tbuckley/cabot-search huggingface dataset:
Impact of primary tumor sidedness on erlotinib efficacy in patients with metastatic colorectal cancer treated with bevacizumab maintenance: Results from the DREAM phase III trial.
Authors: Benoist Chibaudel, Thierry Andre, Benoit Samson, Marie-Line Garcia-Larnicol, Jérôme Dauba, Gerard Lledo, Olivier Jean Marie Dupuis, Yves Rinaldi, May Mabro, Nathalie Aucoin, Frédéric Viret, Nicole Tubiana-Mathieu, Ahmed Khalil, Ghaouti Nabil Baba Hamed, Werner Scheithauer, Elisabeth Carola, Dewi Vernerey, Christophe Louvet, Aimery De Gramont, Christophe Tournigand
Journal: Journal of Clinical Oncology (2018)

737 Background: Primary tumor sidedness (PTS) could be a predictive maker for treatment efficacy of EGFR inhibitors monoclonal antibodies in patients with wild-type (WT) RAS metastatic colorectal cancer (MCRC), cetuximab having limited efficacy in patients with WT-RAS right-sided tumors. DREAM study demonstrated that adding erlotinib, an oral EGFR tyrosine kinase inhibitor (TKI) to bevacizumab during maintenance therapy improved clinical outcomes (RR, PFS, OS) in patients with MCRC, whatever KRAS status. The aim of this post-hoc analysis is to evaluate the clinical outcomes according to KRAS mutational status and PTS when adding erlotinib to bevacizumab maintenance therapy. Methods: PTS was retrospectively collected in patients from the DREAM phase III trial treated with bevacizumab with or without erlotinib as maintenance therapy for MCRC who have been controlled by induction therapy. The limit for the definition of PTS was splenic flexure, and rectal tumors were considered as left-sided tumors. The primary endpoint was overall survival (OS). Results: Among 452 patients who received maintenance therapy, PTS ascertainment was 84.7% (n = 383) with 265 (71.0%) patients having left-sided primary tumor and 108 (28.9%) having right-sided primary tumors (3 patients had both and tumor location was unknown in 7 patients). Median OS and treatment effect are presented in table 1. Conclusions: The greatest OS benefit of adding erlotinib to bevacizumab maintenance therapy was observed in patients with WT-KRAS and right-sided MCRC, suggesting a clinical impact of the different mechanism of action between EGFR TKI and monoclonal antibodies. Clinical trial information: NCT00265824. [Table: see text]
Clinical Outcome of Degenerative Mitral Regurgitation
Authors: Clemence Antoine, Giovanni Benfari, Hector I. Michelena, Joseph F. Maalouf, Vuyisile T. Nkomo, Prabin Thapa, Maurice Enriquez-Sarano
Journal: Circulation (2018)

Background: Echocardiographic quantitation of degenerative mitral regurgitation (DMR) is recommended whenever possible in clinical guidelines but is criticized and its scalability to routine clinical practice doubted. We hypothesized that echocardiographic DMR quantitation, performed in routine clinical practice by multiple practitioners, predicts independently long-term survival and thus is essential to DMR management. Methods: We included patients diagnosed with isolated mitral valve prolapse from 2003 to 2011 and any degree of mitral regurgitation quantified by any physician/sonographer in routine clinical practice. Clinical/echocardiographic data acquired at diagnosis were retrieved electronically. The end point was mortality under medical treatment analyzed by Kaplan-Meier method and proportional hazard models. Results: The cohort included 3914 patients (55% male) mean age (±standard deviation) 62±17 years with left ventricular ejection fraction 63±8% and median after routinely-measured effective regurgitant orifice area (EROA) [interquartile range], 19 [0–40] mm 2 . During follow-up (6.7±3.1 years), 696 patients died under medical management, and 1263 underwent mitral surgery. In multivariate analysis, routinely-measured EROA was associated with mortality (adjusted hazard ratio, 1.19; 95% confidence interval, 1.13–1.24; P &lt;0.0001 per 10 mm 2 ) independently of left ventricular ejection fraction and end-systolic diameter, symptoms, and age/comorbidities. The association between routinely-measured EROA and mortality persisted with competitive risk modeling (adjusted hazard ratio, 1.15; 95% confidence interval, 1.10–1.20; P &lt;0.0001 per 10 mm 2 ), or in patients without guideline-based class I/II surgical triggers (adjusted hazard ratio, 1.19; 95% confidence interval, 1.10–1.28; P &lt;0.0001 per 10 mm 2 ) and in all subgroups examined (all P &lt;0.01). Spline curve analysis showed that, compared with general population mortality, excess mortality appears for moderate DMR (EROA ≥20 mm 2 ), becomes notable at EROA ≥30 mm 2 , and steadily increases with higher EROA levels (eg, higher EROA levels beyond the 40 mm 2 threshold). Conclusions: Echocardiographic DMR quantitation is scalable to routine practice and is independently associated with clinical outcome. Routinely-measured EROA is strongly associated with long-term survival under medical treatment. Excess mortality versus the general population appears in the moderate DMR range and steadily increases with higher EROA. Hence, individual EROA values should be integrated into therapeutic considerations, in addition to categorical DMR grading.
Updated efficacy, safety, &amp; PD-L1 status of patients with HR+, HER2- metastatic breast cancer administered abemaciclib plus pembrolizumab.
Authors: Sara M. Tolaney, Peter Kabos, Maura N. Dickler, Luca Gianni, Valerie Jansen, Yi Lu, Suzanne Young, Hope S. Rugo
Journal: Journal of Clinical Oncology (2018)

1059 Background: Abemaciclib is a selective inhibitor of CDK4 & 6 approved to treat HR+, HER2- metastatic breast cancer (MBC) patients (pts) as monotherapy and in combination with fulvestrant. In preclinical models, abemaciclib administered with anti-programmed death-ligand 1 (PD-L1) antibody therapy synergistically induced anti-tumor response and immunologic memory. A Phase I study (JPBJ, NCT02079636) of abemaciclib plus pembrolizumab (Merck & Co.), a programmed death receptor 1 (PD-1) antibody, demonstrated stable disease in 65% of pts with stage IV NSCLC along with a generally manageable safety profile. Methods: JPCE is a multicenter, nonrandomized, open-label, Phase 1b study of abemaciclib plus pembrolizumab in pts with HR+, HER2- MBC or stage IV NSCLC. Key eligibility criteria for the MBC cohort were: HR+, HER2- MBC with 1 - 2 prior chemotherapy regimens, measurable disease, adequate organ function, ECOG PS ≤1, and no prior treatment with CDK4 & 6 or PD-1 & PD-L1 inhibitors. The primary objective was to assess safety of the combination per CTCAE v4.0. Secondary objectives were: objective response rate (ORR), progression-free survival, duration of response, disease control rate, overall survival, pharmacokinetics and pt-reported disease-related symptoms. Pts received the maximum tolerated dose established in JPBJ; orally administered abemaciclib 150 mg twice daily plus IV administered pembrolizumab 200 mg, day 1 of each 21-day cycle. Results: Twenty-eight pts were enrolled in the MBC cohort. Abemaciclib plus pembrolizumab demonstrated a generally manageable safety profile in pts with HR+, HER2- MBC. Single agent toxicity profiles reported previously were not exacerbated, and no new safety signals were detected. Initial ORR was 14.3%. Patient PD-L1 status by IHC staining (positive ≥1%; negative < 1%), efficacy, and safety data from the 24-week analysis will be presented. Conclusions: Abemaciclib plus pembrolizumab demonstrated a generally manageable safety profile upon initial review (Rugo et al. SABCS 2017). Assessment of the effectiveness of this novel combination, with reference to PD-L1 status, for the treatment of pts with HR+, HER2- MBC is ongoing. Clinical trial information: NCT02779751.
Precision medicine in united airways disease: A “treatable traits” approach
Authors: A. C. A. Yii, T.‐R. Tay, X. N. Choo, M. S. Y. Koh, A. K. H. Tee, D.‐Y. Wang
Journal: Allergy (2018)

Abstract United airways disease ( UAD ) is the concept that the upper and lower airways, which are anatomically and immunologically related, form a single organ. According to this concept, upper and lower airway diseases are frequently comorbid because they reflect manifestations of a single underlying disease at different sites of the respiratory tract. Allergic asthma‐allergic rhinitis is the archetypal UAD , but emerging data indicate that UAD is a heterogeneous condition and consists of multiple phenotypes (observable clinical characteristics) and endotypes (pathobiologic mechanisms). The UAD paradigm also extends to myriad sinonasal diseases (eg, chronic rhinosinusitis with or without nasal polyps) and lower airway diseases (eg, bronchiectasis, chronic obstructive pulmonary disease). Here, we review currently known phenoendotypes of UAD and propose a “treatable traits” approach for the classification and management of UAD , wherein pathophysiological mechanisms and factors contributing to disease are identified and targeted for treatment. Treatable traits in UAD can be analyzed according to a framework comprising airway inflammation (eosinophilic, neutrophilic), impaired airway mucosal defense (impaired mucociliary clearance, antibody deficiency), and exogenous cofactors (allergic sensitizers, tobacco smoke, microbes). Appreciation of treatable traits is necessary in advancing the effort to deliver precise treatments and achieve better outcomes in patients with UAD .
HIT: A multicenter phase I-II study of trastuzumab administered by intrathecal injection for leptomeningeal meningitis of HER2+ metastatic breast cancer.
Authors: Maya Gutierrez, Emmanuelle Fourme, Sophie Taillibert, Emilie Le Rhun, Olivier Tredan, Katharina Gunzer, Veronique Dieras, Fawzia Mefti, Nora Vago-Ady, Patricia Tresca, Isabelle Turbiez, Gilles Paintaud, Etienne Brain
Journal: Journal of Clinical Oncology (2012)

TPS662 Background: Leptomeningeal metastases (LM) are commonly associated with breast cancer (BC), announcing short term prognosis that intrathecal (IT) chemotherapy poorly modifies. Incidence is particularly marked in HER2+ tumours. With the better control of extra-cerebral disease and prolonged survival yielded by intra-venous (IV) trastuzumab (T), the main hypothesis is that intra-cerebral recurrences are not reached by this high molecular weight (148 kD) monoclonal antibody. Analyses performed in cerebrospinal fluid (CSF) following IV T have shown low T levels, suggesting that LM of HER2+ BC would remain potentially sensitive to anti-HER2 agents as long as they could by-pass the meningeal blood brain barrier. Intraventricular (via Ommaya port) or IT administration of T would allow keeping control on LM progression through high T therapeutic concentrations in CSF. This prospective trial is the first phase I-II study sponsored by Institut Curie to investigate the safety and efficacy of the IT administration of T for HER2+ LM BC. Methods: Eligible patients must be 18+, have a diagnosis of LM either on CSF with HER2+ cytology or on clinical/MRI pictures of meningitis, and normal end-organ functions. The phase I cohort investigates the maximum tolerated dose (MTD) and recommended dose of T given weekly IT (or via Ommaya port) + hemisuccinate hydrocortisone 25 mg, while aiming at yielding a T target-concentration in CSF close to the plasma one (30 µg/mL) obtained with standard IV schedule. The MTD is defined as the highest dose level (DL) tested with ≥2 dose-limiting toxicity (DLT, any grade ≥3 NCI CTCAE v4.0 attributed to T) observed in ≤6 patients (3+3 Fibonacci dose escalation design, 4 DL 30-150 mg) with a maximum of 24 patients. The phase II cohort will investigate the efficacy of the recommended dose (DL MTD-1 ) defined in cohort I on neurological progression-free survival at 2 months, in ≤19 patients. Secondary endpoints include CSF and MRI response, quality of life, FCGR3A influence, and comparative CSF/plasma pharmacokinetics. Since study activation in May 2011, 5 patients have been included at DL1, 3 being evaluable for DLT. DL2 is now open for accrual.
From PCR to miRNA profiling: Where is the true?
Authors: Paola Fuso, Mariantonietta Di Salvatore, Concetta Santonocito, Donatella Guarino, Antonino Mulè, Damiano Arciuolo, Flavio Mignone, Antonina Rinninella, Matteo Ramundo, Brunella Di Stefano, Raffaella Vivolo, Antonio Astone, Ettore Domenico Capoluongo, Carlo Barone, Alessandra Cassano
Journal: Journal of Clinical Oncology (2018)

e12665 Background: The prognostic value of pathological complete response (pCR) on survival is still debated. Previous studies have revealed that breast cancer intrinsic subtypes show different molecular profiles and several miRNAs have important roles to determine and regulate such subtypes. We investigated the potential role of miRNA signature as predictor of outcome in early breast cancer. Methods: We retrospectively analyzed 12 patients with locally advanced breast cancer who received neoadjuvant chemotherapy (NAD). Purification of miRNA from paraffin-embedded tissue sections was performed by miRNeasy FFPE kit (QIAGEN); miRNA sequencing libraries, prepared with QIAseq miRNA Library Kit (QIAGEN), was sequenced using Illumina NGS system (MiSeq Personal Sequencer). Identification of miRNAs in the samples was performed using software QIAseq miRNA-NGS data analysis. The miRNAs that differed between pre-NAD and post-NAD were taken into consideration. The miRNA targets were predicted by the MiRDB tool (http://www.mirdb.org). Results: Median follow-up was 61 months (range 43 –93 months). We analyze miRNA expression profile in patient who did not obtain pCR but experimented a long term disease free survival. We found that miR-510-3p, a miRNA related to angiogenesis, is down-regulated in post-NAD samples, regardless to breast cancer subtypes. miR-191-5p and miR100-5p, that promote proliferation and migration of cancer cells, are down-regulated in HER2 luminal post-NAD samples. miR196a-5p is down-expressed in triple negative (TN) post-NAD samples and is associated with important signalling pathways in cancer, including breast carcinogenesis, progression and drug resistance. On reverse, we found overexpression of miR-143-3p and miR30a-5p in TN and in HER2 non luminal post-NAD samples: both miRNAs are inversely correlate with invasive capacity. Conclusions: pCR might not be a surrogate prognostic factor of outcome; indeed, modulation of expression of different miRNAs in pre- and post-NAD samples may be better related to breast cancer prognosis in respect of pCR. The profiling of miRNA expression in breast cancer and clarifying molecular mechanisms of breast cancer-specific miRNAs are important future topics for basic and clinical research of breast cancer.
3D Bioprinting: Patient‐Specific Bioinks for 3D Bioprinting of Tissue Engineering Scaffolds (Adv. Healthcare Mater. 11/2018)
Authors: Negar Faramarzi, Iman K. Yazdi, Mahboubeh Nabavinia, Andrea Gemma, Adele Fanelli, Andrea Caizzone, Leon M. Ptaszek, Indranil Sinha, Ali Khademhosseini, Jeremy N. Ruskin, Ali Tamayol
Journal: Advanced Healthcare Materials (2018)

In article 1701347 by Ali Tamayol and co-workers, alginate-based bioinks are developed that carry platelet rich plasma (PRP) as a source of growth factors and are compatible with commercial bioprinters. The use of autologous PRP in the bioinks is an important step towards bioprinting patient specific tissues and scaffolds. Cover image designed and produced by Masoud Moosavi Basri.
New Agents, Emerging Late Effects, and the Development of Precision Survivorship
Authors: Eric J. Chow, Zoltan Antal, Louis S. Constine, Rebecca Gardner, W. Hamish Wallace, Brent R. Weil, Jennifer M. Yeh, Elizabeth Fox
Journal: Journal of Clinical Oncology (2018)

Incremental improvements in the treatment of children and adolescents with cancer have led to 5-year survival rates reaching nearly 85%. In the past decade, impressive progress has been made in understanding the biology of many pediatric cancers. With that understanding, multiple new agents have become available that offer the promise of more-effective and less-toxic treatment. These include agents that target various cell surface antigens and engage the adaptive immune system, as well as those that interfere with key signaling pathways involved in tumor development and growth. For local control, surgery and radiation techniques also have evolved, becoming less invasive or featuring new techniques and particles that more precisely target the tumor and limit the dose to normal tissue. Nevertheless, targeted agents, like conventional chemotherapy, radiotherapy, and surgery, may have off-target effects and deserve long-term follow-up of their safety and efficacy. These include injury to the endocrine, cardiovascular, and immunologic systems. New radiation and surgical techniques that theoretically reduce morbidity and improve long-term quality of life must also be validated with actual patient outcomes. Finally, with advances in genomics, information on host susceptibility to late effects is beginning to emerge. Such knowledge, coupled with improved metrics that better describe the spectrum of potential late effects across the entire lifespan, can lead to the development of decision models that project the potential long-term health outcomes associated with various treatment and follow-up strategies. These developments will help extend the current focus on precision medicine to precision survivorship, where clinicians, patients, and families will have a better grasp of the potential risks, benefits, and tradeoffs associated with the growing number of cancer treatment options.
Somatostatin receptor type 2 as a radiotheranostic PET reporter gene for oncologic interventions
Authors: Pedram Heidari, Anchisa Kunawudhi, Jordi Martinez-Quintanilla, Alicia Szretter, Khalid Shah, Umar Mahmood
Journal: Theranostics (2018)

Reporter gene systems can serve as therapy targets. However, the therapeutic use of reporters has been limited by the challenges of transgene delivery to a majority of cancer cells. This study specifically assesses the efficacy of targeting human somatostatin receptor subtype 2 (hSSTR2) with peptide receptor radionuclide therapy (PRRT) when a small subpopulation of cells bears the transgene. Methods: The hSSTR2 transgene was delivered to A549 and Panc-1tumors using the lentiviral vector, LV-hSSTR2-IRES-GFP or murine mesenchymal stem cells (mMSC)s using a retroviral vector. SSTR2 expression was assessed using Western blot and correlated to GFP fluorescence and 68Ga-DOTATOC uptake. Wild type (WT), transduced (TD), and mixed population A549 or Panc-1 xenografts were implanted in nude mice. Separate groups with A549WT and Panc-1WT tumors received intratumoral injection of SSTR2-expressing mMSCs. Tumor-bearing mice were treated with 90Y-DOTATOC or saline and evaluated with 68Ga-DOTATOC PET before and after treatment. Results: Cell studies showed a strong correlation between 68Ga-DOTATOC uptake and SSTR2 expression in A549 (p < 0.004) and Panc-1 cells (p < 0.01). 68Ga-DOTATOC PET SUVmean was 8- and 5-fold higher in TD compared to WT A549 and Panc-1 tumors, respectively (p < 0.001). After 90Y-DOTATOC treatment, 100% TD and mixed population TD xenografts showed growth cessation while the WT xenografts did not. A549WT and Panc-1WT tumors with SSTR2-expressing mMSCs treated with 90Y-DOTATOC showed significantly lower tumor volumes compared to controls (p < 0.05). 68Ga-DOTATOC PET SUVmean of treated TD tumors monotonically declined and was significantly lower than that of non-treated xenografts. Conclusions: We showed that SSTR2 delivery to a small population of cells in tumor in conjunction with PRRT is effective in tumor growth cessation. The availability of various transgene delivery methods for hSSTR2 and radiotherpaeutic somatostatin analogs highlights the direct translational potential of this paradigm in the treatment of various cancers.
Predictive factors of response to neoadjuvant chemoradiotherapy in rectal cancer patirnts.
Authors: C. Carlomagno, F. D'Armiento, A. Crispo, G. Della Vittoria Scarpati, M. D'Armiento, M. Marra, L. Cannella, A. De Stefano, M. Colantuoni, S. Alfieri, S. De Placido, Stefano Pepe
Journal: Annals of Oncology (2008)
Severe Hyponatremia After Drinking Horsetail Juice
Authors: Chloe C.A. Grim, Iwan A. Meynaar, Sebastiaan Hammer, Darius Soonawala
Journal: Annals of Internal Medicine (2018)

Letters2 October 2018Severe Hyponatremia After Drinking Horsetail JuiceChloe C.A. Grim, MD, MSc, Iwan A. Meynaar, MD, PhD, MSc, Sebastiaan Hammer, MD, PhD, and Darius Soonawala, MD, PhDChloe C.A. Grim, MD, MScHagaHospital, The Hague, the Netherlands (C.C.G., I.A.M., S.H., D.S.)Search for more papers by this author, Iwan A. Meynaar, MD, PhD, MScHagaHospital, The Hague, the Netherlands (C.C.G., I.A.M., S.H., D.S.)Search for more papers by this author, Sebastiaan Hammer, MD, PhDHagaHospital, The Hague, the Netherlands (C.C.G., I.A.M., S.H., D.S.)Search for more papers by this author, and Darius Soonawala, MD, PhDHagaHospital, The Hague, the Netherlands (C.C.G., I.A.M., S.H., D.S.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L18-0028 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: Horsetail (Equisetum) refers to a genus of perennial plants that reproduce by spores instead of flowers. This family is the only surviving member of an order of plants that was prevalent in forests of the late Paleozoic Era. Different species grow in all parts of the world except Australasia. Horsetail has been used as an herbal remedy for edema since at least early Greek and Roman times.Objective: To alert clinicians to a potential adverse effect of horsetail juice.Case Report: A 32-year-old woman presented to the emergency department because she felt restless. Two hours earlier, the patient drank ...References1. Sandhu NS, Kaur S, Chopra D. Equietum arvense: pharmacology and phytochemistry—a review. Asian Journal of Pharmaceutical and Clinical Research. 2010;3:146-50. Google Scholar2. Wright CI, Van-Buren L, Kroner CI, Koning MM. Herbal medicines as diuretics: a review of the scientific evidence. J Ethnopharmacol. 2007;114:1-31. [PMID: 17804183] CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: HagaHospital, The Hague, the Netherlands (C.C.G., I.A.M., S.H., D.S.)Financial Support: None.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L18-0028.This article was published at Annals.org on 29 May 2018. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoSevere Hyponatremia After Drinking Horsetail Juice Chloe C.A. Grim Severe Hyponatremia After Drinking Horsetail Juice Matthew R. Norris Metrics Cited bySevere Hyponatremia After Drinking Horsetail JuiceMatthew R. Norris, MD 2 October 2018Volume 169, Issue 7Page: 507-508KeywordsBlood plasmaDisclosureDiureticsEdemaEpileptic seizuresHyponatremiaSaltsSodiumVital signsWalking ePublished: 29 May 2018 Issue Published: 2 October 2018 Copyright & PermissionsCopyright © 2018 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...