tbuckley/cabot-search huggingface dataset:
Potentially inappropriate medication use in elderly breast cancer patients.
Authors: Meghan Sri Karuturi, Holly Michelle Holmes, Xiudong Lei, Michael L Johnson, Sharon Hermes Giordano
Journal: Journal of Clinical Oncology (2015)

6588 Background: Screening for potentially inappropriate medication (PIM) use is recommended in elderly cancer patients receiving chemotherapy. However, few studies have examined the patterns and impact of PIM use in this population. Our objective was to determine predictors of PIM use and impact on outcomes in breast cancer patients receiving chemotherapy. Methods: We used data from the Surveillance, Epidemiology, and End Results database linked to Medicare claims. Our cohort included women 66 years and older with a diagnosis of Stage II/III breast cancer receiving adjuvant chemotherapy between 7/1/2007 and 12/31/2009. We used the National Center for Quality Assurance Drugs to Avoid in the Elderly list to define baseline PIM use as a dichotomous variable in the 4 months prior to diagnosis. Outcome measures included ER visits, hospitalization, or death within 6 months of diagnosis. We included age, race, stage, Charlson comorbidity, poverty level, and number of providers as covariates. We used Chi-square or Fisher’s exact test to determine associations of PIMs with covariates and outcomes, and multivariable logistic regression to determine the association of PIMs with outcomes. Results: 1595 patients met our criteria, of whom 339 (21.3%) had PIM use at baseline. In multivariate analysis, baseline PIM was associated with higher comorbidity (OR 1.33, 95% CI 1.0-1.76 for 1; OR 1.51, 1.07-2.13, for 2+), higher poverty level (OR 2.03, 1.43-2.88 for third quartile; OR 1.44, 1. -2.07, for highest quartile), and higher number of providers (OR 1.70, 1.18-2.44 for 4+ providers). 669 (41.9%) had an ER visit, unplanned hospitalization or died within 6 months after diagnosis. Baseline PIM was not significantly associated with the composite outcome in univariate analysis (OR 1.23, 95% CI, 0.97-1.57). Associations with outcome in the multivariate analysis included advanced stage (OR 1.48, 95% CI 1.19-1.82), higher comorbidity index (OR 1.67, 95% CI 1.23-1.26 for 2+ vs. 0) and baseline ER visits/hospitalizations (OR 1.82, 95% CI 1.33-2.49). Conclusions: We found no significant association between overall baseline PIM use and adverse outcomes. Ongoing analyses are evaluating the association between PIM use during chemotherapy and adverse outcomes.
Activity of the novel BCR kinase inhibitor IQS019 in preclinical models of B-cell non-Hodgkin lymphoma
Authors: P. Balsas, A. Esteve-Arenys, J. Roldán, L. Jiménez, V. Rodríguez, J. G. Valero, A. Chamorro-Jorganes, R. Puig de la Bellacasa, J. Teixidó, A. Matas-Céspedes, A. Moros, A. Martínez, E. Campo, A. Sáez-Borderías, J. I. Borrell, P. Pérez-Galán, D. Colomer, G. Roué
Journal: Journal of Hematology & Oncology (2017)

Pharmacological inhibition of B cell receptor (BCR) signaling has recently emerged as an effective approach in a wide range of B lymphoid neoplasms. However, despite promising clinical activity of the first Bruton's kinase (Btk) and spleen tyrosine kinase (Syk) inhibitors, a small fraction of patients tend to develop progressive disease after initial response to these agents. We evaluated the antitumor activity of IQS019, a new BCR kinase inhibitor with increased affinity for Btk, Syk, and Lck/Yes novel tyrosine kinase (Lyn), in a set of 34 B lymphoid cell lines and primary cultures, including samples with acquired resistance to the first-in-class Btk inhibitor ibrutinib. Safety and efficacy of the compound were then evaluated in two xenograft mouse models of B cell lymphoma. IQS019 simultaneously engaged a rapid and dose-dependent de-phosphorylation of both constitutive and IgM-activated Syk, Lyn, and Btk, leading to impaired cell proliferation, reduced CXCL12-dependent cell migration, and induction of caspase-dependent apoptosis. Accordingly, B cell lymphoma-bearing mice receiving IQS019 presented a reduced tumor outgrowth characterized by a decreased mitotic index and a lower infiltration of malignant cells in the spleen, in tight correlation with downregulation of phospho-Syk, phospho-Lyn, and phospho-Btk. More interestingly, IQS019 showed improved efficacy in vitro and in vivo when compared to the first-in-class Btk inhibitor ibrutinib, and was active in cells with acquired resistance to this latest. These results define IQS019 as a potential drug candidate for a variety of B lymphoid neoplasms, including cases with acquired resistance to current BCR-targeting therapies.
Estimating the incidence of oligorecurrent and potentially salvageable prostate cancer on 18F-Choline PET-CT: Screening phase of the STOMP randomized phase II trial.
Authors: Piet Ost, AurÃ©lie De Bruycker, Tom Claeys, Louke Delrue, Gert De Meerleer, Filip De Vos, Karel Decaestecker, Kathia De Man, Valerie Fonteyne, Nicolaas Lumen, Filip Ameye, Ignace Billiet, Steven Joniau, Bieke Lambert
Journal: Journal of Clinical Oncology (2017)

153 Background: To identify sites and patterns of prostate cancer (PCa) recurrence following primary PCa treatment with 18F-choline PET/CT and estimate the number of patients potentially eligible for metastasis-directed therapy (MDT, defined as patients with up to 3 metastatic lesions). Methods: Between 7/7/2011 and 7/6/2016, 229 patients underwent a 18F-choline PET/CT for a biochemical PCa recurrence for potential inclusion in a randomized phase II-trial (STOMP). The trial randomizes patients with oligorecurrent (Orec) PCa between active surveillance (AS) and MDT. Patients were eligible for the trial in case of biochemical recurrence following primary prostate cancer treatment, up to 3 extracranial metastases and testosterone &gt; 50 ng/ml. Patterns of recurrence were classified as local (prostate or prostate bed), distant (N1, M1a/b/c) or a combination of both. The number of lesions were counted per scan and patients with up to 3 distant lesions with or without a local recurrence were considered as ORec vs &gt; 3 lesions as polyrecurrent (PRec). Results: A total number of 229 patients underwent 277 choline PET-CTs, resulting in 208 patients (91%) with a recurrence and 21 patients (9%) without any detectable recurrence. Twenty-two men (10%) had a local recurrence and 186 men (81%) had a distant recurrence, which was combined with a local recurrence in 17 men. Of the 186 patients, 131 (57%) were considered as ORec and 55 (24%) as PRec at median PSA values of 3.4 and 5.4 ng/ml, respectively (p &lt; 0.003). ORec were categorized as N1: 16%, M1a: 8%, M1b: 13%, M1c: 2% or a combination of sites: 17% (Figure 1). Fifty-eight patients had 1 lesion (25%), 39 2 lesions (17%) and 34 3 lesions (15%). Men with ORec PCa were treated with AS, MDT or palliative ADT in respectively 27%, 27% and 1% of the cases. Sixty-two of ORec men (27%) agreed to be randomized in the STOMP-trial. PRec were categorized as N1: 2%, M1a: 1%, M1b: 3%, M1c: 1% or a combination: 17% (Figure 1). Thirteen patients had 4 lesion (6%), 9 5 lesions (4%) and 33 &gt; 5 lesions (18%) Conclusions: Two out of three PCa recurrences on 18F-choline PET-CT are potentially salvageable with local therapy and/or metastasis-directed therapy. Clinical trial information: NCT01558427.
Clinical impact of an online tool to guide choice of therapy (Tx) for patients (Pts) with advanced renal cell carcinoma (RCC).
Authors: Timothy A Quill, Brian I. Rini, Eric Jonasch, Andrew Bowser, Jim A. Mortimer, Robert John Motzer
Journal: Journal of Clinical Oncology (2013)

e17530 Background: Clinical practice guidelines outline multiple treatment options for pts with advanced RCC, but provide little to no guidance on the best Tx for an individual pt. We have previously reported that online interactive decision support tools may help practicing community oncologists identify optimal treatment approaches in breast and lung cancers and CML (ASCO 2011 [abstr 6063]; ASTRO 2012 [abstr 162]; ASH 2012 [abstr 4279]). Here, we assess the impact of a tool on the decisions of clinicians treating pts with advanced RCC. Methods: An online tool was developed based on asurvey of experts who were asked what Tx they would choose for 76 pt case variations. Experts considered patient- and tumor-specific characteristics including histology (clear cell vs nonclear cell), extent of metastases, previous systemic therapy received, MSKCC risk status (good/intermediate vs poor), and ECOG performance score (0 vs 1 vs ≥ 2). The tool was built based on their responses and posted online July 12, 2012. After tool users input specific pt characteristics and indicate their intended Tx plan, a table of expert Tx choices are displayed for that pt scenario. To determine the impact of viewing the expert choices, users are then asked if the expert feedback has confirmed or changed their original Tx plan. Results: Three experts completed the survey. Key factors in the experts’ Tx choices were MSKCC risk status for first-line therapy and previous systemic therapy. Preliminary data of 419 cases entered by participants in the online tool show that expert insight changed or confirmed Tx choice for 81% of participants (changed: 22%; confirmed: 59%). An analysis of expert vs user treatment selections in specific subpopulations will be presented. Conclusions: An online tool designed to provide customized, patient-specific expert advice may increase the number of clinicians who make optimal treatment decisions for patients with advanced RCC. Data indicate that the expert choices influenced clinicians’ Tx decisions and, therefore, may facilitate improvements in pt care and outcomes. The tool was developed through an unrestricted educational grant from Pfizer.
Escalated dose somatostatin analogues (SSAs) in management of neuroendocrine tumors (NETs): A systematic review.
Authors: David Chan, Diego Ferone, Manuela Albertelli, Eva Segelov, Simron Singh
Journal: Journal of Clinical Oncology (2017)

422 Background: SSAs are effective in controlling NET symptoms and more recently have been shown to have anti-proliferative properties. PROMID and CLARINET have established “standard” doses of octreotide and lanreotide, but dose escalation is often employed both for symptom relief and tumor control. Methods: We searched MEDLINE, EMBASE, Cochrane CENTRAL and abstracts of major conferences. Studies investigating patients treated with doses of octreotide higher than 30mg/28d or lanreotide higher than 120mg/28d were eligible for inclusion. Data extracted included patient population, interventions and prior SSA use. The primary endpoint was disease control rate; secondary endpoints included response rate, symptom control, biochemical response, progression-free survival and toxicity. Results: 19 studies (12 prospective; 981 patients) were identified from 609 search results. Of the 13 studies that mandated prior treatment, the reasons for dose escalation were tumor progression (5), symptoms (3), either (2) and not listed (3). SSAs used were octreotide LAR (10), lanreotide ATG (1), short-acting octreotide (3), short-acting lanreotide (3), and mixtures (2). Significant heterogeneity existed in dosing schedules as well as reporting of efficacy data. Disease control rates ranged from 40-100% (pooled rate 248/396) with response rates from 0-42% (pooled rate 24/396). Dose escalation was associated with improvement in carcinoid symptoms in at least 50% of patients. Biochemical response was variably defined but reported rates ranged from 33% to 100% (pooled rate 55/78). Median PFS ranged from 6 months to 30 months. Dose escalation was generally well tolerated with side effect profile and frequency comparable to normal dose SSA. Conclusions: Escalated dose SSA is well tolerated and results in significant rates of disease control and symptomatic improvement. Compared to a prior systematic review (Broder WJG 2015), this review includes studies of lanreotide, includes 721 additional patients, and restricts inclusion to clinical studies. Prospective randomized trials of escalated SSA therapy are warranted.
DNA repair deficiency biomarkers and identification of ER-positive breast cancer patients who may benefit from veliparib/carboplatin: Results from the I-SPY 2 trial.
Authors: Laura van't Veer, Laura Esserman, Ashish Sanil, Annuska Glas, Tessa Severson, Sabine C. Linn, Lamorna Brown Swigart, Gillian Hirst, I-Spy Trial Investigators, Olufunmilayo I. Olopade, Hope S. Rugo, Don Berry, Denise M Wolf, Christina Yau
Journal: Journal of Clinical Oncology (2015)

521 Background: In the I-SPY 2 TRIAL, HER2- patients were adaptively randomized to receive standard chemotherapy or the PARP inhibitor veliparib with carboplatin (V/C) and chemotherapy. V/C graduated in the triple-negative (TN) subtype, and we’ve previously shown that DNA repair deficiency signatures [BRCAness and PARPi-7] may predict V/C response. Here we combine these signatures into a composite measure of DNA repair deficiency. Methods: 115 HER2- patients (V/C: 71 and concurrent controls: 44) are considered in this analysis. BRCA1/2 germline mutation is assessed by Myriad Genetics. The PARPi-7 and BRCAness signature scores are computed from Agilent 44K array data. A patient is predicted DNA repair deficient if carrying a BRCA1/2 mutation or BRCA-like or PARPi7-high. We modify the I-SPY 2 Bayesian model to include DNA repair deficiency status to estimate the predictive probability of V/C demonstrating superiority to control in a 1:1 randomized phase 3 trial of 300 ‘biomarker-positive’ patients. Our stud...
Cancer mortality and published research output: Is there any relationship?
Authors: Francis Patafio, Steven C Brooks, Xuejiao Wei, Yingwei Peng, Janine Biagi, Christopher M. Booth
Journal: Journal of Clinical Oncology (2015)

6596 Background: The relative distribution of cancer research output across disease sites is not well described. Here we evaluate whether the volume of published research and clinical trials is proportional to mortality by cancer site. We also explore whether research output is proportional to research funding by cancer site. Methods: Statistics from the American and Canadian Cancer Societies were used to identify the top ten causes of cancer death in 2013. The OVID MEDLINE database identified all journal articles and clinical trials published in 2013 by US/Canadian authors for these cancer sites. Total research funding in Canada by cancer site was obtained from the 2011 report by Canadian Cancer Research Alliance. Descriptive statistics and Pearson correlation coefficient (r) were used to describe the relationship between research output (volume of publications and clinical trials), cancer mortality, and research funding. Results: We identified 19,361 publications and 2,661 clinical trials. The proportion of publications and clinical trials were substantially lower than the proportion of deaths for lung (41% deaths, 15% publications, 16% clinical trials), colorectal (14%, 7%, 6%), pancreas (10%, 7%, 5%), and gastroesophageal (7%, 5%, 3%) cancers. Conversely, research output was substantially greater than the proportional death for breast cancer (10% deaths, 29% publications, 30% clinical trials) and prostate cancer (8%, 15%, 17%). There was substantial variation in total research investment across cancer sites that was not due to differences in relative mortality. Total investment in 2013 in Canada per cancer death was $599 for bladder cancer, $1039 for lung cancer, $2197 for colorectal cancer, $9212 for prostate cancer, and $14,329 for breast cancer. There was stronger correlation between research output and funding (all publications r = 0.8942 p < 0.001; clinical trials r = 0.9258, p < 0.001), than there was between research output and cancer mortality (r = 0.3625, p = 0.3033 and r = 0.3395, p = 0.3372). Conclusions: Research output is not well correlated to cancer mortality but is correlated to relative level of research funding.
Anti-Tumor Activity of KOS-953, a Cremophor-Based Formulation of the hsp90 Inhibitor 17-AAG.
Authors: Constantine S. Mitsiades, Nicholas Mitsiades, Melissa Rooney, Teru Hideshima, Dharminder Chauhan, Nikhil C. Munshi, Robert Johnson, Alison Hannah, Paul G. Richardson, Kenneth C. Anderson
Journal: Blood (2004)
Benefit of chemotherapy after third line and evaluation of post-progression survival (PPS) in metastatic breast cancer (MBC): A single institution study.
Authors: Rosachiara Forcignano, Mariangela Ciccarese, Vincenzo Emanuele Chiuri, Giuseppe Cairo, Laura Isabella Lupo, Luciana Petrucelli, Abbondanza Gambino, Graziana Ronzino, Antonella Licchetta, Antonio Gnoni, Diana Giannarelli
Journal: Journal of Clinical Oncology (2013)

e11517 Background: MBC remains an incurable disease with median survival of 2-3 years despite new drugs. The gain of benefit from third-line chemotherapy (CT3) in MBC is unknown. The validation of PPS as surrogate endpoint and its correlation to OS is under debate. Methods: From 2006-2012 we analyzed retrospectively consecutive 114 pts treated for MBC, 67 with at least 3 lines CT, to show the gain of benefit after CT3 and predictive factors of response to multiple lines of therapy. Moreover, we evaluated PPS for each line and its relation to OS. Results: Median age at M+ diagnosis was 58 years (29-87), median site of disease 2 (1-6), 66.7% visceral, HER-2+ pts 31.1%, median number of anti-Her-2 treatment 2 (1-6); 56.1% received a maintenance treatment (37% M1, 13% M2), median number of treatment 3 (1-8). Median OS for all pts was 47.1 (95%CI: 36.5-57.6). No difference in OS for pts with maintenance treatment vs not, respectively 49.1 vs 45.6 P=0.17. Multivariate Cox analysis showed that OS is related with ER/Pgr status (positive vs negative p=0.03) number of lines ( &gt;3 vs ≤ 3) p&lt; 0.0001 and number of metastatic sites (&gt;2 vs ≤2) p=0.01. We evaluated relation between PFS and OS and PPS and OS until 6th line of therapy with a linear regression model. Conclusions: These results supported the use of chemotherapy after CT3. PFS and PPS are related to OS until 6th line of treatment. PPS as surrogate endpoint of OS is a valid hypothesis to be evaluated in prospective trials of MBC [Table: see text]
Impact of the trifunctional antibody catumaxomab followed by systemic chemotherapy (CTX) on overall survival (OS): Results of a subgroup analysis in patients (pts) with relapsed ovarian cancer (OC) and malignant ascites (MA).
Authors: Radoslav Chekerov, Pauline Wimberger, Ignace Vergote, Per Rosenberg, Andreas Schneeweiss, Giovanni Scambia, Jean Paul Guastalla, Nicoletta Colombo, A.M. Westermann, Florian Lordick, Elisabeth Schulze, Jalid Sehouli
Journal: Journal of Clinical Oncology (2013)

e16547 Background: MA can compromise QoL in pts with OC. The safety and efficacy of catumaxomab in pts with MA due to EpCAM+ carcinomas where standard therapy was not available, not effective or no longer feasible was confirmed in a phase III trial comparing a 3-h intraperitoneal (i.p.) infusion with and without prednisolone premedication (Sehouli, ASCO 2012). Pts with OC who received subsequent CTX after treatment with catumaxomab (post-catumaxomab CTX) were analysed separately. Methods: OC pts in both treatment arms were pooled. The efficacy parameters time to next puncture (TTPu), puncture-free survival (PuFS) and OS were evaluated in relation to post-catumaxomab CTX. Results: 42/109 (39%) pts with MA due to OC received post-catumaxomab CTX, which included a platinum-containing regimen in 19 pts (17%). 21/109 (19%) received &gt;1 post-catumaxomab CTX regimen. Pts with any post-catumaxomab CTX compared with those without CTX had significantly prolonged OS (median 273 vs 81 d, HR 0.24, p&lt;0.0001) and PuFS (median 138 vs 43 d, HR 0.46, p = 0.0002). The difference in TTPu was not significant (223 vs 110 d, HR 0.68, p = 0.1788). Pts with &gt;1 post-catumaxomab CTX compared with 1 post-catumaxomab CTX had significantly prolonged OS (480 vs 167 d, HR 0.20, p &lt; 0.0001). The difference between the groups with 1 and &gt;1 post-catumaxomab CTX in PuFS (153 vs 123 d, HR 0.64, p = 0.1804) and TTPu (153 vs 169 d, HR 1.52, p = 0.3600) was not significant. Pts who received platinum-containing post-catumaxomab CTX had significantly prolonged OS compared with those who received post-catumaxomab CTX without platinum (462 vs 169 d, HR 0.32, p = 0.0026). The difference between the groups with and without platinum in PuFS (153 vs 123 d, HR 0.76, p = 0.4448) and TTPu (153 vs 229 d, HR 1.68, p = 0.2373) was not significant. Conclusions: The data indicate that pts with MA due to OC who are able to receive CTX after catumaxomab treatment have significantly prolonged survival compared with pts who could not receive CTX. Further trials have been initiated to identify the best patient population to receive i.p. catumaxomab followed by subsequent CTX.
On-demand dissolution of modular, synthetic extracellular matrix reveals local epithelial-stromal communication networks
Authors: Jorge Valdez, Christi D. Cook, Caroline Chopko Ahrens, Alex J. Wang, Alexander Brown, Manu Kumar, Linda Stockdale, Daniel Rothenberg, Kasper Renggli, Elizabeth Gordon, Douglas Lauffenburger, Forest White, Linda Griffith
Journal: Biomaterials (2017)

Methods to parse paracrine epithelial-stromal communication networks are a vital need in drug development, as disruption of these networks underlies diseases ranging from cancer to endometriosis. Here, we describe a modular, synthetic, and dissolvable extracellular matrix (MSD-ECM) hydrogel that fosters functional 3D epithelial-stromal co-culture, and that can be dissolved on-demand to recover cells and paracrine signaling proteins intact for subsequent analysis. Specifically, synthetic polymer hydrogels, modified with cell-interacting adhesion motifs and crosslinked with peptides that include a substrate for cell-mediated proteolytic remodeling, can be rapidly dissolved by an engineered version of the microbial transpeptidase Sortase A (SrtA) if the crosslinking peptide includes a SrtA substrate motif and a soluble second substrate. SrtA-mediated dissolution affected only 1 of 31 cytokines and growth factors assayed, whereas standard protease degradation methods destroyed about half of these same molecules. Using co-encapsulated endometrial epithelial and stromal cells as one model system, we show that the dynamic cytokine and growth factor response of co-cultures to an inflammatory cue is richer and more nuanced when measured from SrtA-dissolved gel microenvironments than from the culture supernate. This system employs accessible, reproducible reagents and facile protocols; hence, has potential as a tool in identifying and validating therapeutic targets in complex diseases.