tbuckley/cabot-search huggingface dataset:
Epidermal growth factor receptor (<i>EGFR</i>) T790M mutation identified in plasma indicates failure sites and predicts clinical prognosis in non‐small cell lung cancer progression during first‐generation tyrosine kinase inhibitor therapy: a prospective observational study
Authors: Shirong Zhang, Lucheng Zhu, Bing Xia, Enguo Chen, Qiong Zhao, Xiaochen Zhang, Xueqin Chen, Xufeng Chen, Shenglin Ma
Journal: Cancer Communications (2018)

Abstract Introduction Plasma circulating tumor DNA (ctDNA) is an ideal approach to detecting the epidermal growth factor receptor ( EGFR ) T790M mutation, which is a major mechanism of resistance to first‐generation EGFR‐tyrosine kinase inhibitor (TKI) therapy. The present study aimed to explore the association of ctDNA‐identified T790M mutation with disease failure sites and clinical prognosis in non‐small cell lung cancer (NSCLC) patients. Methods Patients who progressed on first‐generation TKIs were categorized into failure site groups of chest limited (CF), brain limited (BF) and other (OF). Amplification refractory mutation system (ARMS) and droplet digital PCR (ddPCR) were used to identify the T790M mutation in ctDNA. Prognosis was analyzed with Kaplan–Meier methods. Results Overall concordance between the two methods was 78.3%. According to both ARMS and ddPCR, patients in the OF group had a significantly higher rate of T790M mutation than did patients in the BF and CF groups ( P &lt; 0.001), and a significantly higher T790M mutation rate was also observed in OF‐group patients than in those in the CF and BF groups ( P &lt; 0.001). AZD9291 was found to be an excellent treatment option and yielded the longest survival for T790M+ patients in all groups who had progressed on EGFR‐TKIs; for other treatments, the prognosis of T790M− patient subgroups varied. Conclusions The present study demonstrates that T790M mutation in ctDNA is associated with failure sites for NSCLC patients after EGFR‐TKI therapy and indicates that both failure site and T790M mutational status greatly influence treatment selection and prognosis.
Survivorship Care: What does it take? The experience at Sylvester Comprehensive Cancer Center (SCCC), University of Miami Health Systerm (UHEALTH).
Authors: Adrienne Marie Vazquez, Jessica MacIntyre
Journal: Journal of Clinical Oncology (2018)

82 Background: SCCC faces obstacles similar to programs challenged with the development of a cancer survivorship program. Informatics is one of the major limiting resources in continuing to improve and move the survivorship program forward at a large academic institution. An electronic order referral system is pivotal for success. Sylvester at UHEALTH has 7 campuses spread out over 60 miles in a heavily populated area of South Florida. UHEALTH developed a workflow that allowed providers to enter order referrals for identified patients. Methods: At UHEALTH, within EPIC, patients (PTS) have order referrals placed for their needs. The scheduling department contacts PTS to arrange their appointments. With the assistance of our EPIC team and oncology scheduling service, we developed a survivorship order referral. Its purpose was to streamline the process from identification of appropriate PTS, entering order referral and then scheduling PTS into open templates throughout the institution. This order referral is a useful tool within the electronic health record that assists in tracking and scheduling PTS for the survivorship clinic visit type created. The centralized survivorship clinic established itself at the same time the order referral pilot started. Results: UHEALTH piloted the order referral at main campus and 1 of our 6 satellite locations. The pilot showed that from the period of January 2017 - June 2017, providers referred 142 PTS to a survivorship clinic. PTS had the right to refuse the Survivorship visit, but it was important to offer the clinic and explain its purpose. After a successful 6-month period, we expanded the order referral to include three other satellite locations. Conclusions: It is our recommendation to other institutions who use EPIC to create an ambulatory order referral process for referring and scheduling identified PTS to a survivorship clinic. An EPIC order referral increases PTS referrals to survivorship. Institution specific analytics are tracked through order referrals placed and survivorship visit type appointments made. Further research is necessary to understand reasons for PTS refusing or cancelling survivorship appointments.
Longer follow-up on clinical outcomes of weekly paclitaxel with trastuzumab and pertuzumab in patients with HER2 overexpressing metastatic breast cancer.
Authors: Rui Wang, Lillian Mary Smyth, Neil M. Iyengar, Shanu Modi, Sarat Chandarlapaty, Sujata Patil, Larry Norton, Jose Baselga, Clifford A. Hudis, Chau T. Dang
Journal: Journal of Clinical Oncology (2018)

e13005 Background: Favorable progression-free survival (PFS) and overall survival (OS) results were previously reported on a phase II trial of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) treated with weekly paclitaxel in combination with trastuzumab and pertuzumab in the first- and second-line setting with a median follow-up of 33 months. Here, we report updated PFS and OS results with over 2 years of additional follow-up. Methods: In this phase II study, adult patients with HER2-positive MBC received 0 or 1 prior therapy received intravenous paclitaxel (80 mg/m2 weekly) with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks), administered in 21-day cycles. Primary endpoint was 6-month PFS, and secondary endpoints included median PFS and OS. Results: From January 2011 to December 2013, 69 patients were enrolled: 51 (74 %) and 18 (26 %) treated in first- and second-line metastatic settings, respectively. As of August 21, 2017, the median follow-up was 59 months (range 20-75 months; 67 patients were evaluable for efficacy). The 6-month PFS was 0.86 (95% CI 0.76-0.93). The median PFS was 24.2 months (95 % CI 17-35) for overall population; it was 25.7 months (95 % CI 17.0-NR) and 20.1 months (95 % CI 8.5-33.0) for patients with 0 and 1 prior treatment, respectively. The median OS was not reached for overall group; it was not reached and 39.7 months (95 % CI 32.9-66.7) for patients with 0 and 1 prior treatment, respectively. Treatment was well tolerated with no additional safety concerns. Conclusions: With a longer follow-up of almost 5 years, combination of weekly paclitaxel, trastuzumab, and pertuzumab remains effective with a favorable median PFS and median OS has not been reached. Clinical trial information: NCT01276041.
Phase <scp>II</scp> Study of <scp>ABT</scp>‐122, a Tumor Necrosis Factor– and Interleukin‐17A–Targeted Dual Variable Domain Immunoglobulin, in Patients With Psoriatic Arthritis With an Inadequate Response to Methotrexate
Authors: Philip J. Mease, Mark C. Genovese, Michael E. Weinblatt, Paul M. Peloso, Kun Chen, Ahmed A. Othman, Yihan Li, Heikki T. Mansikka, Amit Khatri, Neil Wishart, John Liu
Journal: Arthritis & Rheumatology (2018)

Objective To investigate the safety and efficacy of ABT ‐122, a tumor necrosis factor ( TNF )– and interleukin‐17A ( IL ‐17A)–targeted dual variable domain immunoglobulin, in patients with active psoriatic arthritis (PsA) who have experienced an inadequate response to methotrexate. Methods Patients (n = 240) were randomized to receive ABT ‐122 (120 or 240 mg every week), adalimumab (40 mg every other week), or placebo in a 12‐week double‐blind, parallel‐group study. The primary efficacy end point was the proportion of patients achieving ≥20% improvement in disease activity according to the American College of Rheumatology response criteria ( ACR 20) at week 12. Secondary and exploratory 12‐week end points included 50% improvement ( ACR 50) and 70% improvement ( ACR 70) response rates, and proportion of patients meeting the Psoriasis Area and Severity Index ( PASI ) response criteria for ≥75% ( PASI 75) and ≥90% ( PASI 90) improvement in skin scores among those with ≥3% of their body surface area affected by psoriasis. Results In both ABT ‐122 dose groups, ACR 20 response rates at week 12 (64.8–75.3%) were superior to that in patients receiving placebo (25.0%) ( P &lt; 0.001) but similar to that in patients receiving adalimumab (68.1%). ACR 50 and ACR 70 response rates were also superior in both ABT ‐122 dose groups (36.6–53.4% and 22.5–31.5%, respectively) compared to the placebo group (12.5% and 4.2%, respectively) ( P &lt; 0.05). Among eligible patients in the placebo, adalimumab, ABT ‐122 120 mg every week, and ABT ‐122 240 mg every week treatment groups, PASI 75 responses were achieved in 27.3%, 57.6%, 74.4%, and 77.6% of patients, respectively, whereas PASI 90 responses were achieved in 18.2%, 45.5%, 48.8%, and 46.9% of patients, respectively. Frequencies of treatment‐emergent adverse events, including infections, were similar across all treatment groups, causing no discontinuations. No serious infections or systemic hypersensitivity reactions were reported with ABT ‐122. Conclusion Dual neutralization of TNF and IL ‐17A with ABT ‐122 had efficacy and safety that was similar to, and not broadly differentiated from, that of adalimumab over a 12‐week treatment course in patients with PsA.
Genetic Risk for Subsequent Neoplasms Among Long-Term Survivors of Childhood Cancer
Authors: Zhaoming Wang, Carmen L. Wilson, John Easton, Andrew Thrasher, Heather Mulder, Qi Liu, Dale J. Hedges, Shuoguo Wang, Michael C. Rusch, Michael N. Edmonson, Shawn Levy, Jennifer Q. Lanctot, Eric Caron, Kyla Shelton, Kelsey Currie, Matthew Lear, Aman Patel, Celeste Rosencrance, Ying Shao, Bhavin Vadodaria, Donald Yergeau, Yadav Sapkota, Russell J. Brooke, Wonjong Moon, Evadnie Rampersaud, Xiaotu Ma, Ti-Cheng Chang, Stephen V. Rice, Cynthia Pepper, Xin Zhou, Xiang Chen, Wenan Chen, Angela Jones, Braden Boone, Matthew J. Ehrhardt, Matthew J. Krasin, Rebecca M. Howell, Nicholas S. Phillips, Courtney Lewis, Deokumar Srivastava, Ching-Hon Pui, Chimene A. Kesserwan, Gang Wu, Kim E. Nichols, James R. Downing, Melissa M. Hudson, Yutaka Yasui, Leslie L. Robison, Jinghui Zhang
Journal: Journal of Clinical Oncology (2018)

Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were ≥ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.
Beclin-1-Dependent Autophagy Protects the Heart During Sepsis
Authors: Yuxiao Sun, Xiao Yao, Qing-Jun Zhang, Min Zhu, Zhi-Ping Liu, Bo Ci, Yang Xie, Deborah Carlson, Beverly A. Rothermel, Yuxiang Sun, Beth Levine, Joseph A. Hill, Steven E. Wolf, Joseph P. Minei, Qun S. Zang
Journal: Circulation (2018)

Cardiac dysfunction is a major component of sepsis-induced multiorgan failure in critical care units. Changes in cardiac autophagy and its role during sepsis pathogenesis have not been clearly defined. Targeted autophagy-based therapeutic approaches for sepsis are not yet developed.
Epinephrine and short-term survival in cardiogenic shock: an individual data meta-analysis of 2583 patients
Authors: Valentine Léopold, Etienne Gayat, Romain Pirracchio, Jindrich Spinar, Jiri Parenica, Tuukka Tarvasmäki, Johan Lassus, Veli-Pekka Harjola, Sébastien Champion, Faiez Zannad, Serafina Valente, Philip Urban, Horng-Ruey Chua, Rinaldo Bellomo, Batric Popovic, Dagmar M. Ouweneel, José P. S. Henriques, Gregor Simonis, Bruno Lévy, Antoine Kimmoun, Philippe Gaudard, Mir Babar Basir, Andrej Markota, Christoph Adler, Hannes Reuter, Alexandre Mebazaa, Tahar Chouihed
Journal: Intensive Care Medicine (2018)
Development of a digital patient navigation application: Preliminary results from patient interviews.
Authors: Thomas William LeBlanc, Kris Herring, Jack Chilcott, Katherine Bletcher, Miya Osaka, Hugo Manassei, Trudy Pendergraft, Cheyenne Corbett, Yousuf Zafar, Adam Higgins, Steven R. Patierno
Journal: Journal of Clinical Oncology (2018)

161 Background: People living with cancer face challenges too numerous to attend to during brief clinic visits, and thus may benefit from additional help with supportive care needs. While patient navigators offer promise, they are a limited resource. Digital navigation offers a scalable solution, to extend navigators’ reach and connect patients with existing resources, thereby enhancing our ability to address unmet needs. Methods: Utilizing a “design thinking” approach, we developed and tested a digital navigation platform to enhance utilization of support resources in the Duke Cancer Institute (DCI). The alpha version of the application (app) was based upon insights gleaned from interactions with patients, caregivers, advisory board members, and staff. It was then tested among adult patients with advanced cancer at the DCI. Subjects participated in qualitative interviews with design/content experts, to elicit supportive care needs and gauge interest in utilizing the app to improve their care experiences. Detailed notes were taken, and emerging themes compiled. Results: We enrolled 10 patients and caregivers. Subjects reported feeling overwhelmed by information, feeling that “they don’t know where to start when looking for support.” They also expressed uncertainty about what questions to ask, and said they are not always comfortable asking for help. All struggled to define “supportive care;” only one knew it refers to a set of services. Subjects felt a digital navigation app would enable them to explore and access services as needed, to help them “feel less alone,” and to know “someone or something was there for them.” They expressed dislike for being asked lots of questions, wanting to explore options on their own instead of being led somewhere. Digital navigation has the promise to increase their sense of control, with one subject noting: “I like to know what my options are and decide for myself…people try to assume they know what you need all the time.” Conclusions: Digital supportive care navigation may be an effective, scalable, and cost-efficient intervention to support patients and caregivers, and ultimately improve outcomes. Further refinement and testing of this approach is needed.
Comparative analysis of multigene assays (MGA) effects on chemotherapy (CT) de-escalation for women with N0, ER+ early stage breast cancer (ESBC).
Authors: Lou Hochheiser, John C. Hornberger, Michelle Turner, Gary H. Lyman
Journal: Journal of Clinical Oncology (2018)

e12519 Background: Therapy de-escalation aims to optimize care with less treatment. Available MGAs aid decisions on CT use for women with N0, ER+ ESBC. Comparative analysis of effects on CT de-escalation has yet to be done on 4 common MGAs: EndoPredict (EP), MammaPrint (MMP), Oncotype DX (ODX), and Prosigna (ROR). Methods: Effects of 4 MGAs on outcomes and costs in N0, ER+ ESBC were summarized using a well-validated analytical framework that adheres to joint ISPOR-SMDM Task Force guidelines for Modeling Good Research Practices. Studies assessing MGA effects on CT use were extracted and summarized using meta-analysis regression to adjust for study differences by study year, academic setting, country, tumor size, and grade. The effect of CT by ODX risk group was based on Paik et al (2006), MINDACT for MMP, and EBCTCG meta-analysis for EP and ROR. Costs (2018 USD) were based on a 2M-member US health plan over 10 y and included CT drugs/administration, supportive care, CT-related ED visits and hospitalizations (ED+H), 2° cancer incidence, MGA testing, and distant recurrences (DR), using published US payer sources. Results: 38 studies met prespecified screening criteria; 23 reported change in CT use by risk group. Studies included 4,364 women: 3% EP, 21% MMP, 63% ODX, and 13% ROR. CT use after covariate adjustment is shown in Table. Based on incidence of 31 per 100,000 women with N0, ER+ ESBC over 10 y (n = 5,574), projected outcomes and costs are shown in Table. Conclusions: Use of MGAs offers precision medicine that can save women, individually and collectively, from unnecessary chemotherapy and can support both de-escalation and improved health outcomes. MGAs have differential effects on these individual and societal objectives. No test EP MMP ODX ROR CT use, % 51 56 64 31 49 DR over 10 y, n 271 259 269 241 273 ED+H over 10 y, n 2260 2274 2435 1630 2113 10-y total cost of care $72.9M $95.1M $102.2M $67.5M $88.0M
Feasibility and fidelity of a reiki intervention for cancer patients by family caregivers.
Authors: Yea-Jyh Chen, Amy Petrinec, Rosanne M. Radziewicz
Journal: Journal of Clinical Oncology (2018)

87 Background: Reiki is a complementary therapy that has been reported to decrease symptoms of stress and promote relaxation. Standards for administrating Reiki have not been established. Additionally, patients with advanced cancer and their family caregivers (FCGs) encounter challenges during the illness experience that preclude them from participating in stress reducing therapies offered outside the home. The purpose of this study was to evaluate the feasibility and fidelity of an “at-home” reiki intervention performed by the FCG of patients with cancer. Methods: Twelve cancer patients and their FCGs were recruited from oncology outpatient facilities in the Greater Cleveland area. A certified Reiki educator provided two 4-hour courses for the FCGs to learn the basics and practice. To develop and promote intervention fidelity, the FCG maintained a daily diary recording frequency, interval, time of day, and position of Reiki practice. The Reiki educator called the FCG weekly to monitor usage, protocol adherence (60-minutues daily practice for three weeks) and answer questions. Satisfaction with the intervention was measured on completion of the study. Results: Compliance to the study protocol was high in this sample. The majority of day-to-day practice episodes (110/126; 87%) were delivered and completed by FCGs over a three week period. Diary entries indicated FCGs were prone to practice Reiki 45 minutes (72%) per day, once daily (79-93%), in a lying position (82%) and in the evening (61%). Deterioration in a patients’ health was most frequently cited for lack of adherence to daily Reiki practice. A few patients and FCGs reported practice time duration as a barrier. Both patients and FCGs reported a high satisfaction with the Reiki intervention. Follow-up phone calls by a Reiki educator were described as supportive by the FCGs. Conclusions: At-home Reiki was reported as feasible with high compliance and satisfaction to the study protocol. Findings will inform protocol refinement to address the limitations of Reiki practice barriers. This study provides initial support for the administration of an “at home” Reiki intervention in a larger sample to further validate fidelity criteria and treatment effects.
Impact of HER2 mutation status on personalized molecular targeted therapy in advanced breast cancers.
Authors: Zongbi Yi, Fei Ma, Yanfang Guan, Lianpeng Chang, Wenna Wang, Xiuwen Guan, Binliang Liu, Lixi Li, Chunxiao Li, Haili Qian, Venkataprasanth P. Reddy, Binghe Xu
Journal: Journal of Clinical Oncology (2018)

1039 Background: Previous studies have indicated that the mechanism of HER2 activation include not only HER2 protein overexpression and gene amplification but also HER2 somatic mutations. The impact of HER2 mutations may be different in HER2-positive (amplified) and HER2-negative (non-amplified) breast cancers. Methods: We used next generation sequencing to detect HER2 mutations in circulating tumor DNA and analyzed the relationship between these mutations and the efficacy of anti-HER2 therapies. Results: Twenty three HER2 somatic point mutations were identified in 16 of the 120 patients (13.3%) studied. HER2 amplified patients with HER2 point mutations have shorter progression-free survival (PFS) compared to non-HER2 mutations, the median PFS was 5.0 months versus 8.4 months. There were three cases identified where HER2 mutation status impacted the selection of personalized anti-HER2 therapies. Case 1 was a HER2 positive patient with an ERBB2 mutation (c.1900T>C/p.C634R) who was resistant to trastuzumab and lapatinib but sensitive to afatinib. Case 2 was a HER2-negative patient with an ERBB2 mutation (p.L755_T759del) was response to afatinib and trastuzumab. Case 3 was a HER2-negative breast cancer patient with two detected mutations in ERBB2 (p.S310F and p.D769Y mutations) who benefited from lapatinib combined with endocrine therapies. Conclusions: Our data suggest that HER2 mutation-positive patients might be resistant to trastuzumab but sensitive to irreversible kinase inhibitors of HER2, whereas HER2-negative patients with HER2 somatic mutations may still be sensitive to anti-HER2 therapies.