tbuckley/cabot-search huggingface dataset:
Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma
Authors: Abram Akopian, Sandeep Kumar, Hariharasubramanian Ramakrishnan, Kaushambi Roy, Suresh Viswanathan, Stewart A. Bloomfield
Journal: Journal of Clinical Investigation (2017)

The progressive death of retinal ganglion cells and resulting visual deficits are hallmarks of glaucoma, but the underlying mechanisms remain unclear. In many neurodegenerative diseases, cell death induced by primary insult is followed by a wave of secondary loss. Gap junctions (GJs), intercellular channels composed of subunit connexins, can play a major role in secondary cell death by forming conduits through which toxic molecules from dying cells pass to and injure coupled neighbors. Here we have shown that pharmacological blockade of GJs or genetic ablation of connexin 36 (Cx36) subunits, which are highly expressed by retinal neurons, markedly reduced loss of neurons and optic nerve axons in a mouse model of glaucoma. Further, functional parameters that are negatively affected in glaucoma, including the electroretinogram, visual evoked potential, visual spatial acuity, and contrast sensitivity, were maintained at control levels when Cx36 was ablated. Neuronal GJs may thus represent potential therapeutic targets to prevent the progressive neurodegeneration and visual impairment associated with glaucoma.
COOLHAIR: A prospective randomized trial to investigate the efficacy and tolerability of scalp cooling in patients undergoing neoadjuvant chemotherapy for early breast cancer.
Authors: Katharina Smetanay, Philippe Junio, Manuel Feißt, Jessica Cecile Hassel, Luisa Mayer, Lina Maria Matthies, Arina Schumann, André Hennigs, Joerg Heil, Christof Sohn, Dirk Jaeger, Andreas Schneeweiss, Frederik Marme
Journal: Journal of Clinical Oncology (2017)

525 Background: Chemotherapy induced alopecia (CIA) is a distressing side effect for women with breast cancer (BC) undergoing chemotherapy (CT). Scalp cooling is a method aiming to prevent CIA, but its efficacy is not well defined. Observational studies show a positive effect of scalp cooling to reduce hair loss, but randomized trials until recently have been lacking. Methods: In our monocentric prospective randomized trial patients with early BC undergoing (neo)adjuvant CT were 1:1 randomized to either scalp cooling (CAP) or not (noCAP). All patients received 18 to 24 weeks of anthracycline (A) and/or taxane (T)-based CT. The DigniCap System was used for scalp cooling. The primary endpoint was patient reported rate of alopecia according to the Dean Scale (Grade 0: no hair loss, grade 1: &gt; 0 - 25%; grade 2: &gt; 25 - 50%; grade 3: &gt; 50 - 75%; grade 4: &gt; 75%). Hair preservation was defined as hair loss £ grade 2. Secondary endpoints were rate of alopecia determined by nursing staff and an independent and blinded evaluator, rate of wig/scarf use as well as quality of life. Results: From August 2014 until January 2016 seventy-nine patients were included (41 CAP and 38 noCAP). The drop-out rate was 32% in the CAP arm and 34% in the noCAP arm. Main reasons for drop out were hair loss, adverse events (CAP) and randomization into control arm. At the time of this analysis all patients had completed CT. Hair preservation was observed in 39% of patients in the CAP arm versus 0% in the No CAP arm (p &lt; 0.001). There was a strong concordance between patients and staff evaluation (weighted Cohen's Kappa = 0.92). Wig/scarf use was significantly less frequent in the CAP group (36% vs 92% at home, p &lt; 0.001; 64% vs 91% outside, p &lt; 0.001). We did not observe any differences in hair preservation between A-based and non A-based regimens. Conclusions: Our prospective randomized trial shows that scalp cooling is effective in preventing CIA in a relevant number of patients. This option should be made available for patients undergoing T+/-A-based (neo)adjuvant chemotherapy for EBC.
The role of taxanes in HR+ve/HER2-ve metastatic breast cancer (MBC) patients (pts) from adjuvant to metastatic setting in the clinical practice: Results from GIM13-AMBRA study.
Authors: Giorgio Mustacchi, Marina Elena Cazzaniga, Emanuela Romagnoli, Filippo Montemurro, Michele De Laurentiis, Ferdinando Riccardi, Anna Turletti, Alessandra Beano, Claudia De Angelis, Vincenzo Graziano, Lorenzo Livi, Lucia Del Mastro, Laura Biganzoli, Ornella Garrone, Sabino De Placido, Paolo Marchetti, Paolo Pronzato
Journal: Journal of Clinical Oncology (2017)

1055 Background: The molecular subtypes of BC have individual patterns of behavior, prognosis and sensitivity to treatment, with subsequent implications for the choice of, or indeed role, for adjuvant (Adj) and metastatic chemotherapy (CHT). Taxanes (T) play a central role in chemotherapy for BC. However, previous studies have reported that T are relatively ineffective in patients with Luminal (HR+ve) BC compared with other subtypes. Aim of the present analysis is to describe the use of T in the clinical practice in Italy in HR+ve pts. Methods: AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve MBC pts receiving at least one CHT (SABCS 2016, P5-15-07 &amp; P5-14-09) in the years 2012-2015. For the present analysis, we focused on the use of T from the AdJ to the metastatic setting. Results: So far, 791/1500 pts have been registered into the study, 651 of them (82,3%) evaluable with HR+ MBC. Main characteristics are: Mean age 52 years; pN: UK 64 (9.8%) N+=405 (62.2%); Adj CHT=397 (61 %), mean DFI=96,99 months. T were used in 60.3% of the cases in the Adj setting, alone or in combination with other drugs, mainly anthracyclines (82.6%), with a mean DFI of 56.9 months. In the metastatic setting, across 1 st to 3 rd line, 460 pts (70.6%) received T, alone (49.7%) or in combination with Bevacizumab (38.2%), or other CHT drugs (11.9%). Details of the use of T in MBC are described in the table below. Conclusions: T have been used in more than 60% of cases of Luminal tumours in the Adj setting. In this population DFS is significantly shorter as compared with the non-T treated luminal population, as previously suggested by different Authors. Re-challenge with T is very frequent across different lines for MBC. Paclitaxel is the most used T, Docetaxel the less used and Nab-paclitaxel, labelled for MBC only, shows an increasing use from 1 st -to 3 rd line of treatment. [Table: see text]
Trabectedin Overrides Osteosarcoma Differentiative Block and Reprograms the Tumor Immune Environment Enabling Effective Combination with Immune Checkpoint Inhibitors
Authors: Chiara Ratti, Laura Botti, Valeria Cancila, Silvia Galvan, Ilaria Torselli, Cecilia Garofalo, Maria Cristina Manara, Lucia Bongiovanni, Cesare F. Valenti, Alessia Burocchi, Mariella Parenza, Barbara Cappetti, Sabina Sangaletti, Claudio Tripodo, Katia Scotlandi, Mario P. Colombo, Claudia Chiodoni
Journal: Clinical Cancer Research (2017)

Purpose: Osteosarcoma, the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested.Experimental Design: We have developed immunocompetent osteosarcoma models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human osteosarcoma. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer.Results: Trabectedin, as monotherapy, significantly inhibited osteosarcoma primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling osteosarcoma progression.Conclusions: These results demonstrate the therapeutic efficacy of trabectedin in osteosarcoma treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors. Clin Cancer Res; 23(17); 5149-61. ©2017 AACR.
Impact of the Prosigna (PAM50) assay on adjuvant clinical decision making in patients with early stage breast cancer: Results of a prospective multicenter public program.
Authors: Cesar Augusto Rodriguez, Maria Garcia-Muñoz, Magdalena Sancho, Maria Garcia-Gonzalez, Carlota Delgado, Diego Soto de Prado, José V. Álvarez, Cristina Bayona, José E. Alés-Martínez, Isabel Gallegos, Javier Puertas Álvarez, Andres García-Palomo, Estefania Arevalo, Eliza Condori, Asunción Gómez, Rebeca Lozano, Natalia de la Fuente, Juan J. Cruz
Journal: Journal of Clinical Oncology (2017)

e12062 Background: Prosigna is a standardized test based on the PAM50 gene signature which provides information on intrinsic subtype and risk of recurrence (ROR) score predicting 10y recurrence probability (NanoString Technologies, Inc., Seattle, WA). We evaluated Prosigna’s impact on adjuvant treatment decision beyond immunohistochemistry (IHC) testing. Methods: 125 pre- and postmenopausal EBC patients with ER+, HER2-, pT1-T2 pN0/pN1mi were enrolled (12 centers; 8/2015-11/2016). FFPE specimens were centrally analyzed using Prosigna to classify patients according to the intrinsic tumor subtype and ROR score. The primary endpoint was the impact of the Prosigna test on adjuvant treatment decision. Results: 64% of tumors were classified by PAM50 as Lum A, 35% as Lum B, 0% Basal, 1% HER2-E. The intrinsic subtype concordance between immunohistochemistry (IHC) and Prosigna (n = 119) was 61.3%. In Lum B tumors by IHC the discordance rate was the highest (48% were reclassified as Lum A by Prosigna) as shown in the Table. ROR risk groups were as follows: ROR low (54; 43%), ROR interm. (38; 30%), and ROR high (33; 27%). Prosigna results led to a treatment recommendation change in 49 (39%) patients. In the 76 (61%) cases with the initial recommendation of Hormonal Therapy (HT) alone the final decision changed to chemotherapy (CT)+HT (CHT) in 24 (32%) patients. In the 49 (39%) cases in which the initial recommendation was CHT the final decision changed to HT in 25 (51%) patients. Among the 38 patients with Prosigna intermediate risk, 21 (55%) were allocated to HT. Conclusions: In this prospective decision impact study, Prosigna results led to a 39% change in adjuvant therapy indication. Patients with initial indication of CHT were changed to HT alone in &gt; 50% of cases. Thus, Prosigna results influenced the treatment decisions and reinforced its clinical utility in real-world settings. The intrinsic subtype classification based on IHC didn’t show to be an adequate surrogate for the genomic subtypes as determined by Prosigna. [Table: see text]
Developments in Molecular Testing and Biosimilars
Authors: Katy Winckworth-Prejsnar, Elizabeth A. Nardi, Lisa Korin Lentz, Jeffrey A. Crawford, C. Lyn Fitzgerald, Robert W. Carlson
Journal: Journal of the National Comprehensive Cancer Network (2017)

Molecular testing and biosimilars offer the potential for increased access to targeted treatment options and reduction in healthcare costs, but come with significant challenges in ensuring patient access to innovation in cancer care while maintaining safe, effective, ethical, and affordable treatment options. As providers, payers, patients, and the larger healthcare systems become inundated with a wide variety of molecular diagnostics and an increased number of biosimilars coming to market, it will be important to understand regulatory guidance and policy implications relating to the appropriateness of molecular testing and the clinical use of biosimilars in cancer care. In September 2016, NCCN hosted the Molecular Testing and Biosimilars Policy Summit to address the challenges, issues, and opportunities in both the molecular testing and biosimilar landscapes. Keynote presentations and panelists further discussed the status and future of molecular testing and biosimilars within the oncology space, as well as patient access and education needs moving forward.
Similar Phenotypes Demonstrated upon Initial Diagnosis and at Time of Recurrence in Relapsed DLBCL
Authors: Jie Qu, Matthew J Maurer, James R Cerhan, Anne J. Novak, Thomas M. Habermann, William R. Macon, Andrew L Feldman, Thomas E. Witzig, Carrie A Thompson, Sergei Syrbu, Brian K Link, Umar Farooq, Stephen Ansell
Journal: Blood (2016)
Pretreatment serum levels of myeloid-derived suppressor cells (MDSC) are effective as a prognostic indicator in patients with breast cancer.
Authors: Kenji Gonda, Masahiko Shibata, Takahiro Nakajima, Yoshiko Matsumoto, Noriko Abe, Tohru Ohtake, Tatsuo Shimura, Seiichi Takenoshita
Journal: Journal of Clinical Oncology (2014)

e14006 Background: A suppression of cell mediated immunity and malnutrition are commonly seen in patients with advanced cancer and it has been reported that chronic inflammation plays a key role in induction of these conditions. We have reported that MDSC: myeloid-derived suppressor cells, found as a new type of immune suppressor cells that is closely related to chronic inflammation, is increased in patients with various types of cancer including gastrointestinal, hepatopancreatic, breast, thyroid and ovarian cancers, and the levels of MDSC were closely related to systemic inflammation, immunosuppression and nutritional impairment. Especially in breast cancer, the levels of MDSC have been reported to decrease after the removal of the tumor and to increase with recurrence. Methods: Peripheral blood mononuclear cells (PBMC) were collected from 106 preoperative patients with breast cancer including 19 patients with stage I, 48 with stage II, 12 with stage III and 27 with stage IV diseases, and these cells were used for the detection of MDSC (CD11b+CD14-CD33+) by flow cytometry. The circulating levels of MDSC were divided with cutoff levels of 1.0% or 3.0% of PBMC, and the prognosis of these patients was analysed with Kaplan-Meier method. Results: Although the overall survival (OS) of patients with stage IV disease was significantly shorter than those with stages I, II, and III diseases in patients with MDSC levels (higher than 1.0%PBMC), there was no differences in patients with MDSC levels of lower than 1.0%PBMC. The OS of stage IV patients with MDSC of higher than 3.0%PBMC was significantly shorter than other stage IV patients (p<0.005). In patients with MDSC of higher than 1.0%PBMC, the OS of the patients with stage IV was shorter than those with stages I (p=0.005) and II (p<0.005), and no difference was found between those with stages III and IV. Conclusions: Therefore, the pretreatment levels of MDSC is effective as a good prognostic indicator especially in patients with advanced breast cancer.
FDA Panel: Keep COX-2 Drugs on Market
Authors: Bridget M Kuehn
Journal: JAMA (2005)

WITH QUESTIONS REMAINING about the safety of nonsteroidal anti-inflammatory drugs (NSAIDs), a Food and Drug Administration (FDA) advisory panel recommended that the agency allow the marketing of NSAIDs that selectively inhibit cyclooxygenase 2 (COX-2) but urged greater caution with the use of all NSAIDs. At press time, the FDA had yet to make a decision about the recommendations. Far from providing the clear-cut answers many had hoped for, the panel’s analysis of clinical data painted a nuanced picture of the risks and benefits of NSAIDs. The panel found important differences between rofecoxib, celecoxib, and valdecoxib—the three COX-2 inhibitors at the center of the debate over NSAID safety, but also noted that all three pose serious risks. “The panel unanimously voted that these drugs appear to cause heart attacks,” said Alistair Wood, MD, who chaired the joint panel of FDA arthritis and drug safety experts. “Physicians obviously need to take that into account if and when they prescribe these drugs.”
House Dust Endotoxin and Peripheral Leukocyte Counts: Results from Two Large Epidemiologic Studies
Authors: Michael B. Fessler, Megan U. Carnes, Päivi M. Salo, Jesse Wilkerson, Richard D. Cohn, Debra King, Jane A. Hoppin, Dale P. Sandler, Greg Travlos, Stephanie J. London, Peter S. Thorne, Darryl C. Zeldin
Journal: Environmental Health Perspectives (2017)

The peripheral leukocyte count is a biomarker of inflammation and is associated with human all-cause mortality. Although causes of acute leukocytosis are well-described, chronic environmental determinants of leukocyte number are less well understood.We investigated the relationship between house dust endotoxin concentration and peripheral leukocyte counts in human subjects.The endotoxin–leukocyte relationship was evaluated by linear regression in the National Health and Nutrition Examination Survey (NHANES) 2005–2006 (n=6,254) and the Agricultural Lung Health Study (ALHS; n=1,708). In the ALHS, we tested for a gene [Toll-like Receptor 4 (TLR4), encoding the endotoxin receptor]-by-environment interaction in the endotoxin–leukocyte relationship using regression models with an interaction term.There is a statistically significant, positive association between endotoxin concentration and total leukocyte number [estimated change, 0.186×103/μL (95% CI: 0.070, 0.301×103/μL) per 10-fold change in endotoxin; p=0.004) in the NHANES. Similar positive associations were found for monocytes, lymphocytes, and neutrophils. Stratified analyses revealed possible effect modification by asthma and chronic obstructive pulmonary disease. We observed similar associations in the ALHS. For total leukocytes, there was suggestive evidence in the ALHS of a gene-by-environment interaction for minor allele carrier status at the TLR4 haplotype defined by rs4986790 and rs4986791 (interaction p=0.15).This is, to our knowledge, the first report of an association between house dust endotoxin and leukocyte count in a national survey. The finding was replicated in a farming population. Peripheral leukocyte count may be influenced by residential endotoxin exposure in diverse settings. https://doi.org/10.1289/EHP661.
A randomised phase 2 study of 3 weekly cabazitaxel vs weekly paclitaxel chemotherapy in the first-line treatment of HER2 negative metastatic breast cancer.
Authors: Amit Bahl, Jeremy Braybrooke
Journal: Journal of Clinical Oncology (2017)

TPS1122 Background: Breast cancer (BC) represents 25% of all cancers in women. Whilst the majority have early stage disease approximately 30% will develop metastatic breast cancer (MBC). In HER2 negative MBC, palliative chemotherapy is one of the main treatment options. It remains to be seen whether the use of adjuvant taxane chemotherapy leads to an increase in taxane resistance at the onset of MBC, although for patients with a relatively short disease free interval this may be the case. Cabazitaxel (CBZ) is a novel taxoid selected for development from preclinical evidence in cell lines resistant to docetaxel and paclitaxel including activity in a HER-2 positive BC tumour xenograft, with innate resistance to docetaxel. Clinically CBZ is licensed for metastatic castration-resistant prostate cancer following progression during or after docetaxel chemotherapy. A phase 3 RCT in this patient group showed a 3 month overall survival benefit for patients receiving CBZ and prednisolone compared with mitoxantrone and prednisolone. Methods: CONCEPT is an open label randomised phase 2 trial of first line chemotherapy in patients with HER-2 negative MBC where paclitaxel would be considered the standard treatment. Patients are randomised to cabazitaxel 25 mg/m 2 every 21 days for 6 cycles or paclitaxel 80 mg/m 2 weekly for 18 weeks. Eligibility includes patients who are PS 0 or 1 who may have received prior docetaxel in the adjuvant setting or be taxane-naïve. The primary endpoint is progression free survival (PFS), defined as the time between the date of randomisation and progression (according to RECIST version 1.1) or death from any cause. Secondary end-points include safety, overall survival and assessment of quality of life factors by FACT-B and EQ-5D-5L. For the current phase 2 study 90 patients will be recruited, with a 1:1 randomisation, proceeding to phase 3 of 160 patients, if the interim analysis does not show futility. To date 38 patients have been recruited from 10 centres. The IDMC met in Oct 2016 and recommended the study continue recruitment.
Real-world dosing patterns of everolimus-based lines of therapy among post-menopausal women with hormone receptor-positive and human epidermal growth factor receptor-negative (HR+/HER2-) metastatic breast cancer (mBC).
Authors: Nicole Princic, Matthew Brouillette, Derek Tang, Chinjune Lin, Brad Lanoue, Victoria E. Barghout
Journal: Journal of Clinical Oncology (2017)

e12528 Background: This study sought to describe dosing patterns of post-menopausal women with HR+/HER2- mBC treated with everolimus during a second or later lines of therapy in the US. Methods: MarketScan Commercial and Medicare Supplemental administrative claims databases were used to select post-menopausal HR+/HER2- mBC females who initiated an everolimus-based line of therapy during 1/1/2013- 7/31/2016. The first secondary malignancy diagnosis was the index date. Patients had 6 months of continuous enrollment in their health plans pre- and post- index, and were followed until the earliest date of disenrollment, inpatient death, or end of study. A line of therapy ended at discontinuation (gap &gt;60 days in all treatment) or switch to a new treatment. Dose modification during 2L, 3L, or 4L was defined by a change in daily dose of &gt;2.5 mg compared to the prior prescription and treatment interruption was defined as a gap &gt;60 days of everolimus followed by a restart of therapy during follow-up. Results: There were 645 mBC patients with everolimus-based line(s) of therapy eligible for analysis (mean age = 61.1 [SD 11.7], mean days to treatment initiation = 33.4 [SD 65.1]). Across all lines, the majority (72.5%-80.8%) of patients were on a combination regimen with endocrine therapy and &lt;10% were on a combination regimen with chemotherapy. Among patients with valid dose data (96.2%), mean initial dose in mg was 8.6 (SD 2.6) in 2L, 8.3 (SD 2.8) in 3L and 9.1 (SD 5.9) in 4L, the majority (71.4%-79%) did not have a dose modification, and &lt;5% had a treatment interruption (Table). Conclusions: Results from this analysis of real-world data suggest that 71%-79% of patients did not experience any modification to the initial dose during an everolimus-based 2L, 3L, or 4L of therapy and less than 4% experienced a treatment interruption. [Table: see text]
Administration of the Dual E-Selectin/CXCR4 Antagonist, GMI-1359, Results in a Unique Profile of Tumor Mobilization from the Bone Marrow and Facilitation of Chemotherapy in a Murine Model of FLT3 ITD AML
Authors: William E. Fogler, Henry Flanner, Curt Wolfgang, Jeffrey Allen Smith, Helen M. Thackray, John L Magnani
Journal: Blood (2016)
B cells control maternofetal priming of allergy and tolerance in a murine model of allergic airway inflammation
Authors: Christine Happle, Adan Chari Jirmo, Almut Meyer-Bahlburg, Anika Habener, Heinz Gerd Hoymann, Christian Hennig, Jelena Skuljec, Gesine Hansen
Journal: Journal of Allergy and Clinical Immunology (2017)