tbuckley/cabot-search huggingface dataset:
Safety and efficacy of lorlatinib (PF-06463922) from the dose-escalation component of a study in patients with advanced ALK+ or ROS1+ non-small cell lung cancer (NSCLC).
Authors: Benjamin J. Solomon, Todd Michael Bauer, Enriqueta Felip, Benjamin Besse, Leonard Philip James, Jill S. Clancy, Karen J. Klamerus, Jean-Francois Martini, Antonello Abbattista, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2016)

9009 Background: Most patients (pts) with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) NSCLC develop resistance to tyrosine kinase inhibitor (TKI) therapy, with the central nervous system (CNS) as a common site of relapse. Lorlatinib is a selective brain-penetrant ALK/ROS1 TKI active against most known resistance mutations. Methods: In Ph. I of the ongoing Ph. I/II study NCT01970865, eligible pts had ALK+ or ROS1+ NSCLC with/without brain metastases (mets) and were treatment naïve or had disease progression after ≥1 TKIs. Pts received lorlatinib on day –7 and daily from day 1. Primary objective was to identify the MTD and recommended Ph. II dose (RP2D). Other objectives were safety and efficacy by RECIST v1.1, including intracranial activity. Results: Of 54 pts treated in Ph. I as of Nov 30 2015, 41 were ALK+, 12 ROS1+; and 1 with mutation status not recorded at cut-off date. Pts were heavily pretreated:27 had received >1 prior TKI, 20 1 prior TKI and 7 were TKI naïve; 39 pts had CNS mets at baseline. Pts were treated across 10 dose levels (10–200 mg). Response rates (RR) are shown in the Table. 29 pts remain on treatment. The most common treatment-related adverse events (AEs) were hypercholesterolemia (54%) and peripheral edema (37%). Hypercholesterolemia was the most common (9%) grade (G) ≥3 treatment-related AE and most frequent reason for dose delay/reduction. No pt discontinued due to a treatment-related AE. One DLT occurred in a pt who received <16/21 planned 200 mg daily doses due to G2 CNS AEs. CSF concentrations in steady-state samples from 3 pts with CNS mets showed excellent penetration of lorlatinib into the CNS. Conclusions: Lorlatinib was well tolerated and demonstrated durable clinical responses, including intracranial responses, in ALK+ (including G1202R+) pts and ROS1+ NSCLC pts, many of whom had CNS mets and ≥1 prior TKIs. The RP2D was identified as 100 mg once daily. Ph. II is enrolling. Clinical trial information: NCT01970865. N CR uCR PR uPR Overall RR n (%) Intracranial (IC) + extracranial 52 2 (4) 1 (2) 22 (42) 1 (2) 26 (50) IC (target + nontarget lesions) 36 8 (22) 2 (6) 4 (11) 2 (6) 16 (44) IC (target lesions) 20 5 (25) 1 (5) 4 (20) 2 (10) 12 (60) Abbreviations: CR, complete response; PR, partial response; U, unconfirmed.
Real-time TaqMan PCR analysis of immune-related genes in bladder cancer
Authors: Sin Mun Tham, Sim Hwee Pook, Kesavan Esuvaranathan, Ratha Mahendran
Journal: Clinical Cancer Research (2007)

A47  The pathogenesis of bladder cancer involves genetic alterations and various gene expression changes. In an effort to provide insight into the underlying molecular and genetic events, the mRNA expressions of 93 genes were analyzed using TaqMan® Low Density Array technology (Applied Biosystems, USA). In the array, real-time quantitative RT-PCR was performed for a panel of immune-related genes simultaneously in a 384 well format on RNA obtained from mouse bladder tumors and normal mouse bladders.  Bladder cancer was induced in C57BL/6 female mice (n=20) when they were 4-6 weeks old using poly-L-lysine (PLL) followed by a modified murine bladder tumor cell-line (MB49 secreting prostate specific antigen (PSA) as a reporter gene). Successful implantation of the mice was confirmed by measuring PSA in the urine using ELISA. Control mice (n=20) were instilled with PLL but not tumor cells. The mice were terminated 7 and 28 days after tumor implantation, and the bladders and draining lymph nodes were harvested for RNA analysis. One sample from each group was used for the LDA study while the rest of the samples were used in real-time PCR for validation. The accuracy of the array is between 60-70%.  Gene expression analysis revealed distinct profiles in the immune-related genes. Only genes displaying at least a 2-fold difference in expression level from normal tissue were considered for analysis. 7 days after tumor implantation, 58 genes were up-regulated in the bladder. Of which, 12 genes were up-regulated more than 20 times compared to a normal bladder. Most of these genes (CCL5/RANTES, STAT1, CD3, CCR7, IL2Rα/CD25) are Th1 related genes involved in T cell activation. Others are pro-inflammatory, immune cell recruitment and apoptosis related. On the other hand, only 9 genes were up-regulated in the draining lymph node. Some of the up-regulated cytokine genes (IL4, IL5) are Th2-related and involved in B cells activation. 28 days after tumor implantation, 19 genes were up-regulated whilst 32 genes were down-regulated in the bladder. The up-regulated genes are also involved in immune regulation/recruitment and inflammation (GMCSF, IFNγ, CCL2, CXCL11/ITAC, IL1β). Interestingly, CTLA4 which is inhibitory to T cells is also up-regulated. The genes that are down-regulated are primarily endothelial receptors and structural component of basement membranes (collagen, fibronectin, endothelin, p-selectin, angiotensin II receptor) and apoptosis related genes (Bax, Fas, Bcl2, Bcl2-like1). Contrastingly in the draining lymph nodes, over 80 genes are down-regulated at day 28 indicating a shut-down of the immune response.  In this study, we applied a high-throughput real-time quantitative RT-PCR assay to characterize changes associated with bladder cancer. This can help to better understand the biology associated with tumorigenesis and identify possible molecular targets. The challenge now is to evaluate the importance of these targets in tumor progression and immune evasion.
AB1075 Physician postgraduate experience has a predictive role for physician efficiency index regarding patients with rheumatoid arthritis: a cohort, exploratory study
Authors: A Emamifar, SM Mousavi, IM Jensen Hansen
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Much effort has been made to improve the efficiency of health care system by delivering cost-effective, high-quality care.Nurse staffing9s contribution to daily practice plays a significant role to reach this goal.[1] <h3>Objectives</h3> To elucidate the differences between ratios of nurse/physician consultation as well as physician efficiency index (PEI) of senior rheumatologists and junior physicians in rheumatology residency training regarding patients with Rheumatoid Arthritis (RA).In addition, to delineate the correlation of physician postgraduate experience and PEI. <h3>Methods</h3> The mean intervals between standard consultation by a physician or nurse for all senior rheumatologists and junior physicians as well as nurse/physician visits ratio and PEI (= nurse/physician visits ratio * mean interval), regrading RA patients seen during Nov 2013–2015, were calculated. Multiple linear regression analysis was performed to delineate the relationship between physician postgraduate experience and PEI. To monitor treatment outcome, Disease Activity Score in 28 joints-C-reactive Protein (DAS28-CRP) and Health Assessment Questionnaire (HAQ) were consecutively measured three times: first at physician consultation, second at following nurse consultation and third either at a nurse or physician consultation. <h3>Results</h3> 3699 visits, belonged to 672 RA patients (64.1% female, the mean of age 64.9±14.1 and DAS28 at baseline 4.5±1.2), were included. There was a significant difference between the nurse/physician visits ratios of senior rheumatologists and junior physicians (P=0.01). Additionally, the mean PEI of senior rheumatologists was significantly higher than of junior physicians (P=0.04) (Table 1). A positive correlation was found between physician postgraduate experience and PEI adjusted for DAS28 at baseline and number of patients for each physician (Regression coefficient (95% Confidence Interval): 5.427 (1.068–9.787), P=0.022). DAS28 and HAQ score were significantly decreased if physician visits were followed by nurse visits (P=0.004 for DAS28 and P=0.025 for HAQ) (Fig.1), indicating a good treatment outcome at nurse consultations. <h3>Conclusions</h3> Junior physicians should be supervised to delegate responsibilities to nurse staffing. So, entire department operates more efficient, leading to prevent extra expenses (due to the differences in yearly salary of physicians and nurses). Quality of care should be monitored continuously by markers of disease activity and CRP. <h3>References</h3> Dall TM,et al.The economic value of professional nursing.Med Care2009;47:97–104. <h3>Disclosure of Interest</h3> None declared
PANTHER: Prospective randomized phase III trial of tailored and dose-dense versus standard tri-weekly adjuvant chemotherapy for high-risk breast cancer in the modern era of endocrine and anti-HER2 therapy.
Authors: Jonas C. S. Bergh, Theodoros Foukakis, Gunter von Minckwitz, Nils-Olof Bengtsson, Birgitta Wallberg, Tommy Fornander, Brigitte Mlineritsch, Sabine Schmatloch, Christian F. Singer, Guenther G. Steger, Eva Karlsson, Lena Carlsson, Sibylle Loibl, Michael Untch, Mats Hellstrom, Hemming Johansson, Per Malmstrom, Michael Gnant, Richard Greil, Volker Moebus
Journal: Journal of Clinical Oncology (2016)

1002 Background: Standard dosing of chemotherapy (ct) based on body surface area results in marked inter-patient variation in pharmacokinetics, toxicities and efficacy. Methods: 2,017 patients with node-positive or high-risk node-negative breast cancer were randomized (1:1) in 86 centers in Sweden, Austria and Germany between February 2007 and September 2011 to either four cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin (E) 38-120 mg/m 2, start at 90 mg/m 2) and cyclophosphamide (C) 450-1200 mg/m 2, start at 600 mg/m 2) Q2W, followed by four cycles of docetaxel (D) 75-100 mg/m 2, start at 75 mg/m 2) Q2W (three weeks pause between EC and D) (tdd arm) or three cycles of standard 5-Fluorouracil (F) 500 E100 C500 Q3W followed by three cycles of D100 Q3W (control arm). Total treatment duration was the same in the two arms. The primary endpoint was breast cancer relapse-free survival (BCRFS) assessed in the intention to treat population. Secondary endpoints included event-free survival (EFS) and overall survival (OS) (Clinicaltrials.gov NCT00798070). Results: The first event-driven analysis was performed in January 2016. With a median follow-up of 5.3 years, 269 BCRFS events were reported, 118 in the tdd arm and 151 in the control arm (Hazard Ratio (HR) (95% CI) = 0.79 (0.62-1.02), p=0.064 by log-rank test). 5-year BCRFS was 88.7% and 85% respectively. Patients in the tdd arm had significantly better EFS (HR 0.79 (0.63-0.99), p=0.043, 5-year EFS 86,7% vs. 82.1%) and a trend to better OS (HR 0.77 (0.57-1.05), p=0.093, 5-year OS 92.1% vs. 90.2%). No significant interactions were found in predefined subgroups, including patients with hormone receptor positive disease and trastuzumab treated. Five cases of myelodysplastic syndrome / acute myeloid leukemia were reported, 3 in the tdd arm and 2 in the control arm. Conclusions: Tailored dose-dense ct resulted in improvement for all studied efficacy endpoints, being statistically significant for EFS compared with conventional ct in the era of contemporary endocrine therapy and trastuzumab. Toxicity data will be presented at the meeting. Clinical trial information: NCT00798070.
Lower proliferation and the efficacy of capecitabine treatment in advanced or recurrent breast cancer.
Authors: Reiki Nishimura, Tomofumi Osako, Yasuyuki Nishiyama, Rumiko Tashima, Masahiro Nakano, Mamiko Fujisue, Yasuo Toyozumi, Nobuyuki Arima
Journal: Journal of Clinical Oncology (2014)

e12012 Background: Treatment strategy for recurrence or advanced breast cancer is determined by menopausal status, tumor subtype, disease-free interval (DFI) and recurrence site. Anthracycline and taxane are placed as a first and second-line chemotherapy. Capecitabine is widely used for third-line treatment. However, there are no predictive factors for predicting the benefits of capecitabine. Therefore, the aim of this retrospective study was to determine the predictive factors related to survival and clinical benefits (CB). Methods: From July 2003 to July 2013, 163 patients with recurrent or advanced breast cancer were treated with capecitabine and the efficacy was assessed. The treatment regimen consisted of capecitabine monotherapy (X-mono; 79 cases), in combination with cyclophosphamide (XC; 68 cases) and trastuzumab (XH; 16 cases). Treatment effect, CB and overall survival after treatment were investigated in relation to ER/PgR (cut point:1%), Ki-67 values (cut point:25%), p53 expression, chemotherapy line (≤ second- vs third-line), dominant recurrence site and disease free interval (DFI). The median observation period after recurrence was 51.4 months. Results: Treatment effect in all cases were as follows; CR was seen in 5 cases (3.1%), PR in 61 cases (37.4%), SD in 54 cases (33.1%) and PD in 43 cases (26.4%). The response rate was 31.6% in X-mono, 48.5% in XC and 50% in XH group. The CB rate was 48.1% in X-mono, 67.6% in XC and 62.5% in XH group. Median survival time from capecitabine treatment was 29.4 months in patients with CB, and 15.3 months in the non-CB group (p<0.0001). Therefore, factors associated with CB were investigated in patients with HER2-negative cases. In the X-mono group, CB significantly correlated with early chemotherapy line, ER positive and lower Ki-67 values. In the XC group, chemotherapy line and Ki-67 values were associated with CB. Multivariate analysis revealed that lower Ki-67 values were an independent significant factor for CB. Conclusions: The capecitabine treatment had a high response rate and CB using a single agent and in combination with cyclophosphamide or trastuzumab in recurrent or advanced breast cancer. The CB was obtained in HER2 negative cases with low proliferation.
Aberrant Let7a/HMGA2 Signaling Axis with Unique Clinical Phenotype in JAK2-Mutated Myeloproliferative Neoplasms
Authors: Chia-Chen Hsu, Chih-Cheng Chen, Jyh-Pyng Gau, Cih-En Huang, Jie-Yu You, Jrhau Lung, YI-Yang Chen, Hsing-Ying Ho, Chian-Pei Li, Chang-Hsien Lu, Kuan-Der Lee
Journal: Blood (2016)
Eating fish regularly is linked to reduced rheumatoid arthritis, study finds
Authors: Susan Mayor
Journal: BMJ (2017)

Eating fish at least twice a week was associated with reduced disease activity in patients with rheumatoid arthritis (RA) in a study that found higher levels of joint swelling and tenderness in patients who ate fish less than once a month.1

Previous research has suggested that fish oil supplements containing high doses of omega 3 fatty acids can improve symptoms in patients with RA, but the effect of eating fish was not clear.

Researchers carried out a cross sectional analysis …
Inhibition of the Cardiac Fibroblast–Enriched lncRNA <i>Meg3</i> Prevents Cardiac Fibrosis and Diastolic Dysfunction
Authors: Maria-Teresa Piccoli, Shashi Kumar Gupta, Janika Viereck, Ariana Foinquinos, Sabine Samolovac, Freya Luise Kramer, Ankita Garg, Janet Remke, Karina Zimmer, Sandor Batkai, Thomas Thum
Journal: Circulation Research (2017)

Cardiac fibroblasts (CFs) drive extracellular matrix remodeling after pressure overload, leading to fibrosis and diastolic dysfunction. Recent studies described the role of long noncoding RNAs (lncRNAs) in cardiac pathologies. Nevertheless, detailed reports on lncRNAs regulating CF biology and describing their implication in cardiac remodeling are still missing.Here, we aimed at characterizing lncRNA expression in murine CFs after chronic pressure overload to identify CF-enriched lncRNAs and investigate their function and contribution to cardiac fibrosis and diastolic dysfunction.Global lncRNA profiling identified several dysregulated transcripts. Among them, the lncRNA maternally expressed gene 3 (Meg3) was found to be mostly expressed by CFs and to undergo transcriptional downregulation during late cardiac remodeling. In vitro, Meg3 regulated the production of matrix metalloproteinase-2 (MMP-2). GapmeR-mediated silencing of Meg3 in CFs resulted in the downregulation of Mmp-2 transcription, which, in turn, was dependent on P53 activity both in the absence and in the presence of transforming growth factor-β I. Chromatin immunoprecipitation showed that further induction of Mmp-2 expression by transforming growth factor-β I was blocked by Meg3 silencing through the inhibition of P53 binding on the Mmp-2 promoter. Consistently, inhibition of Meg3 in vivo after transverse aortic constriction prevented cardiac MMP-2 induction, leading to decreased cardiac fibrosis and improved diastolic performance.Collectively, our findings uncover a critical role for Meg3 in the regulation of MMP-2 production by CFs in vitro and in vivo, identifying a new player in the development of cardiac fibrosis and potential new target for the prevention of cardiac remodeling.
PITUITRIN IN LABOUR
Authors: P. A. Hendley
Journal: BMJ (1914)

19 _ZD",JM" MY1,11 So my cases may have little actually to -do with the main issue.However, the symptoms were uncommonly suggestive, except for the absence of the "whoop"; yet, in the circumstances, I think I was justified in rejecting true pertussis as the diagnosis.Again, it is of great interest to read that the cases under Dr. Ross exhibited "a definite incubation period."Perhaps Dr. Ross would be kind enough to give approxi- mately the length of this, and also the duration of the whole illness from his observations.None of my cases persisted for the complete, usual, protracted course, but they varied greatly in the period of recovery from "' epidemic paroxysmal cough," as Dr. Ross has aptly suggested that the disease should be named.I am, etc.,
UGT1A1*28, toxicity and outcome in advanced colorectal cancer: Results from Trial N9741
Authors: H. L. McLeod, L. Parodi, D. J. Sargent, S. Marsh, E. Green, P. Abreu, L. A. Cisar, R. M. Goldberg
Journal: Journal of Clinical Oncology (2006)

3520 Background: This report examines UGT1A1*28, toxicity, and outcome in trial NCCTG N9741 patients (pts) receiving combination chemotherapy for advanced colorectal cancer. Methods: Blood samples were collected from 520 pts randomized between 2/18/00 and 7/18/02. Pts were treated with irinotecan/5-fluorouracil (5FU)/leucovorin (LV) (IFL, n=114), oxaliplatin/5FU/LV (FOLFOX, n=299), irinotecan/oxaliplatin (IROX, n=107). 19% of IFL pts received full-dose (125 mg/m 2 ) irinotecan; the rest received a reduced dose (100 mg/m 2 ). Toxicity was evaluated every cycle. Correlation of dichotomous outcomes and genotype status used Fisher’s exact tests. Univariate logistic regression was used to test the association between continuous variables and binary outcomes, including a test of trend, and multivariate logistic regression to adjust for known risk factors: performance status, age, gender. Time to progression (TTP) and overall survival (OS) were tested for association with UGT1A1 using the log-rank test. Statistical significance was prospectively set at .01 to control for multiple comparisons. Results: Frequency of UGT1A1 genotype was 44% 6/6, 42% 6/7, and 9% 7/7. In all arms, the rate of grade (G) 4 neutropenia (neut) ( Table ) and G3+ febrile neut (FN) was higher in pts with the 7/7 than in pts with 6/7 and 6/6. No association was seen between UGT1A1 and diarrhea, tumor response, TTP, or OS overall or for any treatment arm. The odds ratios for pts with 7/7 developing G4 neut and G3+ FN compared with pts with 6/6 are shown ( Table ). Statistically significant associations between the 7/7 polymorphism and G4 neut were seen in pts treated with IROX (P=.004) and in all pts (P=.007). The association between 7/7 and G3+ FN was also significant for IROX (P=.006). Conclusions: There is a higher risk of neut in 7/7 pts. Due to low frequency of the 7/7, exclusion of all pts with 7/7 reduces the overall G4 neut rate from 18% to 17%. UGT1A1 was not a predictor of response, TTP, or OS for any arm. [Table: see text] [Table: see text]
Outcome of neo-adjuvant treatment in triple-negative breast cancer in underserved community employing carboplatin taxane combination.
Authors: Martin Majer, Tu Quach, Tien Nguyen, Randell Skau, Rebecca Vierra, Elizabeth Johnston, Milton Conley, Ravi Nagubandi, Edward J. Ordorica, Lucie Tomanova, Susan Schmidt, Steve DeMartini, Greg Schneringer, Leona Roberts, Ashley Schaffer, Megan Powell
Journal: Journal of Clinical Oncology (2016)

e12581 Background: Triple-Negative Breast Cancer (TNBC) is associated with poor prognosis compared to other types of breast cancer. Achieving complete pathological response (pCR) is a strong predictor of survivorship and surrogate goal of neoadjuvant treatment. We analyze the outcome of neoadjuvant chemotherapy in our TNBC patients. Methods: This is a retrospective observational study of an underserved, low income, rural population in Oroville, California over 5 years (2011 to 2016). Neo-adjuvant chemotherapy was offered to ten women with ages ranging from 40 to 77 years (mean age is 60). One received standard AC+T regimen and rest obtained docetaxel/carboplatin regimen. Either a mastectomy or lumpectomy was performed on all patients following completion of chemotherapy. The primary end point of this study was pCR. Minimal requirement for adequate chemotherapy was 3 cycles within 90 days of starting it. Results: Our study resulted in an unexpectedly high response rate. All but two patients 7/9 (77%) achieved pCR. Remaining two patients had clinical partial response. One patient was excluded from analysis due to non-compliance failing to receive adequate treatment. Toxicity of the treatment was acceptable. All nine patients are alive without sign of recurrence. Conclusions: The high success with pCR within our patients was twice higher than expected. This result might due to our small sample, employment of platinum, and in one patient additive effect of bevacizumab. We plan to analyze samples from patients without pCR in regard of androgen receptors for further treatment options.
Abstract 19822: Epicardial and Pericardial Adipose Tissue are Correlated with Vascular Stiffness Measured as Pulse Wave Velocity
Authors: Tae-Young Choi, Naser Ahmadi, Souraya Sourayanezhad, Irfan Zeb, Matthew Budoff
Journal: Circulation (2010)

Background: Epicardial adipose tissue (EAT) has been reported to influence coronary atherogenesis and adverse cardiac events. Aortic stiffness measured as pulse wave velocity (PWV) is an independent risk factor of cardiovascular outcome as well. We evaluated the relationship of EAT(inside the pericardium) and pericardial adipose tissue (PAT, outside the pericardium) measured volumetrically by 64 multidetector computed tomography (MDCT) with PWV. Methods: This study consists of 106 consecutive subjects (Age: 53±13 yrs, 74% male) who underwent MDCT and PWV. EAT volume (ml) was measured from slice level 10 mm above left main coronary artery ostium to bottom of the heart. PAT was calculated as [Intrathoracic adipose tissue - EAT]. Coronary artery calcium (CAC) was defined as CAC 0, CAC 1–100, CAC 101–400 and CAC 400+. Carotid-radial PWV (mm/s) was measured using SphygmoCor tonometery (Atcor Med., Australia). The significant EAT and PAT was defined as their highest tertile. Results: There was a modest correlat...