tbuckley/cabot-search huggingface dataset:
Toxicogenomic profiling of fluorouracil/leucovorin/oxaliplatin/docetaxel (FLOT) in advanced gastric cancer: A translational study of the German Arbeitsgemeinschaft Internistische Onkologie (AIO).
Authors: E. Goekkurt, S. Al-Batran, M. Kramer, C. Pauligk, N. Homann, J. T. Hartmann, M. H. Moehler, R. Hofheinz, G. Ehninger, J. Stoehlmacher
Journal: Journal of Clinical Oncology (2010)

e14624 Background: To develop toxicogenomic profiles as predictors of clinically relevant grade 3/4 toxicities of chemotherapy in advanced gastric cancer (AGC). Methods: This randomized phase II study compared fluorouracil, leucovorin, oxaliplatin ± docetaxel (FLO vs. FLOT) in pts with AGC. As part of the study protocol blood samples of 143 pts were prospectively collected for DNA extraction and genotyping. 24 polymorphisms in 17 genes as part of the metabolism or transmembrane transport of the applied drugs, the folate metabolism or DNA repair were analyzed. Toxicity data were analysed using aggregated data and univariate Poisson regression to take into account varying therapy cycles. Multiple regression analysis was performed using non-aggregated data with repeated measures and generalized estimation equations in SAS Proc Genmod. Thereby, it was possible to include maximum information of each cycle per individual. The modified variance structure was modelled as exchangeable. Results: For clinical study data see abstract of Al-Batran et al. Univariate analyses revealed significant associations between various covariates (genotypes, clinical factors) and toxicities. Generalized estimation equations confirmed most of them in the multivariate setting. Significant associations were observed between neutropenia and treatment arm (p = 0.002), TS1394del6 (p = 0.016), GSTT1 (p = 0.028), GSTM1 (p = 0.023), ABCG2-C421A (p < 0.001), XRCC1-R399Q (p < 0.001), XPD-D312N (p = 0.004), XPD-K751Q (p = 0.007), SDF1-1'A (p = 0.033); between diarrhea and treatment arm (p = 0.001), ABCB1-G2677T (p = 0.032), XPD-K751Q (p = 0.013), MAD1-G558A (p = 0.015); between sensory neuropathy and performace status (p = 0.001), oxaliplatin dose (p = 0.009), XPD-K751Q (p = 0.029), OPRT-G213A (p = 0.003), SDF1-1'A (p = 0.035), MAD1-G558A (p = 0.017). Conclusions: Toxicogenomic profiling represents a powerful tool to identify potential relevant polymorphisms to predict chemotherapy induced toxicity in AGC pts. Validation of these markers is warranted and ongoing within the next clinical study of FLOT in AGC that has recently closed accruel with a total of 250 pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis
Abstract 10794:Intubation Does Not Result in a Survival Advantage in a Swine Hemorrhagic Shock Model Simulating Penetrating Trauma
Authors: Sharven Taghavi, Senthil Jayarajan, Swapnil Khoche, Jason Duran, Rich Milner, Lewis Holt-Bright, John Gaughan, Joseph Rappold, Lars Sjoholm, Jay Dujon, Abhijit Pathak, Thomas Santora, Steven Houser, Amy Goldberg
Journal: Circulation (2012)

2012 Finalist and Presenting Author
Outcome of patients malnourished at diagnosis of a metastatic lung adenocarcinoma.
Authors: Damien Vansteene, Sandrine Hiret, Hélène Senellart, Jean-Yves Douillard, Jaafar Bennouna, Dominique Darmaun
Journal: Journal of Clinical Oncology (2014)

213 Background: The objective of this retrospective study was to assess the impact of malnutrition in patients treated in 2012 at the Integrated Center for Oncology René Gauducheau (Nantes, France) by palliative platinium based chemotherapy and pemetrexed for a lung adenocarcinoma. We studied toxicities of chemotherapy, overall survival of patients, nutritional support and outcome of the patients. Methods: We determined for these patients if they were malnourished or well-nourished at diagnosis (as defined by a weight loss &gt; 5% in 1 month or &gt; 10% in 6 months, or a body mass index ≤ 18.5 under 70 years old or &lt; 21 after 70 years old, or hypoalbuminemia &lt; 30 g/L under 70 years old or &lt; 35 g/L after 70 years old). Results: Among the 48 patients eligible for study, 15 were not included because it was impossible to determine if they were malnourished or not; 14 patients were malnourished at diagnosis and 19 patients were well-nourished. Other than in cases of anorexia, malnourished patients didn’t experience more adverse effects of chemotherapy. Treatment response was equal in the two groups. The median overall survival was shorter for malnourished patients than for well-nourished patients (8 vs 23 months, p=0,0089, HR 3,747 ; 95% CI : 1,443 – 9,732). Nutritional support was given most frequently to malnourished patients than to well-nourished patients (64,3% vs 21,1%, p=0,0286) and care consisted of counseling for 7,1% of malnourished patients and 10,5% of well-nourished patients and oral supplements for 50% and 10,5% respectively. Enteral feeding was given to one malnourished patient and another one refused it. None received parenteral nutrition. At relapse, well-nourished patients received more lines of chemotherapy than malnourished patients (p=0,0377). Conclusions: Our results suggest that malnourished patients upon diagnosis don’t suffer more side effects from chemotherapy than well-nourished patients. Yet they have poorer overall survival and received less other lines of chemotherapy at relapse. Early nutritional care integrated to support care is required for patients with metastatic lung cancer.
Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors
Authors: Jing Qi, Zizheng Dong, Jianguo Liu, Robert C. Peery, Shaobo Zhang, Jing-Yuan Liu, Jian-Ting Zhang
Journal: Cancer Research (2016)

Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule-based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable.
Are there disparities in the utilization of sentinel lymph node biopsies in patients with breast cancer?
Authors: Archana Radhakrishnan, Paula Silverman, Robert R. Shenk, Cheryl L. Thompson
Journal: Journal of Clinical Oncology (2013)

117 Background: Racial disparities in outcomes continue to persist amongst breast cancer (BC) patients (pts). Standard of care for the surgical evaluation of early BC has changed from axillary lymph node dissection being recommended for axillary staging to sentinel lymph node biopsy (SLNB) for clinically node-negative pts. SLNB, however, can be deferred if findings would not alter treatment plans. The goal of this study is to determine if SLNB rates differ by race, age, insurer, community vs academic setting or surgeon. Causes contributing to disparities will be considered. Methods: Pts undergoing primary surgery for early stage BC from 2010-2011 at our academic teaching hospital and two affiliated community medical centers were identified from the tumor registry. Data abstracted included demographics, insurance type, medical center and surgeon. For pts without SLNB, clinical information was confirmed with medical record review. Unadjusted comparison of factors for pts who did and did not have SLNB was evaluated with a t-test or chi square test. Logistic regression modeling assessed significance of demographic and clinical factors predicting SLNB. Results: 499 pts were identified; 114 (23%) were black, 373 (75%) white, and 12 (2%) others/unknown race. SLNB was performed in 443 (89%) of total pts, without racial differences (86% of black and 89% of white pts (p=0.31) had SLNB). Average age of pts who had SLNB was younger (60.4) than those who did not (76.3) (p&lt;0.01). As compared to those with managed care insurance (97%) or Medicaid (91%), only 78% of Medicare pts had SLNB (p&lt;0.01). There was no statistical difference in SLNB rates between academic and community medical centers or by surgeon. Chart review determined that the standard of care was met in 55/56 pts who did not have SLNB; reasons for no SLNB include advanced age (range 79-95), in-breast recurrences, and positive nodes pre-operatively. Conclusions: Utilization rates of SLNB did not differ between black and white BC pts. Differences were seen based on age and insurer. Although only 89% of pts had SLNB, careful evaluation for reasons reveals medically appropriate treatment in almost all cases. These results suggest cautionary interpretation of large database findings.
Junior doctors’ contract talks will resume on Friday
Authors: Abi Rimmer
Journal: BMJ (2016)

Talks on the junior doctors’ contract are set to resume between the government and the BMA on Thursday 14 January.

The Advisory, Conciliation and Arbitration Service (Acas), which previously facilitated talks between the two parties, said that both sides had agreed to take part in talks on 14 and 15 January.

On 12 January …
How To Do It: Run an emergency helpline
Authors: C Stark, P Christie, A C Marr
Journal: BMJ (1994)

Telephone helplines are an effective way of dealing with health related incidents in which large numbers of people need personal counselling or information for reassurance or case finding. Helplines often have to be set up at short notice, which is labour intensive and makes recruitment of appropriate staff difficult. They should ideally be part of local emergency planning resources. Doctors need to be included in the team organising the helpline to ensure that staff are properly briefed, to determine what data need to be collected, and to deal with specialised queries.
Abstract #LB-219: K01109, a potent, novel selective FLT-3 inhibitor for the treatment of acute myelogenous leukemia
Authors: Ching-Huai Ko, Chih-Hung Chen, On Lee, Yen-Chun Chen, Ting-Shou Chen, Hsiang-Wen Tseng, Ying-Chu Shih, Chih-Peng Liu, Yuan-Jang Tsai, Shu-Jiau Chiou, Ling-Mei Wang, Chrong-Shiong Hwang
Journal: Cancer Research (2009)

One of the intracellular signaling tyrosine kinase receptor, FLT3 (fms-related tyrosine kinase 3/Flk2/Stk-2), is recognized as an important factor in leukemogenesis and is responsible for chemosensitivity in acute myelogenous leukemia (AML). Approximately 30% of AML patients harbor an activating internal tandem duplication (ITD) of the FLT3 receptor, are associated with poor prognosis, suggesting that it may be a target for kinase inhibitor therapy. For this purpose, we used molecular and cellular level kinase panel assay system for fast screening the anti-tumor activities of BEL-K series drugs which constructed by rationale/computer-assisted drug design and virtual screening approaches. We have developed K01109, a potent antagonist that inhibits FLT3, c-Kit and VEGFR-2. In 32D cells expressing different FLT3-ITD mutants, K01109 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation. In human FLT3-ITD-positive AML cell lines, K01109 inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the STAT-5, and ERKs Pathways. Therapeutic efficacy of K01109 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease.    Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-219.
Complete remissions with weekly dosing of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in a phase I dose-escalation study in patients with relapsed or refractory Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (sALCL)
Authors: N. Bartlett, A. Forero-Torres, J. Rosenblatt, M. Fanale, S. J. Horning, S. Thompson, E. L. Sievers, D. A. Kennedy
Journal: Journal of Clinical Oncology (2009)

8500 Background: A defining feature of HL and sALCL is CD30 expression on malignant cells. The ADC SGN-35 comprises an anti-CD30 antibody conjugated to the antitubulin agent monomethyl auristatin E (MMAE). SGN-35 causes cell cycle arrest and apoptosis by binding to CD30 on the tumor cell surface, internalizing, and releasing MMAE into the cell. In a previous phase 1 study with q3 wk dosing, 54% of pts achieved an objective response (CR/PR) at SGN-35 doses ≥1.2 mg/kg [ASH 2008 abstract 1006]. Methods: To assess if more frequent dosing might maximize anti-tumor activity with acceptable tolerability, a multicenter, phase 1, weekly dosing, dose-escalation study (3+3 design) was conducted in pts with refractory or recurrent HL or sALCL. SGN-35 was administered weekly at doses of 0.4–1 mg/kg (2-hr IV infusions). Pts with stable disease or better (Cheson 2007) after two 28-day cycles (6 doses) were eligible to continue SGN-35 treatment. Results: In 17 pts, median age was 38 yrs (range 25–67). Pts received a median of 4 prior therapies; 65% received an autologous SCT. MTD has not been defined. One related G3 event (diarrhea) and no related G4 events occurred. The most common related adverse events were G1/G2 rash, nausea, and peripheral neuropathy. Exposure to SGN-35 (AUC) increased relative to dose level. Multiple CRs were observed at higher doses ( table ); observed time to response in the 1 mg/kg dose group was approximately 8 wks. The 7 pts with CRs all remain on treatment. Enrollment to SGN-35 monotherapy continues at 1.2 mg/kg; combination therapy will be subsequently explored. Conclusions: SGN-35 was generally well tolerated and induced CRs in 7 of 8 evaluable pts at the two highest doses in heavily pretreated patients. Pivotal trials of this antibody-drug conjugate will initiate in early 2009. [Table: see text] [Table: see text]
Reply to S. Lehrer et al and J.C. Dowdy and R.M. Sayre
Authors: Marianne Berwick
Journal: Journal of Clinical Oncology (2016)

Thank you for thoughtful responses to the paper and editorial in the Journal of Clinical Oncology, July 1, 2015. We all seem to agree that dietary warnings are premature and that it will be important to identify clearly the dose-response for the photocarcinogenic properties of furocoumarins in citrus and other plant foods. It is known that grapefruit in juice or fruit interferes with the metabolism of drugs such as statins, cholesterol-blocking drugs. However, because it also interferes with other drugs, it is important to be aware of the potential interactions of drugs with furocoumarins. Thus, further investigation into the role of furocoumarins is important. Several misunderstandings are noted. Dowdy and Sayre stated that Wu et al stated that furocoumarin levels can increase in response to plant stress, poor handling postharvest, and suboptimal shipping or storage; in fact, Wu et al note a reduction of the contents of furocoumarin with such problems. The relationship between direct handling cross-contamination of edible parts and skin transfer needs to be clarified. According to the Senate Commission on Food Safety, most of the furocoumarins are in the peel. If that is true, then it is unlikely that there is a crosscontamination problem. There is a contradiction between the comment by Dowdy and Sayre that “only minimal UVexposure is required to induce photochemical reactions between furocoumarins and biological macromolecules” and the statement by Wu et al, based on their data, that such foods “may have a stronger photocarcinogenic effect in the presence of higher UV radiation as compared with that in the presence of lower UV radiation.” It is of interest to evaluate a “different UV exposure pattern for citrus-associated melanoma” that “may indicate evidence for action of persistent dietary photocarcinogens.” The potential for selection bias from this particular study population should not be dismissed. Additionally, the direction of any bias from noninclusion of nonmelanoma skin cancer history cannot be estimated without the data. It is interesting that both the editorial and the letter writers, although coming from different angles, are in agreement with the idea that there is a need for more data before any dietary recommendations.
The contribution of rare variation to prostate cancer heritability
Authors: Nicholas Mancuso, Nadin Rohland, Kristin A Rand, Arti Tandon, Alexander Allen, Dominique Quinque, Swapan Mallick, Heng Li, Alex Stram, Xin Sheng, Zsofia Kote-Jarai, Douglas F Easton, Rosalind A Eeles, Loic Le Marchand, Alex Lubwama, Daniel Stram, Stephen Watya, David V Conti, Brian Henderson, Christopher A Haiman, Bogdan Pasaniuc, David Reich
Journal: Nature Genetics (2015)
Phase I/II trials of high-intensity focused ultrasound (HIFU), a non-invasive technique for the ablation of colorectal (CRC) liver metastases
Authors: M. J. Allen, I. Rivens, G. Ter Haar, D. Cunningham
Journal: Journal of Clinical Oncology (2005)

3647 Background: Minimally invasive techniques for ablation of liver metastases are being increasingly used in colorectal cancer. The principle of HIFU is to bring a high-intensity ultrasound beam to a tight focus deep within tissue, where heating causes cell death, while surrounding tissue is undamaged. HIFU is non-invasive, eliminating the risk of seeding tumour along needle tracks. Methods: Patients for whom no standard oncological treatments existed were eligible for the phase I study. Phase II patients had a metastasis which could be entirely treated in one HIFU session and underwent MRI scan pre- and post-HIFU (radiology study) or liver resection post-HIFU (histology study). Before and 1 week after HIFU, all patients had an ultrasound scan, CEA measurement and completed a pain questionnaire. Treatment was out-patient based, given without anaesthesia or sedation, using a prototype (‘TELESON’) constructed at the above institution. Results: 19 treatments were given to 17 patients (12M:5F; median age=65, range 39–79). No patient reported severe pain; 11/19 treatments caused moderate pain, but only for the duration of the HIFU pulse. No changes were seen in 1 patient who underwent MRI, nor in 4 histology specimens. CEA reduction was seen in 5/11 patients with metastases confined to the liver, and stabilisation in a further 3. 2/3 patients with a CEA rise post-HIFU had multiple liver metastases. Conclusions: HIFU was well tolerated. Although no clear radiological or histological changes were seen, it is encouraging that reductions in CEA occurred, particularly when a significant proportion of the overall tumour burden was treated. We believe HIFU merits further investigation in this setting. No significant financial relationships to disclose.
New Strategies in Prostate Cancer: Prostate-Specific Membrane Antigen (PSMA) Ligands for Diagnosis and Therapy
Authors: Uwe Haberkorn, Matthias Eder, Klaus Kopka, John W. Babich, Michael Eisenhut
Journal: Clinical Cancer Research (2016)

Abstract Key issues for prostate cancer patients are the detection of recurrent disease and the treatment of metastasized cancer. Early detection is a major challenge for all conventional imaging modalities. Furthermore, therapy of patients with hormone-resistant tumor lesions presents a major clinical challenge. Because the prostate-specific membrane antigen (PSMA) is frequently overexpressed in prostate cancer, several PSMA-targeting molecules are under development to detect and treat metastatic castration-resistant prostate cancer (mCRPC). mCRPC represents a situation where cure is no longer achievable and novel therapeutic approaches for palliation and increase of survival are needed. In this article, we discuss the recent development for noninvasive detection of recurrent disease and therapy of mCRPC with corresponding PSMA-targeted radioligands. Clin Cancer Res; 22(1); 9–15. ©2016 AACR.
Abstract 263: Emergencies and Resuscitation in the Catheter Laboratory: High-Fidelity Simulation as a Training Tool to Improve Multidisciplinary Team Communication and Confidence
Authors: Charles J Butcher, Zubair Sarang, Rebecca Green, Oscar Duke, Timothy Knowles, Odiri Eneje, Geraldine McVeigh, Mark Bowers, Mark Mason, David Jones
Journal: Circulation (2014)

Purpose: Multi disciplinary team (MDT) emergency and resuscitation training for acute device related complications in the catheter laboratory commonly takes the form of didactic instruction or post event debriefing. High fidelity simulation offers the opportunity to role-play clinical emergencies in a controlled environment in a dynamic and interactive setting. This technique allows for immersive training whilst protecting patients from unnecessary risk and may enhance performance. Methods: Two sessions, each with two high fidelity in-situ resuscitation scenarios, using a simulation manikin, were run as a pilot (Session 1 - pacing failure during device generator change; tamponade during lead extraction, Session 2 - Primary angioplasty with cardio pulmonary arrest, Primary angioplasty requiring acute temporary pacing). These were viewed by other members of the department on a live video feed. 45 members of the MDT (including Cardiologists, Anesthetists, Radiographers, Nurses and Physiologists of all levels) participated in each the session, attending a formal facilitated debrief after each scenario. The debrief outcome of scenario 1 was designed to influence the behavioral strategy during the conduct of scenario 2. Anonymous pre and post scenario questionnaires measured improvement in confidence, clinical knowledge and inter-professional relationships. Results: We collected 72 pre-course and 67 post-course questionnaires in total. 92% agreed or strongly agreed that the session enhanced inter-professional working relationships and communication skills. 73% felt their clinical knowledge was increased. The number of people who felt ‘confident’ or ‘very confident’ in ‘speaking up about something they disagreed with in a clinical emergency’ increased from 45% to 65% (p&lt;0.05). All respondents would recommend the session to a colleague &amp; attend themselves again. Conclusions: High fidelity in-situ simulation may be a useful tool to actively engage the MDT in improving clinical knowledge and communication in emergency resuscitation situations, whilst enhancing inter-professional relationships. This may have important implications for patient safety in the Catheter Laboratory.
Cost-Effectiveness of Transcatheter Aortic Valve Replacement With a Self-Expanding Prosthesis Versus Surgical Aortic Valve Replacement
Authors: Matthew R. Reynolds, Yang Lei, Kaijun Wang, Khaja Chinnakondepalli, Katherine A. Vilain, Elizabeth A. Magnuson, Benjamin Z. Galper, Christopher U. Meduri, Suzanne V. Arnold, Suzanne J. Baron, Michael J. Reardon, David H. Adams, Jeffrey J. Popma, David J. Cohen
Journal: Journal of the American College of Cardiology (2016)