tbuckley/cabot-search huggingface dataset:
Abstract 152: IL-10 Inhibits Angiotensin II-induced Pathological Autophagy in Myocardium.
Authors: Suresh K Verma, Prasanna Krishnamurthy, Tatiana Abramova, Garikipati Srikanth, Mohsin Khan, Alexander R Mackie, Aiko Klingler, Veronica Ramirez, Sol Misener, Gangjian Qin, Raj Kishore
Journal: Circulation Research (2014)

Background: In heart, persistent pressure overload causes pathological autophagy leading to cardiac cell death and heart failure. The role IL-10, a pleiotropic anti-inflammatory cytokine, on pathological autophagy is largely unknown. Here we hypothesized that IL-10 inhibits stress-induced pathological autophagy and therefore attenuates cardiac cells death and improve heart function. Method and Results: Cardiac stress was induced in C57 BL/6 mice by Angiotensin II treatment (Ang II-1.2mg.kg b.wt/day for 28 days) using mini osmotic pumps. Ang II treatment markedly induced autophagy in mice as measured by electron microscopy (autophagosome numbers) and Western blotting (Becline1 and LC3II proteins expression). Interestingly, systemic recombinant mouse IL-10 administration markedly inhibited Ang II-induced autophagy. To further understand the mechanism of IL-10 protection, neonatal rat ventricular myocytes (NRCM) were transfected with monomeric Red Fluorescent Protein-Enhanced Green Fluorescent Protein (mRFP-EGFP) tandem fluorescent-tagged LC3 (tfLC3) adenovirus (to measure autophagic flux) and then treated with AngII (1μM) and/or IL-10 (20ng/mL), in vitro. Ang II treatment significantly increased the numbers of both yellow (merged EGFP and mRFP signals) and red puncta, indicating active formation of both autophagosomes and autolysosomes, however, this flux was strongly inhibited by IL-10. Furthermore, Ang II significantly increased the Beclin1 and LC3II proteins expression, which was markedly reduced by IL-10 as measured by Western blot analysis. In addition, Ang II-inhibited AKT signaling (anti-autophagic signaling component) was strongly enhanced by IL-10. Ang II-induced autophagic signaling was mimicked by AKT inhibitor, suggesting AKT as the downstream target of IL-10 effects. Conclusion: Inhibition of pathological autophagy is a novel mechanism for cardio-protective effects of IL-10.
Abstract 1391: Atherogenic Dyslipidemia Predicts Accelerated Progression of Atherosclerosis in Patients with Coronary Artery Disease
Authors: John M Galla, E. M Tuzcu, Kathy Wolski, Srinivasa Kalidindi, Steven E Nissen, Stephen J Nicholls
Journal: Circulation (2007)

Background: Atherogenic dyslipidemia (AD) is characterized by the combination of elevated serum triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C) and small-dense low-density lipoprotein cholesterol (LDL-C) and has emerged as a powerful risk factor of coronary disease. The effect of AD on the progression of plaque burden remains incompletely defined. This analysis aimed to determine the impact of AD on measures of atherosclerotic progression in patients receiving intensive lipid lowering therapy. Methods: 910 patients with angiographic coronary artery disease treated with atorvastatin to a goal LDL-C of 100 ± 15mg/dl received torcetrapib or placebo. Atheroma burden was determined by intravascular ultrasound performed at baseline and following 24 months of treatment. Baseline and changes in atheroma burden were investigated in patients stratified according to the presence or absence of an AD phenotype (HDL-C &lt; 45 mg/dL for men and &lt; 50mg/dL for women, triglycerides 150 – 600mg/dL and LDL-C &lt; 160mg/dL) Results: 20.4% of patients met the criteria for AD. Patients with AD were younger (55.5 v 58 years, p=0.003), had higher body mass index (30.9 v 29.3 kg/m2, p&lt;0.001) and were more likely to fit the definition of the metabolic syndrome (93 v 30.3%, p&lt;0.001). Accelerated progression of percent atheroma volume (PAV, +0.76 v +0.01%, p=0.001) and total atheroma volume (TAV, −4.75 v −7.18 mm3, p=0.022) was observed in patients with AD. Patients with AD were less likely to undergo substantial regression (reduction in PAV &gt;5%, 12.9% v 24.2%, p=0.001) and more likely to undergo substantial progression (increase in PAV &gt;5%, 34.9% v 23.2%, p=0.001) No differences were observed between treatment groups with regard to changes in PAV (0.59 v 0.99%, p=0.727) or TAV (−5.7 v −3.8 mm3, p=0.461) in patients with AD. On multivariate analysis, the presence of atherogenic dyslipidemia was an independent predictor of increase in PAV (p=0.004) and TAV (p=0.045). Conclusions: Despite aggressive lipid lowering therapy, AD is an independent predictor of accelerated progression of atherosclerosis. With a rise in the prevalence of obesity and its metabolic complications there is an increasing need to intensively modify factors that place these patients at high risk.
The Finnish Allergy Programme 2008–2018 works
Authors: Tari Haahtela, Erkka Valovirta, Jean Bousquet, Mika Mäkelä
Journal: European Respiratory Journal (2017)

In Finland (population 5,5 million), a 10-year national campaign to treat allergic diseases was initiated in 2008. It was carefully planned and based on consensus among experts [1–3] because the long-term strategy of allergen avoidance had not reduced the burden or stopped the "epidemic". New insights into immune development in modern, urban societies have challenged conventional thinking. A public health programme has now been implemented, and an avoidance strategy was replaced with a tolerance strategy [4]. This course of action was supported by the Ministry of Social Affairs and Health and the National Institute for Health and Welfare. Revisiting the asthma and allergy paradigms has led to actions relevant to society and healthcare as a whole <http://ow.ly/MBG530bPvd6>
Incidence and risk of neutropenia with palbociclib in patients with cancer: A systematic review and meta-analysis.
Authors: Yan Mao, Janice Lu, Haibo Wang, Gang Nie
Journal: Journal of Clinical Oncology (2017)

e12530 Background: Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6 and has improved the progression-free survival of estrogen receptor positive, metastatic breast cancer (MBC). Its application in other cancers is also undergoing clinical evaluation. Neutropenia, especially high grade (grade 3 or 4), is one of the major side-effects of palbociclib, and the incidence was reported too vary in different studies. In order to better understand the overall risk of palbociclib associated neutropenia, we conducted a systematic review and meta-analysis. Methods: We conducted a systematic literature search (including Medline, Web of Science to November, 2016 and abstracts presented at the ASCO annual meetings from 2009 to 2016). Eligible studies include prospective clinical trials of patients with cancer treated with palbociclib on a 125mg daily 3/4 week schedule and have available data on neutropenia. The incidence and relative risk (RR) of neutropenia were calculated using a random-effects or fixed-effects model, depending on the heterogeneity of the included studies. Results: Eight studies published between 2012 and 2016 included a total of 1515 patients with cancer were eligible for analysis. For patients treated with palbociclib, the overall incidence of all-grade and high grade neutropenia were 77.4% (95% CI 70.9-82.8%) and 60.9% (57.8–63.8%), respectively. Surprisingly, the incidence of neutropenia was significantly different between MBC patients and non-MBC patients (all grade: RR 1.26 [95% CI 1.01–1.56], p = 0.041; high-grade: RR 1.57 [1.23–2.00], p = 0.000) who received palbociclib. Palbociclib was associated with a significantly increased risk of all-grade neutropenia in patients with cancer with an RR of 15.03 (10.17–22.21, p &lt; 0.001) compared with controls. Conclusions: Patients with cancer who received palbociclib have a significant risk of developing neutropenia, especially MBC patients. It is strongly recommended to monitor these patients who are treated with palbociclib to adjust dose, treatment intervals, and avoid infections.
A systematic literature review of radiological gastrostomy in adults (1981–2003)
Authors: CE Watson, J Cuthbertson, A Webster, MS Dennis, MI Wiggam
Journal: Endoscopy (2005)

Aims: To investigate the safety of radiological gastrostomy (RG) as an alternative to percutaneous endoscopic gastrostomy (PEG), we have performed a systemic review of the literature from 1981–2003.
Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: Safety, clinical activity, and PD-L1 expression.
Authors: Raffit Hassan, Anish Thomas, Manish R. Patel, John J. Nemunaitis, Jaafar Bennouna, John D. Powderly, Matthew H. Taylor, Afshin Dowlati, Franklin Chen, Joseph Leach, Ulka N. Vaishampayan, Claire F. Verschraegen, Jean-Pierre Delord, Hans Juergen Grote, Anja von Heydebreck, Jean-Marie Cuillerot, James L. Gulley
Journal: Journal of Clinical Oncology (2016)

8503 Background: Avelumab* is a fully human anti-PD-L1 IgG1 antibody under clinical investigation in multiple cancers. We report safety and clinical activity of avelumab in patients (pts) with unresectable mesothelioma (NCT01772004). Methods: Pts with unresectable pleural or peritoneal mesothelioma, progressed after a platinum-pemetrexed-containing regimen and unselected for PD-L1 expression, were treated with avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 wks (RECIST 1.1). Objective response rate (ORR) and progression-free survival (PFS) were evaluated. Adverse events (AEs) were graded by NCI CTCAE v4.0. PD-L1 expression was assessed by IHC. Results: As of Oct 23, 2015, 53 pts were treated with avelumab and followed for a median of 46 wks (range 11-59). Median age was 66 y (range 32-84), ECOG PS was 0 (26.4%) or 1 (73.6%), median number of prior treatments was 1.5 (range 0-7). Histology was epithelial (81.1%), mixed (11.3%), sarcomatoid (3.8%), or unknown (3.8%). Treatment-related (TR) AEs occurred in 41 pts (77.4%); most common (>10%) were infusion-related reaction (20 [37.7%]), fatigue (8 [15.1%]), chills (8 [15.1%]), and pyrexia (6 [11.3%]), all of grade 1/2. Grade ≥3 TRAEs occurred in 4 pts (7.5%; colitis, decreased lymphocytes, and increased GGT or CPK [each 1 event]); there were no treatment-related deaths. Unconfirmed ORR was 9.4% (5 PRs; 95% CI: 3.1, 20.7); 4 were ongoing. Stable disease was observed in 25 pts (47.2%); disease control rate was 56.6%. Median PFS was 17.1 wks (95% CI: 6.1, 30.1), and PFS rate at 24 wks was 38.4% (95% CI: 23.3, 53.4). Using a ≥5% cutoff for tumor cell staining, 14/39 evaluable (35.9%) were PD-L1+, ORR was 14.3% in PD-L1+ (2/14) vs 8.0% in PD-L1– pts (2/25), and median PFS was 17.1 wks (95% CI: 5.4, ne) in PD-L1+ vs 7.4 wks (95% CI: 6.0, 30.1) in PD-L1− pts. Conclusions: Avelumab showed an acceptable safety profile and clinical activity in PD-L1+ and PD-L1− pts with advanced unresectable mesothelioma, a dataset representing the largest study to date of an all-comer population in this tumor type treated with anti-PD-(L)1. *Proposed INN. Clinical trial information: NCT01772004.
Effect of progesterone receptor on outcome of women with breast cancer.
Authors: Shaheenah S. Dawood, Sudeep Gupta, Paul N. Mainwaring, Shona Milon Nag, Rebecca Alexandra Dent
Journal: Journal of Clinical Oncology (2016)

573 Background: The aim of this study was to examine the prognostic effect of progesterone receptor (PR) among women with breast cancer (BC). Methods: Using data derived from the Surveillance, Epidemiology, and End Results (SEER) Program we identified women with stage I – IV breast cancer diagnosed between 1990 and 2012. Patients (pts) were divided into four groups: ER-/PR-, ER-/PR+, ER+/PR- and ER+/PR+. The primary endpoint was BC-specific survival (BCSS) and was computed using the Kaplan-Meier method and Cox model was fitted to evaluate factors independently associated with BCSS. HER2 information was limited to data collected from 2010 onwards. The analysis was repeated for pts with stage IV disease stratified by HER2 status. Results: 714,662 eligible pts were identified with mean age 60.7±14.5 years, 89.9% white and 46.4%, 34.4%, 13.8% and 5.4% of pts had had stage I, II, III and IV disease respectively. Of these, 19.9% (n = 121333) were ER-/PR-, 1.8% (n = 11078) were ER-/PR +, 12.6% (n = 76807) ER+/PR- and 65.7% (n = 400063) were ER+/PR+ and the corresponding 5-year BCSS rates were 68.5%, 73.9%, 76.4% and 83.5%, respectively (p < 0.001). Similar trends were observed among black and white pts across the four groups. In the adjusted Cox model, compared to pts with ER-/PR- BC, those with ER-/PR+ (HR = 0.89), ER+/PR- (HR = 0.75) and ER+/PR+ (HR = 0.52) disease had significantly decreased risk of BC death. Among pts with HER2 positive BC (2010 onwards, stage IV) 1-year BCSS was 62.6%, 60.9%, 66.8% and 77.3% respectively among patients with ER-/PR-, ER-/PR+, ER+/PR- and ER+/PR+ BC (p = < 0.001). Conclusions: In this large population based breast cancer cohort, PR expression is associated with increased BCSS, including among pts with HER2 receptor positive disease. Molecular subtyping systems should continue to incorporate PR expression in classifying breast cancer.
Dicer Deficiency Differentially Impacts Microglia of the Developing and Adult Brain
Authors: Diana Varol, Alexander Mildner, Thomas Blank, Anat Shemer, Neta Barashi, Simon Yona, Eyal David, Sigalit Boura-Halfon, Yifat Segal-Hayoun, Louise Chappell-Maor, Hadas Keren-Shaul, Dena Leshkowitz, Eran Hornstein, Martin Fuhrmann, Ido Amit, Nicola Maggio, Marco Prinz, Steffen Jung
Journal: Immunity (2017)
A first-in-human phase 1 study of GC1118, a novel monoclonal antibody inhibiting epidermal growth factor receptor (EGFR), in patients with advanced solid tumors.
Authors: Keun Wook Lee, Do-Youn Oh, Sae-Won Han, Jin Won Kim, Jung-Won Shin, Seong-Jin Jo, Na Hyung Kim, Ahmi Woo, Jonghwa Won, Seokyung Hahn, Howard Lee, Woo Ho Kim, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2016)

2521 Background: GC1118 is a novel anti-EGFR monoclonal antibody and has unique binding epitopes and affinity. We conduct a first-in-human phase 1 study to investigate the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, pharmacokinetics, and preliminary efficacy of GC118 in patients with refractory solid tumors (NCT02352571). Methods: GC1118 was intravenously administrated over 2 hours on days 1, 8, 15 and 22 followed by additional 2 week rest in the first cycle, during which dose limiting toxicities (DLTs) were evaluated. If there was no tumor progression, GC1118 was administrated weekly thereafter. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: Twenty-four patients, 17 with colorectal cancer (CRC), were treated with GC1118 at five dose levels: 0.3 mg/kg (n = 4), 1.0 mg/kg (n = 4), 3.0 mg/kg (n = 4), 4.0 mg/kg (n = 6) and 5.0 mg/kg (n = 6). In the 5.0 mg/kg cohort, two patients experienced DLTs, which were grade 3 skin toxicities. No DLTs were observed in the other cohorts. The MTD was determined as 5.0 mg/kg. GC1118-related adverse events (AEs; ≥ 10%) included skin toxicities [pruritus (58%), dermatitis acneiform (50%), dry skin (42%), paronychia (29%) and maculo-papular rash (25%)] and stomatitis (29%). Diarrhea developed in 2 patients ( ≤ grade 2). AEs of grade ≥ 3 included skin (n = 2) and hepatic toxicities (n = 1). Pharmacokinetic study showed typical target-mediated drug disposition profiles via ligand-receptor coupling. Considering toxicity and pharmacokinetic data, 4.0 mg/kg was determined as the RP2D. Partial response (PR) was shown in 3 patients (all with CRC) and stable disease in 12. Median progression-free survival was 13.3 weeks (95% confidence interval: 5.1-21.1). Expansion cohorts were opened, and updated results will be presented. Conclusions: We determined the MTD as 5 mg/kg and the RP2D as 4 mg/kg. DLTs were grade 3 skin toxicities. GC1118 was generally well tolerated. Skin toxicities were the most common AEs and diarrhea was uncommon. GC1118 showed promising preliminary anti-tumor activity, especially in wild-type KRAS CRC with 3 PRs (18%) among 17 patients. Clinical trial information: NCT02352571.
Stringent complete response (sCR) in patients (pts) with newly diagnosed multiple myeloma (NDMM) treated with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX).
Authors: Andrzej J. Jakubowiak, Kent A. Griffith, Dominik Dytfeld, David H. Vesole, Sundar Jagannath, Tara B. Anderson, Brian K. Nordgren, Kristen Detweiler-Short, Daniel Lebovic, Keith Stockerl-Goldstein, Terri L. Jobkar, Sandra Marija Wear, Ammar Al-Zoubi, Asra Z. Ahmed, Melissa A Mietzel, Daniel R. Couriel, Mark Stefan Kaminski, Mohamad A. Hussein, Homa Yeganegi, Ravi Vij
Journal: Journal of Clinical Oncology (2012)

8011 Background: Combination treatment (tx) with CFZ, LEN, and DEX (CRd) is well tolerated and highly active in NDMM. In a phase 1/2 study, CRd provided rapid reduction of disease by 68% after cycle (C) 1 and 94% ≥partial response (PR) at a median of 8C, including 65% ≥very good PR and 53% ≥near CR (nCR), which improved to 79% ≥nCR after C12 (ASH 2011, Abstr 631). Here, we examine the clinical significance of the response rates with longer follow-up. Methods: Pts with NDMM were treated in 28-day (d) C with CFZ 20–36 mg/m 2 IV (d1, 2, 8, 9, 15, 16), LEN 25 mg PO (d1–21) and DEX 40/20 mg PO weekly (C1–4/5–8). After C4, autologous stem cell transplant (ASCT) candidates achieving ≥PR could collect stem cells but then continued CRd with the option to proceed to ASCT. After C8, pts received CRd maintenance, using the last tolerated doses, with LEN/DEX at the same schedule but a modified CFZ schedule (d1, 2, 15, 16). Response was assessed by IMWG criteria plus nCR. Results: As of Nov 30, 2011, median follow-up was 14 mo (range 4–25) with 33/53 (62%) pts achieving ≥nCR and 42% sCR. After a median of 13C (range 1–25), 36 pts completed C8 and continued CRd maintenance, 64% achieving sCR. 20/22 pts in CR evaluated for minimal residual disease (MRD) by multiparameter flow cytometry had no MRD. Progression-free survival (PFS) rate was 97% at 12 and 92% at 24 mo. All pts who achieved sCR have maintained response for a median of 9 mo (range 1–20). Extended CRd tx was well tolerated. During CRd maintenance, the most common toxicities (all grades) were lymphopenia (30%), leukopenia (26%), and fatigue (25%), and peripheral neuropathy remained limited (11%, all G1/2). There were no tx discontinuations due to toxicity during maintenance and limited dose modifications (CFZ 19%, LEN 28%, DEX 31%). Conclusions: CRd is highly active in NDMM, providing rapid and deep responses. Extended tx was well tolerated and resulted in improved depth of response with a high sCR rate and a significant proportion of pts without evidence of MRD. Responses were durable with very promising PFS. All pts who achieved sCR remained on CRd with sustained sCR. These results compare favorably to other frontline regimens.
Trastuzumab-related cardiotoxicity in patients with breast cancer with comorbidities of obesity, dyslipidemia, and diabetes.
Authors: Olexiy Aseyev, Christopher Johnson, Michele Turek, Angeline Law, Jeffrey Allen Sulpher, Susan Faye Dent
Journal: Journal of Clinical Oncology (2016)

e12503 Background: Clinical trials have demonstrated an increased risk of cancer treatment related cardiac dysfunction (CTCD) during trastuzumab (H) therapy. Diabetes, dyslipidemia, and obesity are also known risk factors for cardiovascular disease.The objective of this study was to evaluate the incidence of asymptomatic drop in left ventricular ejection fraction (AD-LVEF) and symptomatic CTCD (S-CTCD) in women with breast cancer (BC) and co-morbidities receiving H, referred to a dedicated cardio-oncology clinic (COC). Methods: This was a retrospective cohort study of women with breast BC (all stages) referred to The Ottawa Hospital COC between 2008 and 2015, who received H. Data collected included: demographics, reason for referral, cardiac testing (MUGA/ECHO) co-morbidities (diabetes, dyslipidemia) and cardiac outcomes. Obesity (O) defined as body mass index > 30. S-CTCD include SOB, PND, orthopnea, peripheral edema, congestive heart failure. AD-LVEF was defined as a decrease of > 10 points to an LVEF of < 53%. Results: 247 patients (pts) were included: 185 – anthracycline-based chemotherapy (A-CT) followed by H, 62 received H without A-CT. 139 patients with no history diabetes, dyslipidemia, or obesity, referred with AD-LVEF (68%), with S-CTCD (30%), pre-CT assessment (2%). Combination of obesity and other conditions significantly increase incidence of S-CTCD: O+L – 67% (Relative Risk -2.2, p = 0.04), O+D – 69% (RR-2.3, p = 0.02), O+L+D – 72% (RR-2.4, p = 0.18). Conclusions: The combination of two or three co-morbidities significantly increases the incidence of S-CTCD. BC patients with pre-existing history of diabetes, dyslipidemia, and obesity who experience CTCD may require more proactive strategies for prevention, detection and treatment of cardiotoxicity during trastuzumab-based treatment. Reason for referral to COC. pre-CT assessment AD-LVEF S- CTCD N % N % N % N % No history of diabetes (D), dyslipidemia (L), or Obesity (O) 139 77 3 2 94 68 42 30 D 29 12 4 13 19 66 6 21 O 63 26 3 5 40 63 20 32 L 52 21 6 11 31 60 15 29 O+D 36 15 2 - 10 28 24 69 O+L 23 9 2 - 6 26 15 67 O+D+L 14 6 3 - 1 - 10 72
BMA annual meeting: Sending mental health patients out of area for treatment is “endemic,” says BMA
Authors: Jacqui Wise
Journal: BMJ (2017)

The number of patients with mental disorders who are being sent out of area for treatment has risen by almost 40% in the past two years, with some sent more than 500 miles away from home, according to figures uncovered by the British Medical Association.

The BMA sent out freedom of information requests to all 54 mental health trusts and all clinical commissioning groups in England. Figures from 44 trusts and CCGs stated that 5876 adults were sent out of area for mental health treatment in 2016/17, up from 4213 in 2014/15. The amount spent on placing patients in out …