tbuckley/cabot-search huggingface dataset:
RECIST 1.1 for Response Evaluation Apply Not Only to Chemotherapy-Treated Patients But Also to Targeted Cancer Agents: A Pooled Database Analysis
Authors: Saskia Litière, Gaëlle Isaac, Elisabeth G.E. De Vries, Jan Bogaerts, Alice Chen, Janet Dancey, Robert Ford, Stephen Gwyther, Otto Hoekstra, Erich Huang, Nancy Lin, Yan Liu, Sumithra Mandrekar, Lawrence H. Schwartz, Lalitha Shankar, Patrick Therasse, Lesley Seymour
Journal: Journal of Clinical Oncology (2019)

The mode of action of targeted cancer agents (TCAs) differs from classic chemotherapy, which leads to concerns about the role of RECIST in evaluating tumor response in trials with TCAs. We investigated the performance of RECIST using a pooled database from 50 clinical trials with at least one TCA.We examined the impact of the number of target lesions (TLs) on within-patient variability of tumor response. The prognostic effect of TL response (at 12 weeks or on study on the basis of a maximum five TLs) on survival was studied through landmark and time-dependent Cox models adjusted for baseline tumor load, occurrence of new lesions, or unequivocal progression of nontarget disease.Data were obtained from 23,259 patients with cancer (36% lung, 28% colorectal, 11% breast, and 25% other); 15,620 received TCAs, predominantly transduction or angiogenesis inhibitors, as a single agent (37%), combined with other TCAs (7%), or as chemotherapy (56%); 28% received chemotherapy only; and 5% received best supportive care or placebo. A total of 17,222 patients contributed to the analyses. Within-patient variability decreased with increasing number of TLs, similarly for TCAs (with/without chemotherapy) and chemotherapy only. Mixed responses occurred proportionally in all treatment classes. Landmark analyses showed an ordinal relationship between percentage change from baseline to 12 weeks and overall survival, and demonstrated a clear distinction between tumor shrinkage and progressive disease according to RECIST. Time-dependent analysis showed no marked improvement in the ability to predict survival on the basis of TL tumor growth compared with nontarget progression or new lesion occurrence, regardless of treatment. Similar results were seen for major tumor types and different classes of TCAs.This work reinforces that RECIST version 1.1 perform well for response assessment of TCAs.
CANTATA: Randomized, international, double-blind study of CB-839 plus cabozantinib versus cabozantinib plus placebo in patients with metastatic renal cell carcinoma.
Authors: Nizar M. Tannir, Neeraj Agarwal, Nancy Ann Dawson, Robert J. Motzer, Carmel Maree Jacobs, Toni K. Choueiri, John Stewart Hrom, Daniel M. Geynisman, Nancy B. Davis, Robert A. Figlin, Mary Kathleen O'Keeffe, Jigarkumar R. Parikh, Daniel A. Vaena, Ping-Yu Liu, Bridget O'Keeffe, Xuan Tran, Bernard Escudier
Journal: Journal of Clinical Oncology (2019)

TPS682 Background: Glutamine metabolism is upregulated in renal cell carcinoma (RCC) and important for RCC tumor cell proliferation and survival. CB-839 is a first-in-clinic, potent, oral inhibitor of the mitochondrial enzyme glutaminase (GLS), which controls a critical step in tumor cell metabolism of glutamine. CB-839 demonstrated synergistic anti-tumor activity when combined with cabozantinib, a VEGFR2/MET/AXL inhibitor, in preclinical RCC models. In a phase 1 study cohort, CB-839 plus cabozantinib as 2L+ therapy showed encouraging safety and efficacy results, with 50% overall response rate (ORR; RECIST v1.1) and 100% disease control rate in 10 patients with clear cell advanced/metastatic RCC (mRCC). A randomized, double-blind study comparing CB-839 plus cabozantinib vs. cabozantinib plus placebo has been initiated in patients with clear cell mRCC. Methods: In this ongoing international, randomized, double-blind, multi-center study, enrollment is planned for ~300 patients with clear cell mRCC. To be eligible, patients should have received 1-2 prior lines of systemic therapy for mRCC including ≥1 anti-angiogenic therapy or the combination of nivolumab + ipilimumab, have KPS ≥70%, measurable disease (RECIST v1.1), and no prior cabozantinib (or other MET inhibitor). Patients are randomized 1:1 to receive either CB-839 (800 mg twice daily per oral [PO] route) plus cabozantinib (60 mg daily PO) or cabozantinib plus placebo in 28-day cycles until disease progression or unacceptable toxicity. Patients are stratified by prior PD-1/PD-L1 inhibitor therapy and by IMDC prognostic risk group (favorable vs. intermediate vs. poor). The primary endpoint is progression-free survival (PFS) per RECIST v1.1, determined by blinded independent radiology review. Secondary endpoints are investigator-assessed PFS and overall survival. Safety, response per RECIST, and quality of life are also assessed. Findings of this randomized, international clinical trial will inform the efficacy and safety profile of CB-839, a first-in-clinic metabolic inhibitor, in combination with cabozantinib in patients with mRCC. Clinical trial information: NCT03428217.
Is Estrogen the Answer for Osteosarcoma?
Authors: Ryan D. Roberts
Journal: Cancer Research (2019)

Abstract Bone biologists have long understood how estrogen drives osteoclasts to make new bone. While evidence hinted that a loss of estrogen signals might also play a role in bone-forming cancers like osteosarcoma, this idea has remained untested. Lillo Osuna and colleagues present data demonstrating widespread epigenetic silencing of estrogen receptor in human osteosarcomas. Exposure to demethylating agents caused reexpression of estrogen receptor, which promoted therapeutic differentiation of these tumors. See related article by Lillo Osuna et al., p. 1054
Severe mental disorders among prisoners in low-income and middle-income countries: reaching the difficult to reach
Authors: Oye Gureje, Jibril Abdulmalik
Journal: The Lancet Global Health (2019)

Several studies, most of which have been done in high-income countries, have highlighted the proportionately higher occurrence of mental disorders among prison populations compared with the general population.1 The interests in these studies range from the underlying conditions of incarcerated people (for example, the question of whether some mental disorders are more likely to predispose to offending); the indication that attending to the care of such populations might be a pointer to the readiness of the larger society—and the health system—to extend humane care to vulnerable populations; and the possibility that untreated mental disorders might be a risk factor for recidivism.
Suppression of Myeloid Cell Arginase Activity leads to Therapeutic Response in a NSCLC Mouse Model by Activating Anti-Tumor Immunity
Authors: Juan J. Miret, Paul Kirschmeier, Shohei Koyama, Mingrui Zhu, Yvonne Y. Li, Yujiro Naito, Min Wu, Venkat S. Malladi, Wei Huang, William Walker, Sangeetha Palakurthi, Glenn Dranoff, Peter S. Hammerman, Chad V. Pecot, Kwok-Kin Wong, Esra A. Akbay
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Tumor orchestrated metabolic changes in the microenvironment limit generation of anti-tumor immune responses. Availability of arginine, a semi-essential amino acid, is critical for lymphocyte proliferation and function. Levels of arginine are regulated by the enzymes arginase 1,2 and nitric oxide synthase (NOS). However, the role of arginase activity in lung tumor maintenance has not been investigated in clinically relevant orthotopic tumor models. <h3>Methods</h3> RNA sequencing (RNA-seq) of sorted cell populations from mouse lung adenocarcinomas derived from immunocompetent genetically engineered mouse models (GEMM)s was performed. To complement mouse studies, a patient tissue microarray consisting of 150 lung adenocarcinomas, 103 squamous tumors, and 54 matched normal tissue were stained for arginase, CD3, and CD66b by multiplex immunohistochemistry. Efficacy of a novel arginase inhibitor compound 9 in reversing arginase mediated T cell suppression was determined in splenocyte ex vivo assays. Additionally, the anti-tumor activity of this compound was determined in vitro and in an autochthonous immunocompetent Kras<sup>G12D</sup> GEMM of lung adenocarcinoma model. <h3>Results</h3> Analysis of RNA-seq of sorted myeloid cells suggested that arginase expression is elevated in myeloid cells in the tumor as compared to the normal lung tissue. Accordingly, in the patient samples arginase 1 expression was mainly localized in the granulocytic myeloid cells and significantly elevated in both lung adenocarcinoma and squamous tumors as compared to the controls. Our ex vivo analysis demonstrated that myeloid derived suppressor cell (MDSC)s cause T cell suppression by arginine depletion, and suppression of arginase activity by a novel ARG1/2 inhibitor, compound 9, led to restoration of T cell function by increasing arginine. Treatment of Kras<sup>G12D</sup> GEMM of lung cancer model with compound 9 led to a significant tumor regression associated with increased T cell numbers and function, while it had no activity across several murine and human non-small cell (NSCLC) lung cancer lines in vitro<i>.</i> <h3>Conclusions</h3> We show that arginase expression is elevated in mouse and patient lung tumors. In a KRAS<sup>G12D</sup> GEMM arginase inhibition diminished growth of established tumors. Our data suggest arginase as an immunomodulatory target that should further be investigated in lung tumors with high arginase activity.
Abstract P034: Circulating Odd-Chain Fatty Acids in Relation to Intake of Dairy and Fiber in Post-Myocardial Infarction Patients
Authors: Kamalita Pertiwi, Leanne K Küpers, Anne J Wanders, Peter L Zock, Johanna M Geleijnse
Journal: Circulation (2019)

Background: Odd-chain fatty acids (OCFA) pentadecanoic (15:0) and heptadecanoic acid (17:0) are considered to reflect dairy intakes in studies on cardiometabolic outcomes. A recent randomized controlled trial on dietary fiber showed that circulating proportions of these OCFA may also be related to fiber intake, which may result from fermentation by gut microbes. Objective: To examine the associations between circulating OCFA and dairy and fiber intake in patients with a history of myocardial infarction. Methods: We performed cross-sectional analyses in a subsample of 896 Dutch post-MI patients of the Alpha Omega Cohort. Proportions of OCFA (as % of total fatty acids) were measured in plasma phospholipids (PL) and cholesterol esters (CE). Dietary intakes (g/d) were assessed using a 203-item validated food frequency questionnaire. Spearman correlations ( r ) were computed between circulating OCFA in PL and CE and intakes of total dairy, types of dairy products, dietary fiber and total meat. Results: Patients were on average 69 years old, 78% was male and 89% used statins. Dairy intake was predominantly from milk and yogurt. PL 15:0 was positively correlated with total dairy intake ( r =0.16, p&lt;0.001; Table 1), especially yogurt. PL 15:0 was not correlated with dietary fiber ( r =0.01, p=0.75). For CE 15:0, correlations were similar. PL 17:0 was positively correlated with total dairy ( r =0.15, p&lt;0.001), but also with dietary fiber ( r =0.13, p&lt;0.001). For CE 17:0 similar correlations were observed, although somewhat weaker (dairy: r =0.10, p=0.003; fiber: r =0.09, p=0.009). OCFA were not significantly correlated with meat intake. Conclusions: Plasma PL 15:0 and CE 15:0 were related to dairy and not to fiber intake. PL 17:0 and CE 17:0 were equally related to dairy and fiber intake. Cardiometabolic health benefits attributed to biomarkers of dairy intake, especially 17:0, may be (partly) attributable to fiber intake. Further research is needed into endogenous OCFA synthesis as a result of fermentation of dietary fiber by gut microbes.
<i>ARV7</i> and <i>ARFL</i> mRNA in blood to predict androgen receptor inhibitors and docetaxel response in castration-resistant prostate cancer patients.
Authors: Mercedes Marin, Natalia Jiménez, Òscar Reig, Maria Verónica Pereira, Maria Mila, Daniel Benitez, Raquel Cabezón, Azucena González, Lourdes Mengual, Antonio Alcaraz, Maria Jose Ribal, Susana García-Recio, Manel Juan, Aleix Prat, Begona Mellado
Journal: Journal of Clinical Oncology (2019)

207 Background: The constitutively active androgen receptor (AR) variant 7 ( ARV7) has been associated with AR inhibitors (ARI) resistance, while its role predicting taxanes response remains controversial. We investigated the association between ARV7 and AR full length ( ARFL) expression pre-docetaxel treatment and changes pre- post-treatment in blood with docetaxel activity in metastatic castration-resistant prostate cancer (mCRPC) patients. Methods: ARV7 and ARFL mRNAs were tested by quantitative reverse-transcription PCR in peripheral blood mononuclear cells (PBMC) from mCRPC patients. Measurements were performed before docetaxel treatment and in a subset of patients also post-treatment. A cohort of patients treated with ARI was also included as a control. Results: We included 105 patients: 50 with treated with docetaxel and 55 with ARI. In 28 patients ARV7 and ARFL were evaluated pre and post-docetaxel. High ARV7 correlated with longer PSA-PFS (HR 0.42; 95%CI 0.18-0.99; P= 0.049), radiologic (RX)-PFS (HR 0.32; 95%CI 0.14-0.72; P= 0.006), and overall survival (OS) (HR 0.41; 95%CI 0.18-0.91; P= 0.028) to docetaxel. When relativizing to ARFL we observed that high ARV7/ ARFL ratio also correlated with a better PSA-PFS (HR 0.38; 95%CI 0.17-0.85; P= 0.0179) and RX-PFS (HR 0.43; 95%CI 0.2-0.91; P= 0.0273) to docetaxel. High ARV7 and ARV7/ ARFL were correlated with lower prostatic-specific antigen (PSA) progression-free survival (PFS) to ARI therapy (HR 2.18; 95%CI 1.03-4.6; P= 0.043 and HR 3.84; 95%CI 1.54-9.4; P= 0.004, respectively). ARV7/ ARFL and treatment- ARV7/ARFL interaction were independently associated with better PSA-PFS to docetaxel treatment and lower PSA-PFS to ARI. The increase of ARV7 mRNA levels after docetaxel treatment was indicative of longer OS (HR 0.07; 95%CI 0.008-0.57; P= 0.013). Conclusions: High ARV7 expression and ARV7/ ARFL ratio evaluated in PBMC pre-docetaxel are associated with better clinical outcome in mCRPC patients and lower ARI benefit. The increase of ARV7 levels after docetaxel exposure was also indicative of better outcome.
The Impact of the Mutational Landscape upon the Molecular Responses to Interferon-Alfa2 in Calr-Mutated MPN Patients
Authors: Vibe Skov, Lasse Kjær, Mads Thomassen, Steffen Koschmieder, Julia Czech, Nicolas Chatain, Niels Pallisgaard, Sabrina Cordua, Torben A Kruse, Hans Carl Hasselbalch
Journal: Blood (2018)
hnRNP U and DDX47 Are Novel FANCD2 Interactors That May Help to Resolve R-Loops during Mild Replication Stress
Authors: Yusuke Okamoto, Masako Abe, Akiko Itaya, Junya Tomida, Akifumi Takaori-Kondo, Masato Taoka, Toshiaki Isobe, Minoru Takata
Journal: Blood (2018)
Recommended Heart Failure Medications and Adverse Drug Reactions in Women
Authors: Sophie H. Bots, Hester M. den Ruijter
Journal: Circulation (2019)

omen treated with guideline-recommended cardiovascular medications experience more adverse drug reactions (ADRs) than men. 1 These women are not only at higher risk of hospitalization but may also discontinue their medications as a result of some of the adverse reactions, thus losing the potential benefit. 2 The safety of cardiovascular medications is evaluated both in clinical trials and through postmarketing surveillance.The latter is important because many ADRs rarely occur in clinical trial populations, which are generally younger and healthier than the target population.This is especially true for women, because their systematic underrepresentation in cardiovascular trials hinders the identification of gender differences in the efficacy and safety of cardiovascular medications.The underrepresentation of women is clearly illustrated in heart failure (HF) trials.Although approximately half of all HF patients are women and ≈60% of these women die from this syndrome, on average only 30% of HF trial populations are women, 3 possibly because of their older age at HF onset.The evaluation of medication safety in women is further hampered by poor inclusion of sex-specific data in trial reports. 3The increasing prevalence of the women-dominated HF subtype with preserved ejection fraction adds impetus to this issue, as the underlying mechanism of this syndrome appears to exhibit sex differences, and therapies are lacking. 4e performed a systematic review of the literature to quantify sex-specific reporting of ADRs of HF medications.HF medications recommended by the 2016 HF guidelines from the European Society of Cardiology 4 were grouped into 5 groups: angiotensin-converting enzyme inhibitors, β-blockers, angiotensin II receptor blockers, mineralocorticoid receptor antagonists, and ivabradine. 4Digoxin was included because of its suggested harmful effects in women. 1 First, all clinical trials cited in the European Society of Cardiology 2016 HF guidelines were extracted.Second, a systematic search of the website clinicaltrials.govwas performed on November 11, 2017.The search strategy included "heart failure" and the intervention options "ACE inhibitor," "beta blocker," "mineralocorticoid receptor antagonists," "digoxin," "ivabradine," and "angiotensin II receptor blocker."Records were excluded in the following instances:1.The study was ongoing, had been withdrawn or terminated, or had no published report available.2. The intervention was not part of 1 of the 6 drug families mentioned above.3. The primary study population consisted of patients with comorbidities such as diabetes mellitus, chronic kidney disease, pulmonary hypertension, cancer, or Chagas disease.4. The outcome of interest was not (a) the incidence of cardiovascular disease, (b) hospitalization for cardiovascular disease, or (c) (cardiovascular) mortality.The European Society of Cardiology guidelines cited 15 trials and 2 trial substudies, adding up to 17 trials in total.The systematic search identified 6 additional
The genomic landscape of metastatic clear cell renal cell carcinoma (ccRCC) after treatment with systemic therapy.
Authors: Johannes Van Der Mijn, Kenneth Eng, Evan Fernandez, Clara Oromendia, Tuo Zhang, Rohan Bareja, Sinan Ramazanoglu, Aram Vosoughi, Lorraine J. Gudas., Olivier Elemento, Scott T. Tagawa, Bishoy Morris Faltas, David M. Nanus, Himisha Beltran, Juan Miguel Mosquera, Andrea Sboner, Ana M. Molina
Journal: Journal of Clinical Oncology (2019)

675 Background: The most frequent genomic alterations in patients (pts) with ccRCC have been identified in primary tumors. Here we investigated the genomic landscape of ccRCC in a cohort enriched for metastatic tumors after treatment with systemic therapy. Methods: We prospectively enrolled pts with ccRCC in a clinical study in which Whole-Exome Sequencing (WES) of normal and tumor tissue was performed. Clinical features, treatment outcome and survival were evaluated. Results: Forty-five pts with ccRCC with a median age of 65 years (range 38–86) were enrolled. According to the Heng risk criteria, 15 pts (33.3%) were classified as favorable-risk 23 pts (51.1%) were intermediate-risk and 7 pts (15.6%) were poor-risk. Pts received a median number of 3 lines (range 0–9) of therapy including cytokines (n=7), anti-VEGF (n=36), mTOR inhibitors (n=10) and/or immune checkpoint inhibitors (n=23). The median progression free survival (PFS) after treatment was 3.5 months (0.7-13.1), 11.1 months (1.1–54.2), 2.7 months (0.7-36.2) and 4.9 months (1.4–29.2) after cytokines, VEGF-, mTOR- and immune checkpoint inhibitors, respectively. The median overall survival (OS) from start of treatment to last follow up was 2.2 years (range 0.2–14.9 years). A total of 68 samples were sequenced. These included 9 (12.5%) primary tumors, 38 (55.9%) collected after treatment with anti-VEGF, 16 (23.5%) after mTOR- and 8 (11.8%) after immune checkpoint inhibitor. VHL, KDM5C, SETD2 and PBRM1 were the most frequent somatic mutations detected in this cohort. In two cases with a short and long response to VEGF targeted therapy (PFS 2.8 versus 50.3 months) rapid autopsies were performed which allowed multiregional (n=7, n=4) sampling. The multiregional sequencing in the rapid autopsy case with a prolonged response to VEGF targeted therapy revealed recurrent KDM5C mutations. Conclusions: We present the genomic landscape of metastatic ccRCC after treatment with systemic therapy. We report an increased frequency of KDM5C mutations, previously described to be associated with a favorable response to VEGF-inhibitors.
Excess Deaths After Hurricane Maria in Puerto Rico
Authors: Raul Cruz-Cano, Erin L. Mead
Journal: JAMA (2019)

To the Editor Drs Santos-Lozada and Howard1 estimated 1139 excess deaths in Puerto Rico from Hurricane Maria, which made landfall on September 20, 2017. They found that the observed death toll for September through November 2017 fell outside the 95% CIs of the mean death counts.
Dual-drug loaded nanoparticles of Epigallocatechin-3-gallate (EGCG)/Ascorbic acid enhance therapeutic efficacy of EGCG in a APPswe/PS1dE9 Alzheimer's disease mice model
Authors: Amanda Cano, Miren Ettcheto, Jui-Hsien Chang, Emma Barroso, Marta Espina, Britta A. Kühne, Marta Barenys, Carmen Auladell, Jaume Folch, Eliana B. Souto, Antoni Camins, Patric Turowski, Maria Luisa García
Journal: Journal of Controlled Release (2019)

Epigallocatechin-3-gallate (EGCG) is a candidate for treatment of Alzheimer's disease (AD) but its inherent instability limits bioavailability and effectiveness. We found that EGCG displayed increased stability when formulated as dual-drug loaded PEGylated PLGA nanoparticles (EGCG/AA NPs). Oral administration of EGCG/AA NPs in mice resulted in EGCG accumulation in all major organs, including the brain. Pharmacokinetic comparison of plasma and brain accumulation following oral administration of free or EGCG/AA NPs showed that, whilst in both cases initial EGCG concentrations were similar, long-term (5-25 h) concentrations were ca. 5 fold higher with EGCG/AA NPs. No evidence was found that EGCG/AA NPs utilised a specific pathway across the blood-brain barrier (BBB). However, EGCG, empty NPs and EGCG/AA NPs all induced tight junction disruption and opened the BBB in vitro and ex vivo. Oral treatment of APPswe/PS1dE9 (APP/PS1) mice, a familial model of AD, with EGCG/AA NPs resulted in a marked increase in synapses, as judged by synaptophysin (SYP) expression, and reduction of neuroinflammation as well as amyloid β (Aβ) plaque burden and cortical levels of soluble and insoluble Aβ(1-42) peptide. These morphological changes were accompanied by significantly enhanced spatial learning and memory. Mechanistically, we propose that stabilisation of EGCG in NPs complexes and a destabilized BBB led to higher therapeutic EGCG concentrations in the brain. Thus EGCG/AA NPs have the potential to be developed as a safe and strategy for the treatment of AD.