tbuckley/cabot-search huggingface dataset:
Sexual function, anxiety, and surgical decision making in BRCA mutation carriers.
Authors: Matthew T. Oliver, Rebecca Kwait, Jessica Kent Laprise, Jennifer Scalia Wilbur, Sarah Spinette, Christina Raker, Julia Gutierrez, Katina Robison, Robert Duffy Legare, Jennifer S. Gass, Ashley Stuckey
Journal: Journal of Clinical Oncology (2017)

e21572 Background: To describe BRCA mutation carriers’ perspectives on quality of life from prophylactic surgical decision making. Methods: A cross-sectional survey of BRCA mutation carriers identified from a genetic counseling database at an academic women’s oncology program was conducted using Research Electronic Data Capture. Survey items included Female Sexual Function Index (FSFI), Hospital Anxiety and Depression Scale, and investigator-generated questions. Statistical analysis was performed using Fisher’s exact test and Wilcoxon rank-sum or Kruskal-Wallis tests. Results: 66 BRCA mutation carriers completed the survey (39% response rate) with a median age of 50 (range 18 to 79); 23% of respondents were pre- or perimenopausal and 11% reported a history of ovarian/fallopian tube cancer. Overall, 25% of respondents reported anxiety regarding the timing of bilateral salpingo-oophorectomy (BSO) or mastectomy. Women who had a BSO were less likely to be sexually active and had lower total FSFI scores, with arousal and desire approaching significance compared to women without BSO (p = 0.05). Women who had a BSO had slightly higher median total anxiety scores, but were not more likely to have abnormal levels of anxiety. Women who were &lt; 40 years of age at discovery of mutation were more likely to have had a discussion regarding preimplantation genetic diagnosis (p &lt; 0.0001), more likely to have anxiety regarding prophylactic surgery and childbearing (p &lt; 0.0001), and more likely to say BRCA mutation impacted their decisions about childbearing (p = 0.001) compared to women &gt; 40. 57% of women age 18-39 at time of mutation diagnosis delayed BSO for childbearing as compared to none of the women &gt; 40 (p &lt; 0.0001). Only 20% of the pre- or perimenopausal women used hormone replacement therapy after BSO. Conclusions: BRCA mutation carriers face challenging decisions concerning prophylactic surgical management. Counseling sessions often focus on effective risk reducing surgeries but may not directly address other emotional and physical consequences of prophylactic surgery. Counseling regarding use of hormone replacement therapy is an area identified in this study that may improve quality of life issues seen in women undergoing prophylactic BSO.
Effect of increasing radiation dose for rectal cancer patients with nonoperative management after neoadjuvant chemoradiotherapy.
Authors: Jinghua Tang, Yuan-Hong Gao, Desen Wan, Zhi-zhong Pan, Pei-Rong Ding
Journal: Journal of Clinical Oncology (2018)

e15676 Background: Neoadjuvant chemoradiotherapy (nCRT) combined with radical surgery is the standard treatment for locally advanced rectal cancer. The strategy of watch and wait for patients with clinical complete remission (cCR) avoided major surgery without compromise oncological safety. However, only 10-20 percent patients achieved cCR and approximately quarter of them will regrow, which requires salvage surgery for cure. High-dose radiotherapy can improve the response of tumor to CRT, but there is no study reported the effect of dose-escalation CRT in patients with nonoperative management after nCRT. Methods: From January 2012 to December 2016, 54 patients with locally advanced rectal cancer who underwent nCRT (50 Gy in 25 fractions to tumor, 46 Gy in 23 fractions to elective lymph node volumes, concomitant with capecitabine or XELOX) without planned surgery were retrospectively reviewed. Five to 8 weeks after the end of nCRT, 27 patients received dose-escalation chemoradiotherapy (30Gy in 15 fractions to tumor, concomitant with XELOX). Data were collected to determine the effect of dose-escalation radiotherapy in these patients. Results: The median follow-up was 27 (IQR, 11-38) months. Ten patients achieving cCR after nCRT received dose-escalation CRT and no patients developed local relapse. Seventeen patients who did not meet the criteria of cCR after nCRT received dose-escalation CRT, 8 (47.5%) were re-evaluated as cCR at subsequent follow-up. leucopenia was the most common acute grade 3 adverse event during dose-escalation CRT, which affected 5 (18.5%) patients. Late toxicity was reported in 1(3.7%) patient with grade 3 bleeding from rectal mucosa. Conclusions: Dose-escalation CRT might increase the rate of cCR and reduce local regrowth for rectal cancer patients with nonoperative management after nCRT. Longer follow-up and prospective trials are warranted to evaluate this promising treatment option.
Public Health England’s sugar reduction programme did not “fail”
Authors: Jack Winkler
Journal: BMJ (2018)

The BMJ's account of Public Health England's sugar reduction programme misleads readers.Public Health England did not "fail." 1 Measuring what food people buy is difficult, analysing the data arduous.Public Health England honestly acknowledged, up front, that the figures on sugar reductions in foods were based on purchasing surveys conducted in August-September 2017, 8-9 months before the report was published.Reformulation takes time.Even with soft drinks, where sugar reduction is easiest, many companies only completed work just before the levy came into force.Reformulating foods is technically more difficult.
Development of a novel mouse model to delineate the role of tumor microenvironment on mechanism of action and efficacy of PD-1 and CTLA-4 checkpoint blockade.
Authors: Kalyan Chakravarthy, Raquel Sevilla, Michael Caniga, Weisheng Zhang, Lily Moy, Milenko Cicmil
Journal: Journal of Clinical Oncology (2016)

e14556 Background: The cellular environment in which the tumor exists, also known as tumor microenvironment, includes surrounding blood vessels, immune cells, fibroblasts, signaling molecules, and the extracellular matrix. This microenvironment can contribute to the growth and metastases of tumors, potentially influencing the efficacy of therapeutic agents. Thus, understanding the contribution of the microenvironment on tumorigenesis may enable us to investigate biology and kinetics between tumor and surrounding environment and improve target selection for standalone or combination therapies. Methods: To interrogate the role of the microenvironment we developed a tumor model in which the tumors can grow inside an air-pouch created in the dorsal part of the mouse. The air-pouch serves as the local microenvironment, which can be modulated by pro or anti-inflammatory stimuli to study the impact of local cells and cytokines on tumor growth as well as the efficacy of therapeutic agents. Results: Using luciferized mouse colon carcinoma (mc38-LUC2) syngeneic cells, we demonstrate that the kinetics of tumor growth within the air-pouch is similar to standard subcutaneously induced tumor models and was quantified via bioluminescence imaging. Additionally, further characterization of the tumor microenvironment was performed using MR and CT imaging, cytokine expression, and cell phenotyping. Furthermore, we also evaluated checkpoint inhibitor agents as monotherapy or in combination targeting PD-1, and CTLA-4 pathways in order to evaluate their effect on tumor growth and impact on cellular and cytokine microenvironment. Conclusions: Taken together, our novel model can facilitate innovative assessment of the mechanism of action of immunomodulatory agents across multiple oncological malignancies and evaluation of next generation therapeutics.
ATP-activated decrosslinking and charge-reversal vectors for siRNA delivery and cancer therapy
Authors: Zhanwei Zhou, Qingyan Zhang, Minghua Zhang, Huipeng Li, Gang Chen, Chenggen Qian, David Oupicky, Minjie Sun
Journal: Theranostics (2018)

Stimuli-responsive polycations have been developed for improved nucleic acid transfection and enhanced therapeutic efficacy. The most reported mechanisms for controlled release of siRNA are based on polyelectrolyte exchange reactions in the cytoplasm and the degradation of polycations initiated by specific triggers. However, the degradation strategy has not always been sufficient due to unsatisfactory kinetics and binding of cationic fragments to siRNA, which limits the gene silencing effect. In this study, a new strategy that combines degradation and charge reversal is proposed. Methods: We prepared a polycation (CrossPPA) by crosslinking of phenylboronic acid (PBA)-grafted 1.8k PEI with alginate. It was compared with 25k PEI, 1.8k PEI and 1.8k PEI-PBA on siRNA encapsulation, ATP-responsive behavior and mechanism, cytotoxicity, cell uptake, siRNA transfection, in vivo biodistribution and in vivo anti-tumor efficacy. The in vitro and in vivo experiments were performed on 4T1 murine breast cancer cells and 4T1 tumor model separately. Results: The crosslinking strategy obviously improve the siRNA loading ability of 1.8k PEI. We validated that intracellular levels of ATP could trigger CrossPPA disassembly and charge reversal, which resulted in efficient and rapid siRNA release due to electrostatic repulsion. Besides, CrossPPA/siRNA showed strong cell uptake in 4T1 cells compared with 1.8k PEI/siRNA. Notably, the cytotoxicity of CrossPPA was pretty low, which was owing to its biodegradability. Furthermore, the crosslinked polyplexes significantly enhanced siRNA transfection and improved tumor accumulation. The high gene silencing ability of CrossPPA polyplex led to strong anti-tumor efficacy when using Bcl2-targeted siRNA. Conclusion: These results indicated that the ATP-triggered disassembly and charge reversal strategy provided a new way for developing stimuli-responsive siRNA carriers and showed potential for nucleic acid delivery in the treatment of cancer.
TCT-9 Coronary pressure and flow in patients with severe aortic stenosis and coronary artery disease undergoing TAVI: implications for clinical indices of coronary stenosis severity
Authors: Yousif Ahmad, Matthias Gotberg, Christopher Cook, James Howard, Iqbal Malik, Ghada Mikhail, Darrel Francis, Jamil Mayet, Justin Davies, Sayan Sen
Journal: Journal of the American College of Cardiology (2018)
Antibiotic use and overall survival in lung cancer patients receiving nivolumab.
Authors: Tien Phuc Do, Aparna Madhukeshwar Hegde, Cynthia R. Cherry, Chipman Robert Geoffrey Stroud, Nitika Sharma, Sulochana Devi Cherukuri, Mark Bowling, Paul R. Walker
Journal: Journal of Clinical Oncology (2018)

e15109 Background: Recent evidence indicates that the gut microbiome modulates immunotherapy responses in multiple tumor types. Some studies report antibiotics (ATB) may alter the microbiota composition and compromise the therapeutic response of immunotherapy in renal cell carcinoma and melanoma. Methods: We conducted an institutional retrospective review of patients with advanced lung cancer who started nivolumab between April 2015 and May 2017. Follow up cut off was December 31, 2017. Patients who received ATB 30 days before initiating nivolumab to 30 days after the last dose of nivolumab were identified. Kaplan-Meier analysis and Cox proportional hazard model were used to estimate overall survival (OS) and hazard ratios respectively. Results: Among 109 lung cancer patients who received nivolumab in the prespecified time frame, 87(79.8%) received ATB (ATB+), and 22(20.2%) did not (ATB-). Histological types were adenocarcinoma (44/109; 40.4%), squamous cell carcinoma (43/109; 39.5%), small cell (14/109; 12.8%), and other histology (8/109; 7.3%). Of the 87 patients in ATB+ group, 12(13.8%) received penicillins, 11(12.6%) quinolones, 7(8.1%) other antibiotics, and 57(65.5%) multiple antibiotics. The indications for antibiotic use included respiratory (43/87; 49.4%), urinary (9/87; 10.4%), gastrointestinal (4/87; 4.6%), multiple (24/87; 27.6%) and other infections (7/87; 8%). There was no significant difference in the incidence of grade 3-4 adverse events between the two groups (χ2= 0.025, p = 0.88). Survival estimates are as follows- Conclusions: Antibiotic use is prevalent among lung cancer patients treated with immunotherapy. The diminished overall survival in ATB+ group may be due to antibiotic-induced primary resistance to immunotherapy. Prospective trials focused on the minimization of antibiotic use by differentiating true infections from immune related adverse events are necessary. Group 1-year OS (%) Median OS (95% CI) (months) Log rank p = 0.0002 HR (95% CI) p- value ATB- 62.0 17.2 (8.8- 17.2) 0.29 (0.15- 0.58) 0.0004 ATB+ 24.3 5.4 (3.1- 7.7) - -
Concordance of mutations identified using circulating tumor DNA (ctDNA) compared to tissue based next generation sequencing (NGS) in gastrointestinal malignancies: A single institution experience.
Authors: Suneel Deepak Kamath, Aparna Kalyan, Timothy J. Taxter, Firas Wehbe, Sheetal Mehta Kircher, Halla Sayed Nimeiri, Mary Frances Mulcahy, Al Bowen Benson, Massimo Cristofanilli, Francis J. Giles
Journal: Journal of Clinical Oncology (2017)

e23023 Background: The role of the ctDNA in the management of solid organ malignancies is an area of active research. A potential application of this technology is for monitoring disease progression in patients who had sequencing of their tumor tissue at time of diagnosis. This approach relies on concordance between tumor tissue NGS and the ctDNA, which can vary due to biology and technology. Biologic variability can be due to tumor heterogeneity, ctDNA concentration fluctuations and genomic alterations in clonal non-malignant hematopoietic cells. Methods: We retrospectively evaluated 41 patients who had NGS with Foundation Medicine’s FM1 panel performed on tumor tissue from diagnosis and follow up ctDNA NGS using the Guardant 360 panel(G360). Only genes shared by both panels with the same level of gene coverage were evaluated. This eliminated several genes and alterations, particularly amplifications and splice site alterations. Results: Patient demographics are in Table 1. 148 alterations were identified by G360, of which 42 (28%) alterations were also seen on FM1 testing. When these alterations were restricted to KRAS, APC and TP53, the most common genes altered in GI cancers, 53 alterations were identified and 32 (60%) were also identified by FM1 testing. These results demonstrate that concordance between ctDNA and tissue NGS can be improved if restricted to driver mutations. This restriction eliminates potential passenger mutations acquired by subclones of the original tumor and controls for clonal hematopoiesis. Conclusions: It is difficult to base treatment decisions on the overall concordance seen here between ctDNA and tissue NGS. However, quantification of driver mutations using ctDNA may offer another monitoring tool for disease progression beyond tumor markers, which sometimes can be non-specific or absent.
Feasibility and safety of mass drug coadministration with azithromycin and ivermectin for the control of neglected tropical diseases: a single-arm intervention trial
Authors: Lucia Romani, Michael Marks, Oliver Sokana, Titus Nasi, Bakaai Kamoriki, Handan Wand, Margot J Whitfeld, Daniel Engelman, Anthony W Solomon, Andrew C Steer, John M Kaldor
Journal: The Lancet Global Health (2018)

Mass drug administration has made a major contribution to the public health control of several important neglected tropical diseases. For settings with more than one endemic disease, combined mass drug administration has potential practical advantages compared with separate programmes but needs confirmation of feasibility and safety. We undertook a study of mass drug administration in the Solomon Islands for trachoma and scabies control using ivermectin and azithromycin, key drugs in the control of neglected tropical diseases worldwide.
Leptomeningeal metastases after the effective first-generation EGFR TKI treatment in advanced non-small cell lung cancer.
Authors: Yong-Mei Liu, Ya-Lan Wu, Qian Zhao, Lei Deng, Yan Zhang, Xiaojuan Zhou, Yanying Li, Min Yu, Lin Zhou, Bingwen Zou, You Lu
Journal: Journal of Clinical Oncology (2018)

e21059 Background: Leptomeningeal metastasis (LM) has become increasingly common in non-small cell lung cancer (NSCLC) patients effectively treated with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), but data are incomplete about clinical features and treatment outcomes of LM in this population. Methods: We retrospectively evaluated 420 advanced NSCLC patients receiving the effective first-generation EGFR TKI treatment. We studied LM progression of those patients, and analyzed the incidence, time to progression, and treatment outcome. Results: Among 420 patients, 29 (6.9 %) developed LM. The incidence was 10.7% (21/197) in patients harboring L858R and 3.4% (7/203) in those harboring exon 19 deletions (P = 0.006). The median time to LM progression was 16.5 months (95% CI, 11.9-20.8). The median overall survival (OS) after LM diagnosis was 5.2 months (95% CI, 3.2-7.2). For subgroup analysis, better OS was observed in patients with performance status (PS) ≤2 (14.2 months vs. 2.3 months, P < 0.001), receiving anti-tumor treatments (6.0 months vs. 1.9 months, P < 0.001), or receiving whole brain radiotherapy (WBRT) (6.0 months vs. 3.9 months, P = 0.038). No statistical difference on median OS was found between patients switched to erlotinib or those who did not after LM (P = 0.941), or in the subset analysis of patients with stop/continue taking gefitinib (P = 0.330). Multivariate analysis indicated WBRT was a good prognostic factor (P = 0.048), whereas BSC (P = 0.033) and PS > 2 (P = 0.034) were poor prognostic factors. Conclusions: For advanced EGFR-mutated NSCLC patients receiving the effective first-generation EGFR TKI treatment, primary mutation of L858R might mark higher risk of LM compared with exon 19 deletions.
Gemcitabine plus nab-paclitaxel until progression or given sequentially with 5-fluorouracile plus irinotecan (FOLFIRI.3) for first-line treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC): A randomized phase II study (PRODIGE 37-FIRGEMAX).
Authors: Julien Taieb, Yves Rinaldi, Anne-Laure Pointet, Emilie Barbier, Faiza Khemissa, Alain Gratet, Laurent Miglianico, Hortense Laharie-Mineur, Karine Bouhier-Leporrier, FranÃ§ois Ghiringhelli, Anne Thirot Bidault, Patrick Texereau, Romain Coriat, Eric Terrebonne, Marie-Claude Gouttebel, David Malka, Come Lepage, Jean-Baptiste Bachet
Journal: Journal of Clinical Oncology (2018)

4107 Background: Chemotherapy is effective in mPDAC but new approaches are still needed to improve patients (pts) survival and quality of life. We have previously published successful results of a sequential treatment strategy of gemcitabine followed by an intensified FOLFIRI regimen1 with good efficacy and tolerability results. In the present study, we tested the same sequence with the new gemcitabine + nab-paclitaxel (G+A) first-line standard therapy2. Methods: We randomized chemotherapy-naive pts with proven mPDAC, bilirubin levels ≤1.5 ULN and performance status (PS) 0-2 to receive in alternance G+A (MPACT regimen)2 (2 months [mo]) and FOLFIRI.3 (FIRGEM regimen)1 (2 mo; arm A), or G+A alone (arm B). The primary objective was to increase the 6-mo progression-free survival (PFS) rate from 40% (H0) to 60% (H1; binomial exact method; required 124 pts). Analyses were done in preplanned modified intent-to-treat (mITT, pts who received at least one dose of treatment) and per-protocol (PP, pts reaching the 2 mo treatment switch) populations. Results: Between Nov 2015 and Nov 2016, 127 pts were enrolled. Mean age was 64 years (range: 38-76), PS was 0/1/2 in 37/51/12%, no major imbalance for baseline characteristics was noted between arms. Main grade 3-4 toxicities per pt (%) were (arms A/B): diarrhea (13/2), nausea/vomiting (9/2), neutropenia (42/31), febrile neutropenia (2/0), skin toxicity (5/14), and peripheral neuropathy (13/20). No toxic deaths occurred. Best objective response rates (mITT) were A: 40% (95%CI, 28-54) and B: 25% (95%CI, 15-38). 6-mo PFS rates were A: 45% and B: 23% in mITT (n = 122; HR: 0.70; 95%CI, 0.48-1.03) and A: 60% and B: 30% in PP (n = 90; HR: 0.57; 95%CI, 0.36-0.90). Median OS (PP) was A: 15.8 and B: 12.4 mo (HR: 0.66. 95%CI, 0.37-1.16). Conclusions: The FIRGEMAX strategy with G+A followed by FOLFIRI.3 every 2 mo, appears to be feasible and effective, with manageable toxicities and decreased neurotoxicity, in patients with mPDAC able to reach > 2mo of treatment for their disease. 1-Trouilloud EJC 2014 2-Von Hoff NEJM 2013 Clinical trial information: NCT02827201.
Experience of gynecologic oncologists regarding endometrial cancer after endometrial ablation.
Authors: Hui Chen, Allison M. Saiz, Arthur M. McCausland, Vance M. McCausland, Gary S. Leiserowitz
Journal: Journal of Clinical Oncology (2018)

e17566 Background: Conflicting evidence exists regarding endometrial cancer (EC) after endometrial ablation. Some data describe decreased rates of EC following ablation. While other studies show post-ablation intrauterine scarring can delay diagnosis of EC. The goal of this study is to understand the experience of gynecologic oncologists in treating patients who develop EC after endometrial ablation. Methods: A 17-question survey was sent out to Society of Gynecologic Oncology (SGO) members from Full, Associate, Candidate and Fellow-in-Training membership categories. Responses were collected from November 2017 to January 2018. The questionnaire asked SGO members about their experience in caring for women who developed post-ablation EC. UC Davis IRB exemption status was obtained. Results: 138 of the 1299 gynecologic oncology SGO members responded, with a 10.6% response rate. 116 out of 138 respondents (84.1%) completed the entire survey. Most (70.4%) reported that endometrial ablations were performed “sometimes” or “frequently” in their communities. 93.8% had been referred symptomatic post-ablation patients for further evaluation. 18.5% reported managing over 20 post-ablation patients in their practice. Most respondents found that post-ablation intrauterine scarring made accurate evaluation of the endometrial cavity “moderately” (36%) or “extremely” (48%) difficult. 52.5% reported that a majority of symptomatic post-ablation patients require hysterectomy to make an accurate diagnosis. While 74.4% of respondents thought that at least some patients had a delay in diagnosis of EC due to post-ablation intrauterine scarring, 21.4% believed that the majority of patients had a delay in diagnosis. Finally, 79.5% reported that they do not believe that there is a role for prophylactic endometrial ablation to decrease the risk of endometrial cancer. Conclusions: This study is the first to describe the current views of gynecologic oncologists in treating post-ablation EC. Most believe that post-ablation intrauterine scarring can make diagnosis of EC more difficult and delayed. Although further research is needed, this study helps to understand some of the long term consequences of endometrial ablation.
Complaints about primary care services increased by 4.5% last year
Authors: Declan C Murphy
Journal: BMJ (2018)

There was little change in the overall number of written complaints about primary care, hospitals, and community health services in 2017-18 in England, although dissatisfaction with general practice increased, figures from NHS Digital show.1

“If patients are not satisfied with the service they received, then it is appropriate they make their concerns known,” said Helen Stokes-Lampard, chair of the Royal College …
Abstract 15651: Inhibiting Immune Rejection and Enhancing Ischemic Hindlimb Repair by B2M Knockdown in Allogeneic Human MSC Using CRISPR/Cas9 Technology
Authors: Yangxin Li, Yuqing Zhang, Yanli Wang, Lianbo Shao, Yu Zhang, Juanjuan Wang, Bao Zhu, Chaoshan Han, Lulu Zhang, Xiangbin Pan, Bin Liu, Chun Liang, Yong-jian Geng, Xi-yong Yu
Journal: Circulation (2017)

Introduction: Allogeneic human umbilical mesenchymal stem cells (alloMSC) are convenient cell source for stem cell based therapy. However, immune rejection is a major obstacle for clinical applicat...