tbuckley/cabot-search huggingface dataset:
Combined BRAF, EGFR, and MEK Inhibition in Patients with <i>BRAF</i>V600E-Mutant Colorectal Cancer
Authors: Ryan B. Corcoran, Thierry André, Chloe E. Atreya, Jan H.M. Schellens, Takayuki Yoshino, Johanna C. Bendell, Antoine Hollebecque, Autumn J. McRee, Salvatore Siena, Gary Middleton, Kei Muro, Michael S. Gordon, Josep Tabernero, Rona Yaeger, Peter J. O'Dwyer, Yves Humblet, Filip De Vos, A. Scott Jung, Jan C. Brase, Savina Jaeger, Severine Bettinger, Bijoyesh Mookerjee, Fatima Rangwala, Eric Van Cutsem
Journal: Cancer Discovery (2018)

Abstract Although BRAF inhibitor monotherapy yields response rates &amp;gt;50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism. Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428–43. ©2018 AACR. See related commentary by Janku, p. 389. See related article by Hazar-Rethinam et al., p. 417. This article is highlighted in the In This Issue feature, p. 371
Survival of chemotherapy (chemo) refractory gastric or gastroesophageal junction cancer (GC/GEJC) patients from Flatiron Health (FH): Matched clinical characteristics to ATTRACTION-2 and CHECKMATE-032.
Authors: Yelena Yuriy Janjigian, Dung T Le, Patrick Alexander Ott, Beata Korytowsky, Hannah Le, Trong Kim Le, Ying Zhang, Teresa Sanchez, Gregory Maglinte, Melissa Laurie, Dhiren Patel, Tong Shangguan, Ian Chau
Journal: Journal of Clinical Oncology (2018)

51 Background: Treatments for advanced/metastatic (adv/met) GC/GEJC after failure of second-line (2L) chemo are limited. Nivolumab (NIVO) demonstrated encouraging anti-tumor activity and long-term OS in adv/met GC/GEJC Asian patients (pts) in ATTRACTION-2 compared with placebo (12-month OS rate, 26% vs 11%; HR, 0.63; P &lt; .0001) and in CHECKMATE-032 (CM-032) in Western pts (12-months OS rate, 45%). This study explored outcomes in US GC/GEJC pts by establishing real world (RW) standard of care (SOC) comparators, against placebo in Asian pts and NIVO in Western pts. Methods: Data were captured from FH electronic health record database. Median OS, estimated by Kaplan-Meier, was calculated from last treatment for adv/met GC/GEJC to death. To create a US RW SOC arm to the ATTRACTION-2 placebo pts, a 2-step matching process was applied: (1) similar inclusion/exclusion (I/E) criteria (2) frequency matching based on significant differences in baseline characteristics associated with survival, identified by univariate analysis. A similar approach was used to create a US RW SOC arm to NIVO treated pts in CM-032. Results: 742 adv/met GC/GEJC pts with ≥ 2 prior lines of therapy were identified in FH from Jan11-Apr17. Two-step matching resulted in 90 US RW SOC vs. 163 ATTRACTION-2 placebo pts, and 100 US RW SOC vs. 42 CM-032 pts. All pts had ECOG performance status (PS) of 0 or 1. Median OS of US RW SOC arm was similar to matched placebo in ATTRACTION-2. Comparison of RW SOC to NIVO-treated pts in CM-032 showed a favorable median OS with NIVO therapy (Table). Conclusions: These analyses highlight the grave outcomes in US adv/met GC/GEJC pts in FH and signal a need for more effective treatments. The data also suggest favorable outcomes with NIVO vs. SOC in both Asian and Western pts with 3L adv/met GC/GEJC. [Table: see text]
Abstract P3-10-18: Factors associated with mammographic density in Japanese women
Authors: K Uchida, H Ohashi, N Hiroko, R Mimoto
Journal: Cancer Research (2018)

Abstract Background: Increased mammographic breast density decreases the sensitivity and the specificity of mammography screening and is associated with a significant risk factor for breast cancer. No studies were identified that examined the impact of supplemental screening on breast cancer recurrence rates or mortality for women with dense breasts. The aim of this study is to examine factors associating with breast density in Japanese women. Data sources and methods: We used mammography check-up participants (n=5159, women aged 40 years or older) between Apr 2014 and Mar 2017 as our baseline data. Using a self-administered questionnaire, data of life style were collected. Logistic regression was used to estimate the odds of having dense breasts by age, body mass index (BMI), alcohol consumption, smoking, parity, menopausal status, dysmenorrhea, hormone replacement therapy (HRT), family history of breast cancer, physical exercise, fried foods intake, brightly colored vegetables intake, coffee intake, tea intake and bone mineral density. Breast densities were divided into four categories based on BI-RADS classification. BI-RADS 3 and 4 were defined as dense breast. All statistical tests were two-sided. Results: Dense breast accounted for 62.3% of mammography screening participants. Dense breast at an early age was more frequent as 78.0% in the 40's. Alcohol intake (20 g or more a day, OR=1.62, 0.026) in post-menopausal women showed statistically significant positive interaction with dense breast. Weak positive interaction was seen in bone mineral density&amp;gt;80% (OR=0.63, 0.086, n=775). On the other, age (OR=0.97, &amp;lt;0.001), BMI (OR=0.78, &amp;lt;0.001), number of live birth (one; OR=0.77, &amp;lt;0.030, two or more; OR=0.37, &amp;lt;0.001) and post-menopause (OR=0.60, &amp;lt;0.001) showed statistically significant negative interactions with dense breast. Conclusion: Dense breast accounted for 62.3% of all participants. Dense breast was more frequent at early age as 78.0% in their 40's. Alcohol consumption and bone mineral density in post-menopausal women were positive interaction with mammographic breast density. On the contrary, age, BMI, number of live birth and post-menopause were negative interaction with mammographic breast density. Citation Format: Uchida K, Ohashi H, Hiroko N, Mimoto R. Factors associated with mammographic density in Japanese women [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-10-18.
Educational intervention to improve antibiotic knowledge at Kamuzu Central Hospital, Malawi
Authors: Daniel Kozman, Linnaea Schuttner, Lilian Chunda, Christopher Tymchuk
Journal: The Lancet Global Health (2018)

BackgroundAntibiotic resistance is a global issue that has the potential to significantly affect countries with limited antibiotic choices. At many government hospitals in Malawi, including Kamuzu Central Hospital (KCH), limited laboratory data and antibiotic options are barriers to providing appropriate antibiotics to patients. We aimed to design an educational intervention targeted to Malawian clinician trainees, including registrars, interns, and medical students, with the goal of improving their knowledge of appropriate antibiotic use based on available clinical information and Malawian guidelines.MethodsAs part of an institutional partnership between the University of California—Los Angeles (UCLA) and KCH, an educational intervention was carried out at KCH in January, 2017. The intervention was designed and conducted by UCLA internal medicine-paediatrics residents, with supervision from a UCLA infectious disease specialist and KCH medical leadership. The intervention included a teaching session that reviewed common clinical infections, antibiotic options, duration of therapy, and detailed information regarding antibiotics commonly used in Malawi. Malawian trainees were supplied with an antibiotic prescribing pocket guide which summarised best practices from the Malawi Standard Treatment Guidelines, taking into account the hospital's drug formulary. Trainees were also provided with an algorithmic guide to aid decision-making for initiation of empirical antibiotics based on a patient's clinical presentation. Prior to the educational module, participants completed a multiple-choice survey to assess their baseline knowledge of appropriate antibiotic use for multiple case-based scenarios. A post-intervention survey was performed 2 weeks later, followed by a didactic session to review the correct answers for the cases and reinforce the intervention content.Findings33 pre-intervention surveys and 31 post-intervention surveys were completed. Of the 22 trainees who completed both surveys, the majority were medical students (n=16) and interns (n=4). Paired t-test analysis of the pre-test and post-test results showed a mean 17% increase in test scores (p<0·0001), which equates to an average of 2·4 more cases treated correctly.InterpretationBrief, focused global health educational initiatives such as this may be able to provide local trainees with the knowledge to achieve best practices regarding antibiotic use. Ongoing educational initiatives are planned related to antimicrobial stewardship and other key clinical topics relevant to Malawi.FundingNone.
Meta-analysis in Research on Nutrition
Authors: Simon Thornley, George Henderson, Grant Schofield
Journal: JAMA (2018)

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Learning from our mothers: examining the role of intergenerational knowledge transfer in advancing gender equity among Sri Lankan youth
Authors: Ruvani Fonseka, Samantha Hurst
Journal: The Lancet Global Health (2018)

BackgroundIn a 2013 survey, over half of Sri Lankan men and women expressed gender-inequitable attitudes that equated masculinity with violence, and femininity with obedience to men. High rates of gender-inequitable attitudes are a community-level risk factor for gender-based violence including rape and intimate partner violence. In Sri Lanka, public health practitioners focused on reducing the health disparities resulting from gender inequity need to better understand the processes by which gender-inequitable attitudes develop and how to prevent them. The goal of this research was to identify potential points of intervention at which appropriate programmes and policies could most effectively cultivate gender-equitable attitudes among young people in Sri Lanka.MethodsOver 9 months in 2016 and 2017, we interviewed more than 30 young adults in Sri Lanka to understand how their experiences helped them to develop their own gender identity, as well as to understand and respond to gender norms. Their responses were analysed using a grounded theory approach to explore which factors have most influenced the processes of gender norm learning, acceptance, or rejection throughout Sri Lankan young adults' lives.FindingsMany interviews focused on the impact of elder family members on the interviewee's perception and acceptance of gender norms. Many young adults who did not agree with gender-inequitable norms reported receiving advice from their parents or other elder relatives to disregard norms and pursue their own non-conforming interests. In one example, many non-working mothers insisted on their daughters working and becoming financially independent.InterpretationYoung people in Sri Lanka are repeatedly confronted by gender-inequitable attitudes in school, the media, politics, and society at large. However, family members can support youth to develop gender equitable attitudes and behaviours within this gender-inequitable society. Harnessing elders' positive wishes for their offspring's future may prove essential to advancing gender equity in the next generation of Sri Lankan adults. Even from gender-inequitable roles, parents may still support gender equity, and could be encouraged through public health interventions to support their children in realising their full potential. Elder family members are an untapped public health resource for advancing gender equity and reducing its related health disparities among Sri Lankan youth.Funding2016 Fulbright US Student Grant.
Abstract P1-01-13: Mucin-2 (Muc-2) modulates the biology of breast cancer
Authors: A Astashchanka, T Shroka, BM Jacobsen
Journal: Cancer Research (2018)

Abstract Background: Metastasis and therapeutic resistance are major issues in treating patients with breast cancer. Breast tumors that secrete mucus are generally resistant to chemotherapy. One type of secreted mucin, Mucin-2 (Muc2), is expressed in some breast cancers, but is absent in non-neoplastic breast tissue, suggesting that it plays a role in modulating breast cancer biology. Whether Muc2 expression correlates with breast cancer patient survival is controversial. Thus, the effects of Muc2 on the biology of breast cancer are largely unknown. This study examined the role of Muc2 in modulating breast cancer cell proliferation in vitro and in vivo, response to chemotherapy, and metastasis. Methods: Two novel cell lines were developed from patient derived tumor xenografts. These two cell lines, BCK4 and PT12, both express high levels of Muc2. In order to modulate Muc2 levels in both cell lines, shRNA targeted to Muc2 (shMuc2) were compared to non-targeting control shRNA (shNT). Decreased expression of Muc2 was confirmed using immunoblotting. Proliferation in vitro was measured using the IncuCyte live cell imaging system and crystal violet staining. Response to chemotherapy was measured by examining apoptosis using cleaved-caspase 3 expression. BCK4 and PT12 cells with shNT or shMuc2 were grown as solid tumors in immunocompromised mice and tumor volume measured by caliper. BCK4 cells with high Muc2 (shNT) and low Muc2 (shMuc2) were labeled with luciferase and examined in an experimental metastasis model where total disease was monitored by IVIS imaging. Results: Decreased Muc2 expression decreased proliferation in BCK4 and PT12 cells versus non-targeting control cells both in vitro and in vivo. Treatment with the chemotherapeutic Docetaxel induced minimal apoptosis in BCK4 control cells with high Muc2 however, apoptosis was significantly increased in BCK4 cells with reduced Muc2. In an experimental metastasis model, mice injected with BCK4 cells containing low Muc2 had decreased disease burden versus those injected with control cells with high Muc2. Endogenous Muc2 expression in wild-type BCK4 cells increased with addition of EGF and this effect was abolished by addition of the EGF-receptor inhibitor, Erlotinib. Conclusions: Muc2 expression plays an important role in mediating proliferation, apoptosis and metastasis of breast cancer cells. These data suggest that Muc2 is important in controlling the biology of Muc2 positive breast tumors. In addition, Muc2 may be important in guiding treatment and predicting outcomes in breast cancer patients. Citation Format: Astashchanka A, Shroka T, Jacobsen BM. Mucin-2 (Muc-2) modulates the biology of breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-13.
Price trajectory of individual cancer drugs following launch.
Authors: Noa Gordon, Salomon M. Stemmer, Dan Greenberg, Daniel A. Goldstein
Journal: Journal of Clinical Oncology (2016)

6502 Background: Cancer drug launch prices have increased in recent years. However, it is not fully understood how individual drug prices change over time following launch. For example, following the approval of imatinib, the price had increased threefold over a decade. The objective of this study was to measure the price trajectory of 10 cancer drugs following their launch into the US marketplace. Methods: We studied the quarterly changes in prices of average monthly doses for a cohort of 10 patented IV cancer drugs that were approved by the FDA between 1997 and 2012. In order to account for discounts and rebates, we used the Average Sales Price (ASP) published by the Center for Medicare and Medicaid Services (CMS). US inflation rates were obtained from the United States Department of Labor, and prices were adjusted for inflation. For each drug we calculated the cumulative drug price change. Data was analyzed using IBM SPSS Statistics software. Results: With an average follow-up period of 8 years, the median percent of price change for all drugs was 22% (range 3-74%). After adjusting for inflation, the median percent of price change was 6% (range -10-44%). Rituximab and trastuzumab follow a similar pattern in price increase over time and inflation-adjusted prices rose since approval by 44% and 40% respectively. The inflation-adjusted price of pemetrexed rose by 26%. We clustered drugs for indication, year of approval and company but did not find any significant trends. Conclusions: Cancer drug prices may change substantially following launch. Prices may increase by as much as 44% even after adjusting for inflation. When discussing value, we must take into account that prices are not always static. Generic Name Follow-up time (years) ASP change (US$) ASP change (%) Inflation-adjusted ASP change (%) rituximab 11 3041 74 44 trastuzumab 11 2396 69 40 pemetrexed 11 2632 52 26 panitumumab 8 2020 25 12 bevacizumab 11 2258 24 3 nab-paclitaxel 10 1578 20 2 ipilimumab 4 4660 11 8 cetuximab 11 78 8 -10 denosumab 4 127 7 4 pertuzumab 2 143 3 3
Diploma in Immediate Medical Care (Dip IMC RCSEd)
Authors: Salmin Aseri
Journal: BMJ (2007)

Credit: REX FEATURES



FURTHER INFORMATION 

Application and further details can be obtained from the registrar, Royal College of Surgeons of Edinburgh, Adamson Centre, 3 Hill Place, Edinburgh EH3 9DS. Tel 0131 668 9222, fax 0131 668 9218, email information@rcsed.ac.uk, or go to www.rcsed.ac.uk and then faculty of prehospital care section or examination section.

Medical practitioners, nurses, and paramedics with an interest and experience in prehospital emergency care, immediate medical care, and management of seriously ill or injured …
High durable CR rates and preliminary safety profile for JCAR017 in R/R aggressive b-NHL (TRANSCEND NHL 001 Study): A defined composition CD19-directed CAR T-cell product with potential for outpatient administration.
Authors: Jeremy S. Abramson, Tanya Siddiqi, Maria Lia Palomba, Leo I. Gordon, Matthew Alexander Lunning, Jon E. Arnason, Michael Wang, Andres Forero-Torres, Tina Albertson, Christine Dehner, Jacob Garcia, Daniel Li, Benhuai Xie, David G. Maloney
Journal: Journal of Clinical Oncology (2018)

120 Background: JCAR017 is a defined composition, CD19-directed 4-1BB CAR T cell product administered at a precise dose of CD8 and CD4 CAR T cells in a seamless design Phase 1 pivotal trial of relapsed/refractory (R/R) B-cell NHL (TRANSCEND NHL 001; NCT02631044). Methods: Patients (pts) with R/R DLBCL NOS, PMBCL, FL grade 3B, or MCL and adequate organ function are eligible. The FULL dataset includes all pts in the DLBCL cohort (i.e. excludes MCL). The CORE dataset includes pts meeting inclusion for a planned pivotal DLBCL cohort (DLBCL NOS [ de novo or transformed from follicular lymphoma], ECOG 0-1, no prior allo-SCT). Results: As of July 7, 2017, 69 pts were treated in the DLBCL cohort and evaluable for safety. In the FULL dataset, 21 pts (30%) had cytokine release syndrome (CRS), with 1 serious CRS event (1%; Gr 4). Neurotoxicity (NT) at any grade developed in 14 (20%), including 10 (14%) with Gr 3-4 events. There were no Gr 5 CRS or NT events. Median time to onset of first CRS and NT was 5 days and 10 days, respectively, 13 (19%) received anti-cytokine therapy and only one required vasopressor support. In the CORE dataset (n = 49), similar rates of CRS and NT were shown. The majority of pts, 64% (44/69), had no CRS or NT, and median onset of CRS and NT were 5 and 11 days, respectively, suggesting outpatient delivery of JCAR017 may be feasible. In the DLBCL cohort, 68 pts were evaluable for efficacy; best overall response, 3-month, and 6-month response rates in the FULL dataset were 75% (51/68), 49% (27/55), and 40% (14/35), respectively; and, in the CORE dataset, were 84% (41/49), 65% (26/40), and 57% (13/23). The best overall, 3-month, and 6-month CR rates were 61% (30/49), 53% (21/40), and 52% (12/23), respectively, in the CORE dataset. Among 16 double/triple hit pts, best ORR was 81%, and 3-month CR rate was 60%. A trend toward improved response rate at 3 months was observed in pts treated at DL2 compared to DL1. Conclusions: At the symposium, we will report updated efficacy and the preliminary safety profile for JCAR017, which supports potential outpatient administration in R/R Aggressive B-NHL patients. Clinical trial information: NCT02631044.
What is the layout of a perfect curriculum vitae?
Authors: Adam Poole
Journal: BMJ (2004)

<i>Got a career or related problem that needs answering? Can9t find the right person to point you in the right direction? Log on to the Advice Zone (www.bmjcareers.com/advicezone) for reliable medical careers advice. You can post a question or see if one of our 300 advisers has already answered a similar question. Here is a selection of questions and answers posted on the site:</i>