tbuckley/cabot-search huggingface dataset:
Paclitaxel/carboplatin (PC) intercalated with gefitinib or paclitaxel/carboplatin (PC) for advanced non-small cell lung cancer (NSCLC) in selected population who were smoker or wild-type EGFR: Randomized phase II study.
Authors: Yoon Ji Choi, Sang-We Kim, Dae Ho Lee, Chang-Min Choi, Jung Shin Lee
Journal: Journal of Clinical Oncology (2013)

e19079 Background: The introduction of EGFR inhibitors to standard chemotherapy is an attractive approach to improved outcome. However, the tumor cells which were driven to G0/G1 phase by gefitinib may not sensitive to cytotoxic chemotherapy which is active to G2M arrested tumor cells. This randomized phase II study compared the efficacy of PC intercalated with gefitinib versus PC, as first-line treatment in a clinically selected population of advanced NSCLC patients. Methods: Eligible patients were chemotherapy-naïve advanced NSCLC patients with good ECOG PS of 0 or 1. Non-smoking patients with adenocarcinoma or patients with activating EGFR mutation were excluded because they could benefit from gefitinib alone. They were randomized to either one of the treatments; standard chemotherapy alone (control arm, 46 pts) of paclitaxel (175 mg/m 2 ) and carboplatin (AUC 5) on day 1; or the same chemotherapy plus gefitinib 250 mg/day on day 2 through 15 (study arm, 44 pts). The treatment was repeated every 3 weeks for maximum 4 cycles without maintenance. The primary endpoint included the response rate (RR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: A total of 90 patients (male 85.6%, median age 59, adenocarcinoma 63.3%, smoker 90.0%, wild-type EGFR 24.4%, unknown EGFR status 75.6%) were included. There was no difference in terms of RR (the study arm, 40.9% [95% CI 27.3-56.8%] vs. the control arm, 37.0% [95% CI 23.8-51.2%], p=0.701). There was also not difference in terms of PFS (the median PFS; 4.13 vs. 4.13, HR=0.941 [95% CI 0.61-1.45], p=0.781) and OS (the median OS; 9.33 vs. 10.53, HR=0.95 [95% CI 0.58-1.54], p=0.827). Safety analyses showed a similar incidence of drug-related grade 3/4 toxicity in study group (20.9%) compared with control group (23.3%), while mild rash (58% vs. 9%) and diarrhea (14% vs. 7%) were more common in the study arm. Conclusions: PC chemotherapy intercalated with gefitinib did not improved RR, PFS, and OS compared to PC chemotherapy alone in clinically selected population of advanced NSCLC patients who were smoker or wild-type EGFR. Clinical trial information: NCT01196234.
Take-Home Naloxone for the Emergency Interim Management of Opioid Overdose: The Public Health Application of an Emergency Medicine
Authors: John Strang, Rebecca McDonald, Gabrielle Campbell, Louisa Degenhardt, Suzanne Nielsen, Alison Ritter, Ola Dale
Journal: Drugs (2019)

Naloxone is a well-established essential medicine for the treatment of life-threatening heroin/opioid overdose in emergency medicine. Over two decades, the concept of 'take-home naloxone' has evolved, comprising pre-provision of an emergency supply to laypersons likely to witness an opioid overdose (e.g. peers and family members of people who use opioids as well as non-medical personnel), with the recommendation to administer the naloxone to the overdose victim as interim care while awaiting an ambulance. There is an urgent need for more widespread naloxone access considering the growing problem of opioid overdose deaths, accounting for more than 100,000 deaths worldwide annually. Rises in mortality are particularly sharp in North America, where the ongoing prescription opioid problem is now overlaid with a rapid growth in overdose deaths from heroin and illicit fentanyl. Using opioids alone is dangerous, and the mortality risk is clustered at certain times and contexts, including on prison release and discharge from hospital and residential care. The provision of take-home naloxone has required the introduction of new legislation and new naloxone products. These include pre-filled syringes and auto-injectors and, crucially, new concentrated nasal sprays (four formulations recently approved in different countries) with speed of onset comparable to intramuscular naloxone and relative bioavailability of approximately 40–50%. Choosing the right naloxone dose in the fentanyl era is a matter of ongoing debate, but the safety margin of the approved nasal sprays is superior to improvised nasal kits. New legislation in different countries permits over-the-counter sales or other prescription-free methods of provision. However, access remains uneven with take-home naloxone still not provided in many countries and communities, and with ongoing barriers contributing to implementation inertia. Take-home naloxone is an important component of the response to the global overdose problem, but greater commitment to implementation will be essential, alongside improved affordable products, if a greater impact is to be achieved.
Maternal androgen excess induces cardiac hypertrophy and left ventricular dysfunction in female mice offspring
Authors: Maria Manti, Romina Fornes, Gianluigi Pironti, Sarah McCann Haworth, Zhuge Zhengbing, Anna Benrick, Mattias Carlström, Daniel Andersson, Elisabet Stener-Victorin
Journal: Cardiovascular Research (2019)

Abstract Aims Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is suggested to increase the risk for cardiovascular disease. How PCOS may lead to adverse cardiac outcomes is unclear and here we hypothesized that prenatal exposure to dihydrotestosterone (DHT) and/or maternal obesity in mice induce adverse metabolic and cardiac programming in female offspring that resemble the reproductive features of the syndrome. Methods and results The maternal obese PCOS phenotype was induced in mice by chronic high-fat–high-sucrose consumption together with prenatal DHT exposure. The prenatally androgenized (PNA) female offspring displayed cardiac hypertrophy during adulthood, an outcome that was not accompanied by aberrant metabolic profile. The expression of key genes involved in cardiac hypertrophy was up-regulated in the PNA offspring, with limited or no impact of maternal obesity. Furthermore, the activity of NADPH oxidase, a major source of reactive oxygen species in the cardiovascular system, was down-regulated in the PNA offspring heart. We next explored for early transcriptional changes in the heart of newly born PNA offspring, which could account for the long-lasting changes observed in adulthood. Neonatal PNA hearts displayed an up-regulation of transcription factors involved in cardiac hypertrophic remodelling and of the calcium-handling gene, Slc8a2. Finally, to determine the specific role of androgens in cardiovascular function, female mice were continuously exposed to DHT from pre-puberty to adulthood, with or without the antiandrogen flutamide. Continuous exposure to DHT led to adverse left ventricular remodelling, and increased vasocontractile responses, while treatment with flutamide partly alleviated these effects. Conclusion Taken together, our results indicate that intrauterine androgen exposure programmes long-lasting heart remodelling in female mouse offspring that is linked to left ventricular hypertrophy and highlight the potential risk of developing cardiac dysfunction in daughters of mothers with PCOS.
Dynamic changes in circulating tumor cell levels as a prognostic marker in stage IV non-small cell lung cancer.
Authors: Anders Carlsson, Lyudmila Bazhenova, Anand Kolatkar, Madelyn Luttgen, Kelly Bethel, Jorge J. Nieva, Peter Kuhn
Journal: Journal of Clinical Oncology (2013)

8109 Background: We have previously reported the performance of our immuno-enrichment free HighEDefinition CTC (HDECTC) assay in the enumeration and characterization of circulating tumor cells (CTCs) in lung cancer patients. In the HD-CTC assay, nucleated cells are fluorescently labeled and imaged using automated microscopy. CTCs are defined as morphologically distinct, cytokeratin positive, CD45 negative cells. Here, we investigate further how CTCs numbers and physical properties relate to prognosis in NSCLC patients. Methods: The HD-CTC assay was applied for CTC enumeration in 362 blood samples collected longitudinally from 81 Stage IV NSCLC patients. Blood was collected at time 0, 3 weeks, and every 3 months thereafter. The collection protocol was restarted at disease progression, resulting in a sample number ranging between one and 12 samples per patient. Results: Eighty-one patients were enrolled, with 41 patients in 1 st line therapy, 11 in 2 nd , 17 in 3 rd , 7 in 4 th , 3 in 5 th and 2 in 6 th line therapy. Average age was 63, range 33 to 90; male to female ratio was 1:1.19. Eighty-six percent of patients had CTCs in at least one blood sample; CTC counts ranged from 0 to 885 CTCs/ml with a mean of 23.5 CTCs/ml across all samples. While no correlation was found between the absolute CTC concentration and survival, it was observed that for the 26 patients that had samples collected both at the start and during firstEline chemotherapy, an increase in CTC level between the two time points was significantly associated with longer survival (p &lt; 0.001). Conclusions: As detected with our assay, it is the change in CTC level upon entering 1 st line chemotherapy and not the absolute CTC concentration that carries prognostic information. This observation highlights not only the importance of CTCs as prognostic biomarkers, but also that of access to serially collected specimens. The latter is here made possible only by the fact that the HDECTC assay samples tumor cells from peripheral blood.
Geographical location affects the levels and association of trimethylamine N‐oxide with heart failure mortality in BIOSTAT‐CHF: a post‐hoc analysis
Authors: Yoshiyuki Yazaki, Andrea Salzano, Christopher P. Nelson, Adriaan A. Voors, Stefan D. Anker, John G. Cleland, Chim C. Lang, Marco Metra, Nilesh J. Samani, Leong L. Ng, Toru Suzuki
Journal: European Journal of Heart Failure (2019)
Daily assessment of quality of life during 100 courses of radiation: Pain, anxiety, problems or concerns, and need to see physician.
Authors: David D. Howell
Journal: Journal of Clinical Oncology (2013)

e20625 Background: Patients (Pts) undergoing radiation therapy (RTRx) may have pain, anxiety, distress or other symptoms impacting on quality of life (QOL) at the time of initiation of RTRx. Pts may also develop (or have an exacerbation of) one or more of the above during RTRx. During RTRx, pts are seen at least weekly by the treating physician (MD), and are seen daily by the treating radiation therapy technologists (RTT). Pts may develop problems between weekly MD visits which may benefit from MD interventions. A system was developed where pts would be asked four questions (4?) to assess QOL each treatment day by the RTT: 1) Are you having pain, and if so, how would you rate it on a scale of zero to 10? (PainQ); 2) Are you having anxiety or distress today? (ADQ); 3) Are you having new problems or concerns? (ProConQ); 4) Do you want to see the physician today? (CMDQ). This information was used in pts management. Methods: 100 RTRx courses were reviewed for demographics including gender, age, primary malignancy, region treated, # of visits and total RTRx dose, as well as detailed information from the 4? instrument. Results: Of the 100 pts, 56 were male. Disease distribution: Breast-22; Prostate-20; Head and Neck-20; Lung-13; Brain-7; Other-18. For the ADQ, 83 did not report anxiety or distress; 17 reported anxiety on one or two occasions. For the ProConQ, 35 reported none, 34 reported yes on 1 or 2 occasions, 22 reported yes on 3 to 5 occasions, and 9 reported yes on greater than five occasions; 29 reported yes on 2 days in a row, and 15 reported yes to problems or concerns on 3 days in a row. For the PainQ, 31 reported no pain throughout RTRx, with 22, 23, and 25 reporting pain of any magnitude for 1 to 5, 6 to 10, and greater than ten days, respectively. 22 reported pain greater than 6 on at least one occasion. For CMDQ, 26 of pts did not request additional visits, 71 and 3 requested to see the MD an additional 1 to 5, and 6 to 10 times. Conclusions: A simple instrument prompting a 4? QOL query to pts undergoing RTRx may prompt the need for further evaluation and interventions between scheduled MD visits. This may facilitate more expeditious interventions for RTRx related toxicity as well as for treatment dependent or independent QOL symptoms and needs.
Patient-reported outcomes, hip muscle strength and physical activity in patients with femoroacetabular impingement syndrome before and after surgery (PhD Academy Award)
Authors: Signe Kierkegaard
Journal: British Journal of Sports Medicine (2019)

My PhD included studies on patients with femoroacetabular impingement syndrome (FAIS). We performed (1) a systematic review with meta-analysis1 investigating patient-reported outcomes before and after hip arthroscopic surgery in patients with FAIS; and (2) a cohort study in which I investigated patient-reported outcomes, hip muscle strength and physical activity level in 60 patients with FAIS before and after hip arthroscopic surgery.2–5 

During the past decade, there has been a steep increase in hip arthroscopies performed (eg, a 335% increase from 2007 to 2011 in an American private payer population).6 While several studies had been published on patient-reported outcomes after surgery, none had synthesised studies to get an overview of how patient symptoms developed over time. Furthermore, there was a lack of studies documenting what effect surgery had on physical function and activity limitations in patients with FAIS.

I did the systematic review with two authors independently selecting studies …
Pulmonary pure ground-glass opacity lesions: Use of computed tomography attenuation for predicting tumor progression.
Authors: Takashi Eguchi, Ryoichi Kondo, Satoshi Kawakami, Mina Matsushita, Tetsu Takeda, Takao Sakaizawa, Yoshiaki Tominaga, Gaku Saito, Masahiro Hashizume, Masayuki Toishi, Takayuki Shiina, Kazuo Yoshida, Jun Amano, Tomonobu Koizumi
Journal: Journal of Clinical Oncology (2013)

7548 Background: Cases with pure ground-glass opacity (GGO) are increasing with the use of computed tomography (CT). In some cases, pure GGO on follow-up CT may represent tumor enlargement or the presence of solid components. We evaluated the natural progression of pure GGO lesions during a long-term follow-up period of more than 2 years. Methods: We retrospectively investigated 95 patients with pure GGO lesions detected between February 2003 and December 2010, in whom these lesions were monitored using CT for more than 2 years. Results: The median follow-up period was 64.7 months (range, 24–114 months). During the follow-up period, areas showing GGO increased in size or appeared to have solid components in 49 patients (group 1) and showed no change in 46 patients (group 2). We compared patient characteristics and tumor properties between the 2 groups. Mean CT attenuation values of the tumors differed significantly between groups 1 (-639.9 ± 88.9 HU) and 2 (-709.2 ± 60.9 HU). In contrast, no significant differences were noted with regard to age, gender, smoking history, lung cancer history, tumor size, and total numbers of GGO lesions between the 2 groups. The difference in the time to tumor growth according to the initial mean CT attenuation value was estimated using the Kaplan–Meier method. The growth incidence at 114 months for lesions with a mean CT attenuation value of -650 HU or more (n = 35) and less than -650 HU (n = 60) were estimated to be 96% and 48%, respectively. The difference between the 2 Kaplan–Meier curves was statistically significant (p &lt; 0.0001). The usefulness of the mean CT attenuation value in predicting the growth of GGO lesions was evaluated using receiver operating characteristic analysis. The sensitivity and specificity was 63% and 87%, respectively, for a mean CT attenuation cutoff value of -650 HU. The area under the curve was 0.76. Conclusions: Many pure GGO lesions have potential for growth as seen during long-term follow-up. CT attenuation is useful in predicting the growth of GGO lesions.
Targeting HSP90 attenuates angiotensin II-induced adventitial remodelling via suppression of mitochondrial fission
Authors: Gaojian Huang, Zhilei Cong, Xiaoyan Wang, Yanggang Yuan, Renjie Xu, Zhaoyang Lu, Xuelian Wang, Jia Qi
Journal: Cardiovascular Research (2019)

Adventitial remodelling presenting with the phenotypic switch of adventitial fibroblasts (AFs) to myofibroblasts is reportedly involved in the evolution of several vascular diseases, including hypertension. In our previous study, we reported that heat shock protein 90 (HSP90) inhibition by 17-dime-thylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) markedly attenuates angiotensin II (AngII)-induced abdominal aortic aneurysm formation by simultaneously inhibiting several key signalling and transcriptional pathways in vascular smooth muscle cells; however, little is known about its role on AFs. Given that the AF phenotypic switch is likely to be associated with mitochondrial function and calcineurin (CN), a client protein of HSP90 that mediates mitochondrial fission and function, the aim of this study was to investigate whether mitochondrial fission contributes to phenotypic switch of AF, and if it does, we further aimed to determine whether HSP90 inhibition attenuates mitochondrial fission and subsequently suppresses AF transformation and adventitial remodelling in AngII-induced hypertensive mice.In primary mouse AFs, we found that CN-dependent dephosphorylation of Drp1 induced mitochondrial fission and regulated mitochondrial reactive oxygen species production, which stimulated AF proliferation, migration, and phenotypic switching in AngII-treated AFs. Moreover, AngII was found to increase the binding of HSP90 and CN in AFs, while HSP90 inhibition significantly reversed AngII-induced mitochondrial fission and AF phenotypic switching by modulating the CN-dependent dephosphorylation of Drp1. Consistent with the effects in AFs, in an animal model of AngII-induced adventitial remodelling, 17-DMAG markedly reduced mitochondrial fission, AF differentiation, vessel wall thickening, and fibrosis in the aortic adventitia, which were mediated by CN/Drp1 signalling pathways.Our study suggests that CN/Drp1-dependent mitochondrial fission may be essential for understanding adventitial remodelling in hypertension and that HSP90 inhibition may serve as a novel approach for the treatment of adventitial remodelling-related diseases.
Heat shock protein 70 vaccines activate NK cells through NKG2D
Authors: B. Liu, Y. Qaio, Z. Li
Journal: Journal of Clinical Oncology (2006)

10044 Background: We have previously reported that vaccination with heat shock protein 70 (HSP70) induced natural killer (NK) cell activity in patients with chronic myelogenous leukemia (CML). The underlying mechanism is unclear. Methods: HSP70 was purified from the peripheral blood mononuclear cells. CD56+ NK cells were enriched by magnetic sorting after staining PBMCs with anti-CD56 monoclonal antibody. Dendritic cells (DCs) were derived from peripheral blood monocytes after culture in the presence of IL-4 and GM-CSF. NK activation was measured by the IFNgamma ELISPOT assay. Results: Unexpectedly, HSP70 of autologous, allogeneic as well as xenogeneic origin was found to stimulate IFNgamma production from peripheral blood mononuclear cells of CML patients as well as normal subjects. Further studies demonstrated that the activity of HSP70 was dependent on both NK cells and DCs. HSP70 did not induce significant IFNgamma production from either NK cells or DCs alone. Mechanistically, we found that HSP70-mediated DC-NK cell crosstalk required cell-cell contact, which could be inhibited completely by neutralizing antibody against NK activating receptor NKG2D. The significance of NKG2D was further corroborated by the finding that HSP70 induced the expression of an NKG2D ligand, the MHC class I chain-related protein A (MICA), on DCs; HSP70-augmented IFNgamma release was abrogated by antibody against MICA. Conclusions: Thus HSP70 may serve as a critical link between NK and DCs in mounting immune responses against infections, cancers and self-antigens. Our novel findings support further studies in the development of HSP70-based vaccines against human malignancies. Acknowledgement: Z.L. is a clinical scholar of the Leukemia and Lymphoma Society. No significant financial relationships to disclose.
Ixazomib-Thalidomide-Low Dose Dexamethasone (ITd) Induction Followed By Maintenance Therapy with Ixazomib or Placebo in Newly Diagnosed Multiple Myeloma Patients Not Eligible for Autologous Stem Cell Transplantation; Results from the Randomized Phase II HOVON-126/Nmsg 21#13 Trial
Authors: Sonja Zweegman, Fredrik H. Schjesvold, Bronno van der Holt, Mark-David Levin, Claudia A.M. Stege, Anders Waage, Maria B.L. Leijs, Saskia K. Klein, Damian L. Szatkowski, Per Axelsson, Trung Hieu Do, Dorota Knut-Bojanovska, Ellen van der Spek, Asta Svirskaite, Pino Poddighe, Marian Stevens-Kroef, Markus Hansson, Niels WCJ van de Donk, Einar Haukas, Pieter Sonneveld, Niels Abildgaard
Journal: Blood (2018)
Pemetrexed, Bevacizumab, or the Combination As Maintenance Therapy for Advanced Nonsquamous Non–Small-Cell Lung Cancer: ECOG-ACRIN 5508
Authors: Suresh S. Ramalingam, Suzanne E. Dahlberg, Chandra P. Belani, Joel N. Saltzman, Nathan A. Pennell, Gopakumar S. Nambudiri, John C. McCann, Jerome D. Winegarden, Mohammed A. Kassem, Mohamed K. Mohamed, Jan M. Rothman, Alan P. Lyss, Leora Horn, Thomas E. Stinchcombe, Joan H. Schiller
Journal: Journal of Clinical Oncology (2019)

Pemetrexed or bevacizumab is used for maintenance therapy of advanced nonsquamous non-small-cell lung cancer (NSCLC). The combination of bevacizumab and pemetrexed has also demonstrated efficacy. We conducted a randomized study to determine the optimal maintenance therapy.Patients with advanced nonsquamous NSCLC and no prior systemic therapy received carboplatin (area under the curve, 6), paclitaxel (200 mg/m2), and bevacizumab (15 mg/kg) for up to four cycles. Patients without progression after four cycles were randomly assigned to maintenance therapy with bevacizumab (15 mg/kg), pemetrexed (500 mg/m2), or a combination of the two agents. The primary end point was overall survival, with bevacizumab serving as the control group.Of the 1,516 patients enrolled, 874 (57%) were randomly assigned after induction therapy to one of the three maintenance therapy groups. With a median follow-up of 50.6 months, median survival with pemetrexed was 15.9 months, compared with 14.4 months with bevacizumab (hazard ratio [HR], 0.86; P = .12); median survival with pemetrexed and bevacizumab was 16.4 months (HR, 0.9; P = .28); median progression-free survival was 4.2, 5.1 (HR, 0.85; P = .06), and 7.5 months (HR, 0.67; P < .001) for the three groups, respectively. Incidence of worst grade 3 to 4 toxicity was 29%, 37%, and 51%, respectively, for bevacizumab, pemetrexed, and the combination regimen.Single-agent bevacizumab or pemetrexed is efficacious as maintenance therapy for advanced nonsquamous NSCLC. Because of a lack of survival benefit and higher toxicity, the combination of bevacizumab and pemetrexed cannot be recommended.