tbuckley/cabot-search huggingface dataset:
Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer
Authors: Suriyan Ponnusamy, Yali He, Dong-Jin Hwang, Thirumagal Thiyagarajan, Rene Houtman, Vera Bocharova, Bobby G. Sumpter, Elias Fernandez, Daniel Johnson, Ziyun Du, Lawrence M. Pfeffer, Robert H. Getzenberg, Iain J. McEwan, Duane D. Miller, Ramesh Narayanan
Journal: Clinical Cancer Research (2019)

Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand-binding domain (LBD)-binding antagonists, are inactivated by common resistance mechanisms. It is important to develop next-generation mechanistically distinct drugs to treat castration- and drug-resistant prostate cancers.Second-generation AR pan antagonist UT-34 was selected from a library of compounds and tested in competitive AR binding and transactivation assays. UT-34 was tested using biophysical methods for binding to the AR activation function-1 (AF-1) domain. Western blot, gene expression, and proliferation assays were performed in various AR-positive enzalutamide-sensitive and -resistant prostate cancer cell lines. Pharmacokinetic and xenograft studies were performed in immunocompromised rats and mice.UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and -resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses, when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist enzalutamide and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-protein-coupled receptor kinase and nuclear receptor family members.Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug.
P11.54 Identification of PDGFRA and MYC(N) as somatic driver genes in Glioblastoma
Authors: A D Berezovsky, A Transou, S Irtenkauf, L Poisson, K Hank Wu, T Mikkelsen, A deCarvalho
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Somatic oncogene amplification happens frequently in glioblastoma (GBM). The second most frequently amplified gene encoding receptor tyrosine kinases in GBMs is platelet derived growth factor alpha (PDGFRA) (15%). In contrast, MYC and MYCN amplification occurs in 1.6% and 2.9%, respectively. Our goal was to characterize the role of PDGFRɑ and Myc in GBM. MATERIAL AND METHODS Neurosphere cultures were implanted in cohorts of 10–15 nude mice. 5 PDX lines, presenting median survival of 29–59 days were classified as short survivors, and 5 lines with median survival between 104–134 days classified as long survivors. Total RNA was extracted from PDX terminal tumors (3 biological replicates) and sequenced in a paired-end read format. Mouse reads were filtered out using Xenome. MYC and PDGFRA expression patterns were analyzed in tissue microarrays representing duplicated samples from 40 glioma neurosphere-derived PDX lines by IHC (1 anaplastic oligodendroglioma, 8 recurrent GBM with 2 newly diagnosed/recurrent pairs). Normalized staining intensity (MI) and area (A) were quantified using Fiji/ImageJ. RESULTS PDGFRA, MYC, MYCN gene amplifications were represented in a molecularly diverse panel of GBM patient-derived cancer stem-like cells (CSC) and orthotopic mouse xenografts (PDX). Transforming to a normal distribution (log10), 4/13 of cell lines had a PDGFRA mRNA expression (RPKM) higher than 1.5. Similarly, one PDX line had a staining index of greater than 10, 11 (27.5%) had an index between 5–10. The range of intra-tumoral variance, represented by standard deviation, was 0.09–24.25 highlighting the heterogeneity of PDGFRɑ expression. PDGFRɑ phosphorylation (Y754) did not differ between 8 cell lines cultured in NMGF, but deviated in alternate medias without growth factors, supplemented with FBS. In comparison, MYC(N) mRNA expression is only elevated in the context of a known amplification. Furthermore, a a MYC activity signature consisting of 18 target genes was only evident in the 5 amplified CSC lines. Taking advantage of genomic heterogeneity, we have isolated subclones lacking PDGFRA amplification from a PDGFRA amplified GBM CSC. The absence of PDGFRA amplification reduced the self-renewal potential to 37% of the PDGFRA amplified cell population (p=0.001) in clone 1 and 57% in clone 2 (p=0.013). Pertaining to determinants of in vivo survival, MYC was altered in 80% of short survivors (2/5 MYC, 2/5 MYCN amplification) and in 0% of long survivors. Myc signature was highly correlated with in vivo survival (Pearsons’ corr. = -0.77) and MYC gene expression was correlated with in vivo TMZ resistance (corr. = 0.7). CONCLUSION These results suggest that PDGFRɑ expression and activity can occur in the absence of gene amplification, while Myc activity is dependent on gene amplification. Both oncogenes drive oncogenic pathways that should be explored as therapeutic targets.
Monocentric retrospective analysis of locally advanced and inflammatory breast cancer (IBC) patients (pts) having received a neoadjuvant chemotherapy with docetaxel (D) and anthracyclines
Authors: B. Audhuy, C. Meyer, D. Nierges, J. C. Barats, P. Straub
Journal: Journal of Clinical Oncology (2006)

10743 Background: Anthracycline-based neoadjuvant therapy is a standard treatment, but use of D in the preoperative setting increases clinical and pathological response, as monotherapy or as part of combination chemotherapy for preoperative setting. Our purpose was to assess the efficacy in pts who were treated with D and anthracyclines (doxorubicine A or epirubicine E) in neoadjuvant setting. Methods: Pts with histologically proven, unilateral breast cancer, T2-T4, N0-N2, M0 tumors received every 3 weeks an association of D and A or E, according to different schedules. This retrospective analysis was designed to evaluate the clinical and pathological response rate of this association. Results: Between October 1999 and December 2003 45 pts (44 women and 1 man) were treated with associations: 39 D and E or A, 3 D, A and vinorelbine, 1 D, A and capecitabine (X), 1 D, A and trastuzumab (H), 1 D, X and H; median age 47 [27–71] years; median number of cycles of chemotherapy: 4 [3–6]; median tumour diameter: 50 mm [20–150] with 6 IBC; median radiological size: mammography 32 mm [11–90], echography 32.5 mm [8–90]; tumour stage: 15 T2N0 (33%), 12 T2N1 (27%), 7 T3N0 (15%), 2 T3N1 (4%), 1 T3N2 (2%), 1 T4bN1 (2%), 1 T4cN2 (2%), 3 T4dN0 (7%), 2 T4dN2 (4%), 1 T4N0 (2%); tumour grade: 22 grade II (49%), 22 grade III (49%), 1 unknown; tumour histology : 31 ductal carcinoma (69%), 13 lobular carcinoma (29%), 1 mucineous carcinoma (2%); hormonal status: 29 positive (64%), 16 negative (36%). Among these pts, 13 had nodal curage concomitant with diagnosis biopsy. All pts were evaluable for clinical response: ORR was 91% (18 complete response CR 40%, 23 partial response PR 51%. Histological response was available in 32 pts: Chevallier classification pCR grade 1–2: 5 (11%), Sataloff TA /NA-NB 5 (16%). On 32 pts with postchemotherapy nodal curage, 16 had negative nodal disease. On these 16 pts, 8 were N0 at diagnosis, 5 N1 and 3 N2. Conclusions: Association of D and anthracyclines in breast carcinoma exhibits a high pathological response rate. No significant financial relationships to disclose.
Early prediction of therapeutic efficacy of bevacizumab (Bmab) by measuring plasma concentration of βmab-unconjugated free VEGF-α in patients with recurrent or metastatic colorectal cancer (CRC).
Authors: Yukiko Cho, Shinji Fujieda, Mizuharu Ozeki, Kenji Amagai, Hiroshi Kojima
Journal: Journal of Clinical Oncology (2013)

e14510 Background: Although Bmab plus chemotherapy is widely accepted as the standard treatment for recurrent or metastatic CRC, some patients (Pts) are eventually poor responders. We hypothesized that monitoring of Bmab-unconjugated free VEGF-A concentration (conc.) in plasma is useful for predicting the therapeutic efficacy. Methods: Plasma samples were obtained from 20 (13 males &amp; 7 females) recurrent or metastatic CRC Pts with informed consent before Bmab administration and at 1- and 2-M of the 1st administration. VEGF-A conc. was measured by ELISA. For measuring Bmab-unconjugated free VEGF-A, Bmab-conjugated VEGF-A was immuneprecipitated by using protein A/G-Agarose. VEGF inhibitory ratio (%) was calculated by free VEGF-A / total VEGF-A. Clinical response was evaluated according to RECIST, and Pts achieving CR/PR and remaining NC more than 6 months were defined as good responders. Results: Baselineplasma conc. of VEGF-A was 78.45 ± 113.67 pg/ml (mean ± SD), which was significantly higher than that of healthy volunteers. Administration of Bmab did not result in significant decrease in the conc. of total VEGF-A (1- and 2-M: 85.26 ± 41.42 &amp; 99.63 ± 44.87 pg/ml, respectively). In contrast, Bmab-unconjugated free VEGF-A conc. decreased significantly (30.24 ± 91.94 &amp; 45.22 ± 51.23 pg/ml, respectively) (p&lt;0.05), and each inhibitory ratio was 70.18 ± 25.67 and 65.12 ± 32.15%. We then set inhibitory ratio of 70% as the cut-off level, and analyzed the correlation between inhibitory ratio and therapeutic efficacy. Among 11 Pts whose inhibitory ratio reached ≥70% at both 1- and 2-M, 9 Pts (81%) were good responders. Contrary, among the remaining 9 Pts, only 3 Pts (33%) were good responders. There was no correlation between therapeutic efficacy and total or free VEGF-A conc. Conclusions: We consider that early prediction of therapeutic efficacy of Bmab is possible by monitoring the inhibitory ratio of VEGF-A, and that future prospective study for validating its usefulness was warranted.
P11.05 Reappraisal of CNS embryonal tumors, not otherwise specified and RELA fusion negative supratentorial ependymomas using immunohistochemistry and sequencing for BCOR
Authors: A Nambirajan, N Gurung, A Sashidharan, A Sharma, S Kedia, A Garg, V Suri, C Sarkar, M Sharma
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND BCl2 co-repressor (BCOR) gene internal tandem duplications have recently been identified as the defining molecular alteration in a subset of central nervous system (CNS) high grade neuroepithelial tumors (CNS-HGNET). Their clinicopathological profile is yet to be fully elucidated with available data being largely derived from case reports and small case series. Reported cases presented in young children with a male preponderance, were located predominantly in the posterior fossa, and sometimes but not always showed an ependymoma-like morphology. BCOR protein overexpression and exon 15 internal tandem duplications were characteristic. These tumors associated with a poor overall survival. MATERIAL AND METHODS We designed a retrospective study (2002–2019) wherein all cases of CNS embryonal tumors, not otherwise specified (NOS), by definition lacking C19MC locus amplification and Lin28A protein expression, and supratentorial ependymomas (ST-EPN), NOS, lacking RELA and YAP1 fusions and L1CAM protein expression were retrieved and subject to immunohistochemistry for BCOR. Those tumors showing nuclear expression of BCOR were subject to sequencing of exon 15 of BCOR gene. RESULTS A total of 19 CNS embryonal tumors, NOS, constituting 86% of all CNS embryonal tumors other than medulloblastomas and atypical teratoid rhabdoid tumors, and 11 ST-EPN, NOS constituting 30% of all ST EPNs, were included. Diffuse nuclear staining for BCOR was seen in 6 tumors, including two patients with CNS embryonal tumor, NOS (10 year old male with spinal cord mass; 5-year-old female with left frontal mass) and 4 patients with ST-EPN-NOS (median age 15 years, ranging from 10–28 years, all females). While the CNS embryonal tumors showed high grade small round cell morphology, the remaining showed ependymoma-like morphology, but with increased cellularity and focal to diffuse membranous expression of epithelial membrane antigen and cytokeratins unlike ependymomas. Among these four patients, one was disease free at last follow-up at 17 months, while the remaining suffered recurrences within a median time duration of 26 months after diagnosis (24 months - 36 months). CONCLUSION The clinicopathological spectrum of BCOR-altered CNS tumors appears to be wider than that described in literature. We describe BCOR alterations in a subset of ependymoma-like tumors in older children and young adults with a striking female preponderance. BCOR alterations need to be studied on a broad spectrum of pediatric and adults CNS tumors to aid in better understanding of its true prevalence and biological significance.
Retrospective review of modified dose docetaxel, cisplatin, and 5-flourouracil (DCF) for the treatment of first-line metastatic gastric carcinomas.
Authors: Nuriye Özdemir, Sercan Aksoy, Tulay Eren, Huseyin Abali, Omur Berna Oksuzoglu, Nurullah Zengin
Journal: Journal of Clinical Oncology (2013)

e15175 Background: Docetaxel, cisplatin, and 5FU (DCF) has been shown to be an effective regimen for metastatic gastric carcinomas. However, treatment-related adverse events is quite high with original dose DCF. We evaluated the outcomes of the metastatic gastric carcinomas who treated with modified dose DCF (mDCF) in our institution. Methods: A single institution retrospective review of patients with metastatic gastric cancer treated with three weekly mDCF from 1/2006 to 1/2013 was evaluated. Over this time period a standard order-set was in place in which cisplatin 60 mg/m 2 , 5FU 600 mg/m 2 and docetaxel 60 mg/m 2 was given three weekly. Tumor response was calculated retrospectively using RECIST criteria. Results: One hundred and ninety-one patients were included the study. The median age was 55 years (23 to 76), 74% were male, and 82% were chemo-naive. Eighty percent of the patients were metastatic at the time of diagnosis. The median number of cycles administered was 6 (2-10). Hematological toxicity was mild with grade 3/4 granulocytopenia in 25% of the patients, grade 3/4 thrombocytopenia in 4% of the patients, and grade 3/4 anemia in 9% of the patients. Neutropenic infection occurred in 9 (%5) patients. Grade 3/4 nausea/vomiting was reported by 10% of the patients, and diarrhea by 7%. A total of 19 (10%) patients had dose delays or dose reductions related to toxicity. Six (3%) patients had complete response and 43 (23%) patients had partial response. Stable disease were occurred in 83 (45%) patients and 56 (23%) progressive disease. Ninety percent of the patients have died with median follow-up of 8 months. Progression-free survival was 7 months (95% CI 6 to 7.8 m) and overall survival was 10 months (95% CI 8.7 to 11.2 m). Conclusions: mDCF has mild hematological toxicity and overall excellent tolerance in first line metastatic gastric cancer patients. Response rate and the survival of these patients with a minimal toxicity are comparable with the original dose DCF.
Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG)
Authors: Matthias Preusser, Antonio Silvani, Emilie Le Rhun, Riccardo Soffietti, Giuseppe Lombardi, Juan Manuel Sepulveda, Petter Brandal, Lucy Brazil, Alice Bonneville-Levard, Veronique Lorgis, Elodie Vauleon, Jacoline Bromberg, Sara Erridge, Alison Cameron, Florence Lefranc, Paul M Clement, Sarah Dumont, Marc Sanson, Charlotte Bronnimann, Carmen Balaná, Niklas Thon, Joanne Lewis, Maximilian J Mair, Philipp Sievers, Julia Furtner, Josef Pichler, Jordi Bruna, Francois Ducray, Jaap C Reijneveld, Christian Mawrin, Martin Bendszus, Christine Marosi, Vassilis Golfinopoulos, Corneel Coens, Thierry Gorlia, Michael Weller, Felix Sahm, Wolfgang Wick
Journal: Neuro-Oncology (2021)

Abstract Background No systemic treatment has been established for meningioma progressing after local therapies. Methods This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. Results Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. Conclusions Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.
Participation in Community Preparedness Programs in Human Services Organizations and Faith-Based Organizations — New York City, 2018
Authors: Luis Rivera, Melissa Pagaoa, Beth Maldin Morgenthau, Christopher Paquet, Noelle Angelique M. Molinari, Tanya Telfair LeBlanc
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

Community-based organizations have a long history of engagement with public health issues; these relationships can contribute to disaster preparedness (1,2). Preparedness training improves response capacity and strengthens overall resilience (1). Recognizing the importance of community-based organizations in community preparedness, the Office of Emergency Preparedness and Response in New York City's (NYC's) Department of Health and Mental Hygiene (DOHMH) launched a community preparedness program in 2016 (3), which engaged two community sectors (human services and faith-based). To strengthen community preparedness for public health emergencies in human services organizations and faith-based organizations, the community preparedness program conducted eight in-person preparedness trainings. Each training focused on preparedness topics, including developing plans for 1) continuity of operations, 2) emergency management, 3) volunteer management, 4) emergency communications, 5) emergency notification systems, 6) communication with persons at risk, 7) assessing emergency resources, and 8) establishing dedicated emergency funds (2,3). To evaluate training effectiveness, data obtained through online surveys administered during June-September 2018 were analyzed using multivariate logistic regression. Previously described preparedness indicators among trained human services organizations and faith-based organizations were compared with those of organizations that were not trained (3). Participation in the community preparedness program training was associated with increased odds of meeting preparedness indicators. NYC's community preparedness program can serve as a model for other health departments seeking to build community preparedness through partnership with community-based organizations.
Joint Pain and Proteinuria
Authors: Abdullah S. Al Saleh, M. Hasib Sidiqi, Morie A. Gertz
Journal: JAMA (2019)

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Randomized trial of a hospice video decision aid for patients with advanced cancer and their caregivers.
Authors: Areej El-Jawahri, Olivia Vanbenschoten, Alyssa L. Fenech, Amanda L. Jankowski, Netana Markovitz, Lara Traeger, Joseph Greer, Angelo E. Volandes, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2019)

11513 Background: Although hospice provides high-quality end-of-life (EOL) care for patients with advanced cancer and their family caregivers, the service remains underutilized in part due to lack of adequate information provided to patients and families about hospice care. Methods: We conducted a single-site randomized clinical trial of a hospice video decision aid versus a verbal description in 150 hospitalized patients with advanced cancer and their caregivers. Patients without an available caregiver were still eligible to participate. Intervention participants (75 patients; 18 caregivers) received a verbal description about hospice plus a six-minute video depicting hospice care. Control participants (75 patients; 26 caregivers) received only the verbal description. The primary endpoint was patient preference for hospice care immediately after the intervention, adjusting for baseline preferences. Secondary outcomes included patient and caregiver knowledge and perceptions of hospice (Hospice Perception and Knowledge Questionnaire). Results: Between 2/2017 and 1/2019, we enrolled 55.7% (150/269) of potentially eligible patients and 44 caregivers. Post-intervention, patients assigned to the video group were more likely to prefer hospice care at the EOL (86.7% vs. 82.7%, OR = 2.85, P = 0.08), but this was not statistically significant. Patients in the video group reported greater knowledge about hospice (B = 0.50, P = 0.024) and were less likely to endorse that hospice care is only about death (6.7% vs. 21.6%, OR = 0.28, P = 0.035). Post-intervention, caregivers assigned to the video were more likely to prefer hospice care for their loved ones (94.4% vs. 65.4%, P = 0.031), reported greater knowledge about hospice (B = 1.94, P &lt; 0.001), and were less likely to endorse that hospice care is only about death (0.0% vs. 23.1%, P = 0.066). Conclusions: Patients with advanced cancer and their caregivers who viewed a hospice video decision support tool were more informed about hospice care and reported more favorable perceptions of hospice. Future work should examine the impact of the video on hospice utilization and length-of-stay among patients with advanced cancer. Clinical trial information: NCT03040102.