tbuckley/cabot-search huggingface dataset:
Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER+/HER2+ Breast Cancers: Implications to the ExteNET Trial
Authors: Dhivya R. Sudhan, Luis J. Schwarz, Angel Guerrero-Zotano, Luigi Formisano, Mellissa J. Nixon, Sarah Croessmann, Paula I. González Ericsson, Melinda Sanders, Justin M. Balko, Francesca Avogadri-Connors, Richard E. Cutler, Alshad S. Lalani, Richard Bryce, Alan Auerbach, Carlos L. Arteaga
Journal: Clinical Cancer Research (2018)

The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2+ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER+/HER2+ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib.Experimental Design: Mice with established ER+/HER2+ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab ± pertuzumab for 4 weeks, and then randomized to fulvestrant ± neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses.Mice receiving "extended adjuvant" therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER+/HER2+ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER+/HER2- MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER+/HER2+ breast cancer cells.These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER+/HER2+ breast cancer.
Loss of Shp2 Rescues BDNF/TrkB Signaling and Contributes to Improved Retinal Ganglion Cell Neuroprotection
Authors: Nitin Chitranshi, Yogita Dheer, Mehdi Mirzaei, Yunqi Wu, Ghasem H. Salekdeh, Mojdeh Abbasi, Veer Gupta, Roshana Vander Wall, Yuyi You, Stuart L. Graham, Vivek Gupta
Journal: Molecular Therapy (2018)

Glaucoma is characterized by the loss of retinal ganglion cells (RGC), and accordingly the preservation of RGCs and their axons has recently attracted significant attention to improve therapeutic outcomes in the disease. Here, we report that Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) undergoes activation in the RGCs, in animal model of glaucoma as well as in the human glaucoma tissues and that Shp2 dephosphorylates tropomyosin receptor kinase B (TrkB) receptor, leading to reduced BDNF/TrkB neuroprotective survival signaling. This was elucidated by specifically modulating Shp2 expression in the RGCs in vivo, using adeno-associated virus serotype 2 (AAV2) constructs. Shp2 upregulation promoted endoplasmic reticulum (ER) stress and apoptosis, along with functional and structural deficits in the inner retina. In contrast, loss of Shp2 decelerated the loss of RGCs, preserved their function, and suppressed ER stress and apoptosis in glaucoma. This report constitutes the first identification of Shp2-mediated TrkB regulatory mechanisms in the RGCs that can become a potential therapeutic target in both glaucoma and other neurodegenerative disorders. Glaucoma is characterized by the loss of retinal ganglion cells (RGC), and accordingly the preservation of RGCs and their axons has recently attracted significant attention to improve therapeutic outcomes in the disease. Here, we report that Src homology region 2-containing protein tyrosine phosphatase 2 (Shp2) undergoes activation in the RGCs, in animal model of glaucoma as well as in the human glaucoma tissues and that Shp2 dephosphorylates tropomyosin receptor kinase B (TrkB) receptor, leading to reduced BDNF/TrkB neuroprotective survival signaling. This was elucidated by specifically modulating Shp2 expression in the RGCs in vivo, using adeno-associated virus serotype 2 (AAV2) constructs. Shp2 upregulation promoted endoplasmic reticulum (ER) stress and apoptosis, along with functional and structural deficits in the inner retina. In contrast, loss of Shp2 decelerated the loss of RGCs, preserved their function, and suppressed ER stress and apoptosis in glaucoma. This report constitutes the first identification of Shp2-mediated TrkB regulatory mechanisms in the RGCs that can become a potential therapeutic target in both glaucoma and other neurodegenerative disorders.
Abstract 16930: Increased Risk of Torsades de Pointes in Hospitalized Pediatric Oncology Patients With Prolonged QTc Interval
Authors: Tiffany R Lim, Arun A Rangaswami, Anne M Dubin, Charlotte Sakarovitch, Kristopher I Kapphahn, Kara S Motonaga, Scott R Ceresnak
Journal: Circulation (2017)

Introduction: Prolongation of the QTc interval is common in hospitalized pediatric oncology patients secondary to a combination of medications, electrolyte abnormalities and other factors. A QTc in...
Men’s Fear of Mentoring in the #MeToo Era — What’s at Stake for Academic Medicine?
Authors: Sophie Soklaridis, Catherine Zahn, Ayelet Kuper, Deborah Gillis, Valerie H. Taylor, Cynthia Whitehead
Journal: New England Journal of Medicine (2018)

In response to the #MeToo and Time’s Up movements, some men in positions of power say they are afraid to participate in mentoring relationships with women. This response has serious consequences for women’s career advancement.
Genome-wide association study identifies an acute myeloid leukemia susceptibility locus near BICRA
Authors: Christopher J. Walker, Christopher C. Oakes, Luke K. Genutis, Brian Giacopelli, Sandya Liyanarachchi, Deedra Nicolet, Ann-Kathrin Eisfeld, Markus Scholz, Pamela Brock, Jessica Kohlschmidt, Krzysztof Mrózek, Marius Bill, Andrew J. Carroll, Jonathan E. Kolitz, Bayard L. Powell, Eunice S. Wang, Dietger W. Niederwieser, Richard M. Stone, John C. Byrd, Sebastian Schwind, Albert de la Chapelle, Clara D. Bloomfield
Journal: Leukemia (2018)
Abstract 19449: Real World Blood Pressure Variability in Over 56,000 Individuals With Nearly 17 Million Measurements
Authors: Kwang-Il Kim, Nima Nikzad, Nathan Wineinger, Benoit Brouard, Matthieu Vegreville, Angela Chieh, Alexis Normand, Nicolas Schmidt, Eric J Topol, Steven Steinhubl
Journal: Circulation (2016)

Introduction: Visit-to-visit and day-to day blood pressure variability (BPV) are known to be associated with an increased risk of stroke, coronary events, and mortality independent of the mean blood pressure (BP). However, current data were acquired in the setting of clinical trials or registry. Hypothesis: Our goal was to investigate the real world characteristics of BPV. Methods: We included 56,365 users of Withings’ Wireless Blood Pressure Monitors from US, France, Germany, UK, and 181 other countries who have at least 20 BP measurements separated in time by at least 1 month. We computed standard deviation (SD), coefficient of variation (CV), maximum BP, and maximum minus minimum BP difference (MMD) as an intra-individual BPV index. Results: We analyzed 16,904,844 BP measurements data (median number of BP measurements per person: 146, IQR 73-321). BPV index were higher in female compared with male (p<0.001) and increased with age (p<0.001). In addition, there was significant difference according to geo...
心筋の虚血耐性獲得とその臨床的意義 : 心筋梗塞急性期の治療 : 第56回日本循環器学会学術集会
Authors: 恒彦 葛谷, 隆三 南野, 四朗 星田, 宜繁 山下, 洋史 大江, 正二 堀, 道彦 多田, 武信 鎌田, 雄介 中川, 久和 藤
Journal: Circulation (1993)
Proximal muscle weakness and skin rash
Authors: Ramachandiran Nandhagopal, Suad Al-Jahdhami, Arunodaya R Gujjar
Journal: BMJ (2018)

A 34 year old woman presented with a 9 day history of progressive proximal bilateral limb weakness and mild dysphagia with fluids. On examination, she had a peri-orbital rash (fig 1). Neurological findings included moderately severe (grade 3-4/5) bilateral proximal limb and neck flexor weakness with preserved deep tendon reflexes and sensation.



Fig. 1 
Peri-orbital rash



Her laboratory test findings were

Fat suppressed magnetic resonance imaging (MRI) of the thigh muscles showed abnormal signals (hyperintensities) of the lateral, medial, and anterior compartments (fig 2).



Fig. 2 
Magnetic resonance imaging (MRI) (fat suppressed short tau inversion recovery image) of the thigh muscles. (Left) Coronal section, (right) axial section



Needle electromyography of the proximal arm and leg muscles showed fibrillation, positive sharp waves, and early recruitment of volitional motor unit potentials.



### 1. What is the diagnosis?

Dermatomyositis—an inflammatory disorder involving the skin and muscles. Figure 1 shows dusky bilateral erythematous macular rashes in the slightly swollen peri-orbital regions. This is a heliotrope rash and is characteristic of dermatomyositis.12 The patient’s proximal limb weakness, mild dysphagia, preserved deep tendon reflexes, elevated creatine kinase, MRI findings (fig 3), and needle electromyography findings are also suggestive of myopathy.34



Fig. 3 
Magnetic resonance imaging (MRI) (fat suppressed short tau inversion recovery image) of the thigh muscles. (Left, A) Coronal section, (B, right) axial section. Hyperintensities (stars) …
Emergency Department Visits by Children With Congenital Heart Disease
Authors: Jonathan B. Edelson, Joseph W. Rossano, Heather Griffis, Dingwei Dai, Jennifer Faerber, Chitra Ravishankar, Christopher E. Mascio, Laura M. Mercer-Rosa, Andrew C. Glatz, Kimberly Y. Lin
Journal: Journal of the American College of Cardiology (2018)
Improving patient satisfaction: Introduction of a telephone results clinic in Neuro-Oncology follow-up
Authors: Dr Helen Joyce, Dr Susan Clenton, Dr Caroline Bridgewater
Journal: Neuro-Oncology (2018)

It has been shown in one UK centre that telephone clinics helped improve patient satisfaction and lessened the burden on overbooked outpatient services in the low grade glioma setting1. AIMS We set up a telephone clinic for Neuro-Oncology follow-up patients. We aimed to reduce the burden of patients attending outpatient clinics and improve the follow-up experience for patients who were stable on surveillance imaging. The telephone clinic was offered to selected Neuro-Oncology patients. Only patients stable on standard outpatient follow-up for 12 months and who understood that they may receive bad news over the telephone were eligible. If they were accepting of this and consented to telephone follow-up they were transferred to this clinic. After at least one telephone clinic appointment they were sent a questionnaire to assess their satisfaction. 34 patient satisfaction questionnaires were sent out to all attendees of the telephone clinic. 26 (76%) responses were received. The respondents were aged 24–74 years and were predominantly male (73%). 24 (92%) had a diagnosis of Glioma and the majority of these were high grade (6 low grade patients: 18 high grade patients). There was a consensus from all patients that the telephone clinic was beneficial to their patient experience. It was found to be a prompt way to deliver information and reduce stress levels, as well as eliminating associated travel time and costs. 100% of patients surveyed preferred telephone clinic appointments to a standard outpatient appointment. From our initial survey, telephone clinics appear to reduce burden on outpatient neuro-oncology services whilst maintaining high levels of patient satisfaction. REFERENCES 1.) Oberg I, Price S. Nurse-led telephone clinics improve patient satisfaction and enhance follow up for benign/low grade tumour patients. Neuro-Oncology 2017. Available: https://academic.oup.com/neuro-oncology/article-abstract/19/suppl_l/i10/3059769 [Accessed 01/02/2018].
LARGE VOLUME RE-IRRADIATION IS A VIABLE OPTION IN PATIENTS WITH RECURRENT REFRACTORY GLIOBLASTOMA
Authors: Michael Back, Joseph Chan, Dasantha Jayamanne
Journal: Neuro-Oncology (2018)

Current practice in re-irradiation (reRT) of patients with previously treated Glioblastoma (GBM) has generally been limited to small volume reRT often with stereotactic procedures. Less evidence exists for the safety, toxicity and outcomes of patients who undergo large volume reRT. This study investigates outcomes of large volume reRT in patients with recurrent refractory GBM. Patients with GBM managed with radiation therapy were entered into a prospective ethics approved database. Patients receiving fractionated reRT from 2009–2017 were identified. Potential prognostic data were analysed for the primary endpoint of overall survival (OS) duration post reRT, such as tumour type, tumour site, age, time from diagnosis, ECOG status, MRC Neurological Scale, PTV volume, and use of bevacizumab (BEV). Kaplan Meier survival was calculated and differences between groups assessed by log-rank and Cox regression analyses. Seventy-two patients were managed with ReRT, including 51 patients with GBM. Median PTV was 117.4cm3; 92% received 35-40Gy in 15 fractions; and 80% patients received concurrent BEV and 88% post-reRT BEV. Only one episode of radiation necrosis occurred, and was in a patient with no concurrent BEV. Median OS post reRT of the 51 patients was 7 months (95% 6.2–7.8). ECOG 0–1 had a median OS of 9 months (95% 8.1–9.9) compared with 6 months for ECOG 2–3 (95% 4.4–7.6; p=0.05). Time from diagnosis (p<0.01) was associated with improved survival but not age (p=0.16); MRCscale(p=0.19); PTV volume (p=0.62) or tumour site (p=0.72). Concurrent or post-reRT BEV was not associated with OS (p=0.57; but noting that 88% received BEV and the median OS was 7 months versus 4 months with no BEV). Large volume reRT with BEV produces a meaningful survival in patients with GBM, especially in patients with good performance status. It should be considered as a late salvage therapy in chemorefractory disease.
SAT0141 Trends in the incidence of lymphomas and leukemias in patients with rheumatoid arthritis in spain: an observational cohort study of hospital discharges from 1999 to 2015 (TREND-AR STUDY)
Authors: J. L. Morell Hita, R. Mazzucchelli, E. Perez Fernandez, J. Quiros, C. Macía Villa, N. Crespi, M. Peña, C. Barbadillo, M. Espinosa, H. Godoy, M. Fernandez Prada, M. Galindo, A. Garcia Vadillo, O. Guzon Illescas, A. Herranz, C. Martinez Prada, C. Morado Quiñoa, V. Villaverde
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Oncohematological diseases have an increased incidence in Rheumatoid Arthritis (RA) patients. However, their trend in RA in Spain is unknown <h3>Objectives:</h3> To analyze the incidence and trend of hospital admissions for lymphomas and leukemias in RA patients in Spain from 1999–2015 <h3>Methods:</h3> We performed an observational retrospective population study analyzing the spanish administrative database that includes a Minimun Basic Data Set (MBDS) of hospital admissions of RA patients from 1999–2015. We selected MBDSs for lymphomas and leukemias. Cases were identified by the presence in primary/secondary diagnosis of ICD9 codes. The population at risk was estimated with a prevalence of RA of 0,5% (0,8% women and 0,2% men). Crude and adjusted rates were calculated, and the trend was analyzed using the Generalized Linear Model with the year as the analysis variable. SPSS version 20 (Chicago, IL) was used <h3>Results:</h3> 338.343 RA hospital admissions were detected, being 3561(1,1%) lymphomas (61,5% women, 38,5% men) and 1664(0,5%) leukemias (52,3% women, 47,7% men). Mean age 68,94(SD 11,38) in lymphomas and 71,46(SD 11,24) in leukemias. Age-adjusted rate during the period for lymphoma was 152,19/10<sup>5</sup> inhab/year (92,05 women and 240,14 men). Lymphoma age-adjusted rate increased from 52,46/10<sup>5</sup> inha/year in 1999 to 187,57 in 2015, both women (from 42,74 to 142,95) and men (from 280,77 to 326,63). An annual increase in lymphoma rate of 6,9% is estimated (RRI 1,069; CI 95% 1,054–1,085). Age-adjusted rate during the period for leukemia was 90,87/10<sup>5</sup> inhab/year (37,09 women and 144,65 men). Leukemia age-adjusted rate increased from 18,86/10<sup>5</sup> inhab/year in 1999 to 94,05 in 2015, both women (13,80 in 1999 to 65,93 in 2015) and men (38,70 in 1999 to 204,84 in 2015). An annual increase in leukemia rate of 8,2% is estimated (RRI 1,083; CI 95% 1,069–1,097). <h3>Conclusions:</h3> In Spain from 1999–2015 lymphoma and leukemia hospital admissions in RA patients increased, with an estimation of 6,9% and 8,2% annual increase respectively. <h3>Disclosure of Interest:</h3> None declared
AB0699 Benzathine penicillin in treatment of ulcers of behcet’s disease
Authors: S. Benamour
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Prednisone therapy, Thalidomide, azathioprine, anti–TNF-alpha inhibitors are presently used in resistant mucocutaneous lesions of Behçet's Disease (BD). In this study, we used only ambulatory Benzathine Penicillin (BP), without being preceded by high doses of penicillin infusion. This Study confirm the value of BP in the treatment of refractory ulcers of BD and point out a probable role of Streptococcus on the pathogenesis of BD <h3>Objectives</h3> This open Study confirm the value of BP in refractory oral, genital and skin ulcers of BD. We propose to use BP when ulcers of BD are resistant to colchicine 1.5 mg/day and to add BP in the recommendations of EULAR for the treatment of resistant cases of mucocutaneous involvement. <h3>Methods</h3> 15 patients with BD (12 patients fulfilled all criteria for BD) had Giant (mean size of ulcer superior to 1 cm), or Multiple oral, genital, skin ulcers received BP at the dose of 2.4 million units in intramuscular injection; 3 intramuscular injections with an interval of 3 weeks between injection. Colchicine at the dose of 1 mg/day was maintened. Serology of syphilis was negative. Patients had seen 15 days, 3 months and 1 year after the starting treatment. <h3>Results</h3> This study started in 2012, in a private office and comprised 15 patients:9 males; 6 females. Arthritis was observed in 11 patients, uveitis in 6 cases. BP was used in 8 patients with oral ulcers(4 Giants and 4 multiples), Genital ulcers in 3 patients (2 multiple and 1 Giant), oral and genital ulcers(2 Multiples) and cutaneous aphtosis in 2 patients 0.2 weeks after the first injection of BP, recovery from ulcers was achieved.BP was administrated a second time with success, in 9 patients who have developed resistant ulcers, after 1 to 3 years of recovery. One patient with panuveitis treated with azathioprine in 2013 and interferon alpha in 2015 and 2017, developed refractory ulcers: Excellent efficacy of BP was observed in this patient. <h3>Conclusions</h3> In this study, we confirm the recovery from refractory oral, genital and cutaneous ulcers (Giant, Multiple) in these 15 patients with BP. We recommend using more frequently BP and we propose to add BP in the recommendations of EULAR for the treatment of resistant cases of mucocutaneous involvement because treatment with BP is rather easy in outpatients, it is efficient, it has a low cost and have few side-effects <h3>References</h3> [1] Benamour S, Bettal S, Alaoui Fz and all: Treatment of Giant aphthosis by IV G Penicillin in Behçet's disease.10 th International Conference on Behçet's disease. Berlin, June 2002. [2] BENAMOUR S: Benzathine Penicillin in treatment of oral and Genital ulcers in Behcet's Disease. 17th International Conference on Behçet's Disease. Matera, 15th-17th September 2016 <h3>Disclosure of Interest</h3> None declared
Abstract 14818: Appropriateness of Percutaneous Coronary Intervention in Japan; International Application of 2009 and 2012 ACCF/SCAI/STS/AATS/AHA/ASNC/HFSA/SCCT Appropriateness Use Criteria
Authors: Taku Inohara, Shun Kohsaka, Hiroaki Miyata, Ikuko Ueda, Yuichiro Maekawa, Akio Kawamura, Keiichi Fukuda
Journal: Circulation (2013)

Background: Appropriate Use Criteria (AUC) for Coronary Revascularization has been used widely to assess the quality of percutaneous coronary intervention (PCI). However, reports on its internation...
Treating high-grade glioma (HGG) in the elderly: has anything changed?
Authors: Ms Anna Solth, Mr Jing Xian Lee, Mr Gareth Dobson, Mr Nitin Mukerji, Mr Anil Varma, Prof Philip Kane
Journal: Neuro-Oncology (2018)

Following a previous review1 of our experience managing HGG and finding that carefully selected elderly (age ≥65 years) patients benefit from radical treatment we decided to re-audit our practice. This retrospective audit concerns patients with a histological or radiological diagnosis of HGG over four non-consecutive years, 2011 onwards. Patients were identified via the trust cancer management systems. Survival data was calculated for patients presenting in 2011, 2013 &amp; 2015. 147 patients were identified, 71 of them elderly. The overall median age was 64 years. In 2011 23 patients presented to the MDT (39% of which were elderly), 44 in 2013 (52% elderly), 31 in 2015 (52% elderly) and 49 in 2017 (47% elderly). The median age of the elderly patient group was 67 in 2011, 72 in 2013, 70 in 2015 and 72 in 2017. Most patients underwent debulking +/- adjuvant radio-chemotherapy: 74% of the younger and 66% of the older patients. The median survival was 12 months for younger and 5 months for older patients. Patients who had debulking surgery +/-adjuvant radio-chemotherapy had a 13 and 6 months survival, respectively. Although the percentage of elderly patients referred to the MDT did not increase, the median age of the elderly patient group has increased over the years. Two thirds of elderly patients received aggressive treatment, which was unchanged to our practice in 2007. Median survival times for HGG did not improve compared to our previous audit. Performance status at presentation may be in an important factor in patient selection2 but better measurements of “frailty” in the elderly population are required to assist in management decisions. 1Mukerji et al. J Neurooncol. 2008 Feb;86(3):329–36: Treating high grade gliomas in the elderly: the end of ageism? 2Arvold &amp; Reardon Clin Interv Aging. 2014 Feb21;9:357–67: Treatment options for glioblastoma in the elderly patient.