitted to Northern Sydney Local Health District from 2006-2009 for resection of CRC were evaluated. BRAF and MMR status were determined via IHC methods. Blood counts were retrospectively analysed. Prognostic value of the 3-marker combination was assessed, dividing the cohort into 4 groups according to high and low risk factors from individual marker states: Group 1 all high risk (high NLR, BRAF mutant, microsatellite stable); Group 2, 1 low and 2 high; Group 3, 2 low and 1 high; Group 4 all low risk factors. Kaplan-Meier and Cox regression was used to analyse prognostic utility. Results: The cohort comprised 50% males; median age 72 yrs; stage I 17%, II 36%, III 43%, IV 3%; ≥5 year outcome data. Increased NLR was independently associated with shorter overall survival (OS) after adjustment for other prognostic variables (HR 0.414, 95% CI 0.310-0.554, p<0.001). The combination of NLR, BRAF and MMR status demonstrated prognostic utility for OS by univariate (p<0.001) and multivariate analyses (p<0.001). Group 3 had significantly better outcome than Group 1 (HR 0.231, 95% CI 0.121-0.443, p<0.001) with Group 2 (HR 0.543, CI 0.290-1.016, p=0.056) and Group 4 (HR 0.386, CI 0.106-1.415, p=0.151) trending towards better outcomes than Group 1. Conclusions: A significant association between preoperative NLR was demonstrated with OS for patients with stage I-IV CRC, indicating shorter OS for patients with systemic inflammation prior to surgery. The combination of NLR with BRAF and MMR status demonstrated superior prognostic ability to known factors such as stage, forming a powerful prognostic tool for all stages of CRC from the preoperative setting.
Updated Results of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)
Authors: Sheeba K. Thomas, Jatin J. Shah, Ashley N. Morphey, Hans C. Lee, Elisabet E. Manasanch, Krina K. Patel, Carla P Miller, Suzanne Phillips, Brandon N. Crumpton, Ralph J. Johnson, Lei Feng, Swaminathan P Iyer, Behrang Amini, Donna M. Weber, Robert Z. Orlowski
Journal: Blood (2018)
High-Density CRISPR Scan Identifies Functional Regions of DOT1L That Mediate Therapeutic Response in MLL-r Leukemia
Authors: Chun-Wei Chen, Lu Yang, Xi Wang, Anthony Chan, Chris Delaney, Kazuya Miyashita, Yanchun Guo, Wen-Han Chang, Sandra Li, Sheela Pokharel, Hongzhi Li, Yadira Soto-Feliciano, Takayuki Hoshii, Scott A. Armstrong
Journal: Blood (2018)
The PARAGON phase 2 trial of anastrozole in women with potentially hormone responsive recurrent/metastatic gynecologic neoplasms.
Authors: Katrin Marie Sjoquist, Dirkje Willemien Sommeijer, Janine Margaret Lombard, Linda R. Mileshkin, Philip James Beale, Peter T. Grant, Penny Blomfield, Michael Quinn, Alison Maree Hadley, Peter Sykes, Yoland Catherine Antill, Rachel O'Connell, Julie Martyn, Kim Gillies, David Cannan, Val Gebski, Martin R. Stockler, Richard J Edmondson, Frederic Amant, Michael Friedlander
Journal: Journal of Clinical Oncology (2014)

TPS5621 Background: Gynaecological cancers of several pathological subtypes express estrogen and/or progesterone hormone receptors (ER/PR). Previous studies, [all or mostly] retrospective, have reported variable rates of tumour response and clinical benefit. Prospective studies are needed to determine the activity of aromatase inhibitors in women with potentially hormone responsive recurrent gynaecological cancers, and to determine possible predictors of response. Methods: PARAGON is a Gynecologic Cancer InterGroup phase 2 trial lead by the Australia New Zealand Gynaecological Oncology Group and NHMRC Clinical Trials Centre, in collaboration with Cancer Research UK and the Belgian Gynaecological Oncology Group. The study is designed to facilitate research in rare tumours. The protocol enrols postmenopausal women with recurrent gynaecological cancers of 7 different subtypes: epithelial ovarian cancer (EOC) with only rising CA125 after first line chemotherapy; platinum resistant/refractory EOC; low grade EOC; endometrial carcinomas; endometrial stromal sarcomas; miscellaneous sarcomas; and, granulosa cell and other sex cord stromal tumours. ER/PR positivity must be demonstrated by immunohistochemistry. Each subgroup will enrol 25-50 patients with defined stopping rules based on response and reviewed by an independent data monitoring committee (IDMC). Study treatment is anastrozole 1 mg daily until disease progression or unacceptable toxicity. The primary endpoint is clinical benefit (complete response, partial response, or stable disease at x months). Secondary endpoints include progression free survival, response duration, aspects of QoL, toxicity. Blood and tumour samples are being collected for translational studies and confirmation of ER/PR positivity. Recruitment commenced in 2011 in Australia, New Zealand and the United Kingdom. 236 of 350 planned patients have been enrolled to February 2014. Accrual to the platinum resistant/refractory subgroup closed on 9 December 2013. Anastrozole is being provided by AstraZeneca for study participants in Australia and the UK. This study has been partially funded by a grant from Cancer Australia (APP632740). Clinical trial information: ACTRN12610000796088.
The efficacy of bevacizumab in addition to platinum-based chemotherapy for first-line treatment of patients with advanced nonsquamous non-small-cell lung cancer (NSCLC): Final results of AVALANCHE, an observational cohort study.
Authors: Edina Tolnay, Veronika Sarosi, Erzsebet Juhasz, Zsuzsanna Sztancsik, Gyorgy Losonczy, Gyula Ostoros, Laszlo Mandoky
Journal: Journal of Clinical Oncology (2014)

e19123 Background: Results of two phase III, and two phase IV trials have shown that first-line bevacizumab (BEV) in combination with chemotherapy improves clinical outcomes in patients with advanced NSCLC. The AVALANCHE (ML21783) study was undertaken to assess the clinical outcomes of first-line BEV combined with standard platinum-based regimens in the Hungarian clinical practice. Methods: This observational study was conducted in 28 Hungarian sites. Enrolment: July 2008-April 2011. Patients with untreated locally advanced, metastatic or recurrent lung adenocarcinoma received BEV (7.5 mg/kg, q3w) with any platinum-doublet for up to 6 cycles, then non-progressors proceeded to receive BEV until disease progression or unacceptable toxicity. Primary endpoint was progression-free survival, secondary endpoints included overall survival, tumor control rate and safety. Patients were also analyzed as two cohorts (non-progressors vs progressors) based on whether or not they received BEV maintenance therapy after completion of first-line chemotherapy plus BEV. Log-rank test was used for comparison between groups. Results: The study enrolled 283 patients. Baseline characteristics: median age: 58.2 (18-78) years; males: 50.5%; stage: III/B: 18.4%, IV: 79.9%; adenocarcinoma/other: 95.8/4.2%; ECOG PS 0/1/2/≥3: 30.8/59.7/2.6/1.4%; Centrally located tumor was reported in 21.6%. Cisplatin/carboplatin-based regimens: 53.8/46.2%. Forty-three percent of patients received BEV maintenance therapy. Median number of BEV cycles was 6. Median PFS was 7.2 months and OS was 15.2 months for the entire cohort. Longer PFS and OS times were observed in patients who received BEV maintenance therapy (median OS, 26.2 months versus 10.2 months (p<0.001); median PFS, 9.2 months versus 5.8 months (p<0.001)). Best tumor response: CR/PR/SD/PD/not reported were: 1.5/29.9/26.9/9.1/32.6% of all patients. Conclusions: Clinical outcomes obtained in this real-life population were consistent with pivotal studies. BEV maintenance treatment was associated with a significantly longer PFS and OS.
Genomic and Proteomic Profiling of AF10-Fusion Oncoproteins Reveal Mechanisms of Leukemogenesis and Actionable Targets
Authors: Bo-Rui Chen, Anagha Deshpande, Maria Kleppe, Narayana Yeddula, Sunnie Yoh, Scott A. Armstrong, Ross L. Levine, Sumit Chanda, Aniruddha J. Deshpande
Journal: Blood (2018)
Drug interaction profile of idelalisib and its major metabolite, GS-563117.
Authors: Feng Jin, Michelle Robeson, Huafeng Zhou, Candra Moyer, Sibylle Wilbert, Bernard Murray, Srini Ramanathan
Journal: Journal of Clinical Oncology (2014)

2593 Background: Idelalisib (IDELA), a potent PI3Kδ inhibitor in Phase 3 studies for hematological malignancies, is metabolized mainly by aldehyde oxidase to GS-563117 and partially by CYP3A. In vitro, IDELA inhibits Pgp, OATP1B1, and 1B3 and GS-563117 is a time-dependent CYP3A inhibitor. Accordingly, the present study evaluated the effects of IDELA on these transporters/enzyme, and rifampin (RIF), a strong inducer, on IDELA pharmacokinetics (PK). Methods: Single oral dose of probe Pgp (digoxin; DIG), OATP1B1/1B3 (rosuvastatin; ROS), and CYP3A (midazolam; MDZ) substrates were given alone or with IDELA 150 mg BID. IDELA 150 mg single dose was given alone or with RIF 600 mg QD. PK of IDELA, GS-563117, and probes were determined (N = 11 to 12). Lack of PK interaction was defined as 90% confidence interval of the geometric mean ratio within 70-143% (combination vs alone). Safety was assessed throughout the study. Results: The study enrolled mainly white males (N=24) with median age of 38 years. Upon treatment, most common adverse events (AE) were headache and pyrexia; Gr 3 transaminase increases (5/24 subjects) were reversible. Two subjects had serious AEs after treatment completion. No clinically relevant changes in vital signs/ECGs were noted. IDELA did not affect DIG or ROS PK but increased MDZ plasma exposure, consistent with GS-563117 CYP3A inhibition in vitro. RIF reduced IDELA and GS-563117 exposures, indicating enhanced IDELA metabolism by CYP3A with a strong inducer. Conclusions: IDELA does not affect common drug transporters and is a moderate inhibitor of CYP3A due to GS-563117. Strong inducers of CYP3A decrease IDELA exposure. PK parameters (mean [%CV]). DIG DIG DIG + IDELA % Geometric least squares means ratio (90% CI) Cmax (ng/mL) 1.6 (18) 1.9 (19) 124 (115, 133) AUCinf (ng·h/mL) 38.0 (28) 37.0 (28) 100 (87, 115) ROS ROS ROS + IDELA Cmax (ng/mL) 1.6 (52) 1.9 (67) 115 (97, 137) AUCinf (ng·h/mL) 23.1 (32) 25.7 (59) 103 (83, 124) MDZ MDZ MDZ + IDELA Cmax (ng/mL) 16.6 (29) 38.1 (14) 238 (200, 283) AUCinf (ng·h/mL) 89.1 (36) 454 (24) 537 (456, 632) IDELA IDELA IDELA + RIF Cmax (ng/mL) 2,150 (24) 933 (41) 42 (36, 49) AUCinf (ng·h/mL) 9,600 (37) 2,290 (40) 25 (23, 27) GS-563117 Cmax (ng/mL) 1,990 (39) 675 (44) 32 (28, 37) AUCinf (ng·h/mL) 21,400 (59) 2,240 (49) 11 (9, 12)
Clinical outcome and CD4+ differentiation in anti-CTLA-4/radiation and anti-CTLA-4/steroid therapy.
Authors: Anuj Bapodra, Ines Esteves Domingues Pires Da Silva, Kevin P. Lui, Anna C. Pavlick, Judy Zhong, Iman Osman, Michelle Krogsgaard
Journal: Journal of Clinical Oncology (2014)

3019 Background: Combination of anti-CTLA-4 and radiation therapy with or without steroids are common in the management of melanoma patients. However, their clinical results and effects on immunity have not been examined in depth. In this study we observe the clinical and immune response of melanoma patients treated with anti-CTLA-4/radiation therapy and anti-CTLA-4/steroids. Methods: We anlayzed a cohort of patients treated with anti-CTLA-4 antibody therapy at NYU Medical Center. We examined differences in overall survival using log-rank test in patients treated with 1) anti-CTLA-4 with radiation therapy; 2) anti-CTLA-4 with steroids. Corticosteroids were administered to control symptoms (n=26) and/or toxicity (n=24). T cells were purified from patients; each represented by a minimum of two individual samples (before and after anti-CTLA-4 treatment). CD4+ T-helper cell subset phenotypes were characterized by their cytokine profiles by bead-based cytokine assays after stimulation using CD3/CD28 activation beads. Subsequently, we determined the association between treatment type and concentrations of cytokine production. Results: Patients treated with anti-CTLA-4 and radiation therapy given before, concomittant or after anti-CTL4 treatment (n=53) had better overall suvival prognosis compared to patients treated with anti-CTLA-4 alone (N=83; p=0.02). Anti-CTLA-4 therapy with steroids (n=50) conferred better prognosis compared to anti-CTLA-4 alone (p=0.037). The combination of anti-CTLA-4 and radiation therapy induced T cells to produce more IL-2, IL-17a and TNFa over the 4 cycles of treatment compared to anti-CTLA-4 alone. Similarly, anti-CTLA-4 with steroid treatment increased the production of IL-2 and IL17a, but not TNFa, compared to anti-CTLA-4 alone. No trend differences in IFN-g, IL-4, IL-6 or IL-10 production were detected. Conclusions: Our data suggests the enhanced immune response may be explained by effects of radiation therapy and corticosteroids. Increased production of IL-17a and TNFa indicate skewing towards Th17 CD4+ subset since other cytokines showed no trend. The polarized Th17 has clinical sgnificance due to higher anti-tumor activity than unpolarized Th subsets.
PDGFBR expression on perivascular cells influence the prognosis for TKI-treated mRCC pateints in a retrospective cohort study.
Authors: Magnus Frodin Bolling, Per Sandstrom, Arne Ostman, Lars Egevad, Artur Mezheyeuski, Ulrika Harmenberg
Journal: Journal of Clinical Oncology (2014)

e15599 Background: Tyrosine kinase inhibitors (TKIs) have improved the outcome for patients with metastatic renal carcinoma (mRCC). Absence of response-predictive markers makes it difficult to individualize treatment. Pericytes surround endothelial cells of capillaries and regulate vessel function. Associations between pericyte marker expression and response to TKIs, or overall prognosis, have not been well characterized. Methods: A tissue micro array was constructed with primary tumor samples from 64 TKI-treated mRCC patients . Data on treatment, duration of treatment (progression free survival (PFS)) and overall survival (time form first RCC diagnosis to death (OS)) were collected. Tissues were double-stained with the endothelial cell marker CD 34 and either of three pericyte markers (desmin, PDGF beta receptor (PDGFbR) and alpha smooth muscle actin (ASMA)). Digital images were collected and subjected to image analyses yielding values for 16 tumor stroma characteristics related to abundance and intensity of marker-defined subsets of fibroblasts and pericytes, and to vascular characteristics such as vessel size and vessel density. Associations between “stroma metrics” and survival were determined using Kaplan-Meier analyses, Mantel Cox log rank test and Cox-regression analyses following median-based dichotomization of cases. Results: None of the “stroma metrics” were significantly correlated with PFS. Regarding OS high PDGFbR-expression and low vessel density were both associated worse outcome. For the groups with high (n = 32) and low pericyte PDGFbR (n = 32) median OS were 27 and 55 months, respectively, yielding a Cox-regression based HR of 1.93, 95% CI 1.08-3.45, p=0.026. The group with low vessel density, (n=32) had a median OS of 25 months, versus 56 months for the group with high vessel density (n=32). Cox-regression analyses resulted in a HR of 1.99, 95% CI 1.13-3.51, p=0.018. Conclusions: Metastatic RCC displays a clinically relevant variation in pericyte PDGFrB-expression and vessel density which is associated with OS.