tbuckley/cabot-search huggingface dataset:
Actionable secondary driver mutations in BRAFWT and NRASWT metastatic cutaneous melanoma using the Caris Molecular Intelligence profiling.
Authors: Krisztian Homicsko, Marco Mina, Kenneth Russell, Giovanni Ciriello, Olivier Michielin, Andreas Voss
Journal: Journal of Clinical Oncology (2016)

e21021 Background: Malignant melanoma is a genetically diverse disease. Predominantly, hotspot mutations targeting BRAF (V600) or NRAS drive melanoma development and are associated with clinical benefit. Nonetheless, approximately 25-30% of melanomas do not present these hallmark events. This subgroup could benefit from in depth molecular analyses to inform the design of personalized therapeutic protocols. Here, we leveraged the largest collection to date (n = 1929) of mutational and protein profiles of metastatic melanoma patients, the Caris Molecular IntelligenceTM database, to investigate molecular and actionable drivers. This database is purposefully skewed towards BRAF and NRAS wild-type tumors, making it particularly suitable for our analysis. Methods: We analyzed immunohistochemistry (IHC) and next generation sequencing (NGS) data available for 906 patient samples for which BRAF and NRAS status was available from Caris. We then defined three main melanoma subtypes characterized by mutations in BRAFV600 (n = 253), NRAS (n = 257, 8 also present BRAFV600), and wild-type for both (2xWT, n = 404). Results: Within the 2xWT group, we could identify an enrichment for multiple oncogenic mutations impinging on MAPK signaling and including therapeutically actionable receptor tyrosine kinases. In details we found that 2xWT tumors are enriched for non-V600 BRAF mutations (13% of the 2xWT), KIT (9%), GNAQ (3%), GNA11 (5%), APC (7%), and MET (6%) which also shows elevated protein levels by IHC in 16% of the cases. Interestingly, these alterations are largely mutually exclusive with each other, strengthening the hypothesis of them acting as drivers. Different mutation subtypes show associations with divergent protein and mutation changes. Conclusions: Melanomapatients wild-type for BRAFV600 and NRAS hotspot mutations represent today a clinical challenge. This project oversampled for these tumors representing a particularly useful dataset to investigate secondary melanoma drivers. By analyzing these molecular profiles, we identified multiple oncogenic events significantly associated with 2xWT tumors, shedding new light on the genetic bases of this disease.
Unmet supportive care needs of older adults with advanced cancer.
Authors: Brandon Temel, Margaret Ruddy, Emily Olson, Samantha M.C. Moran, Charn-Xin Fuh, Ardeshir Hashmi, Erin Scott, Vicki Jackson, Areej El-Jawahri, Jennifer S. Temel, Ryan David Nipp
Journal: Journal of Clinical Oncology (2017)

10040 Background: Cancer disproportionately affects older adults, yet research defining the supportive care needs of these patients is lacking. We sought to examine associations between geriatric impairments, quality of life (QOL), and physical and psychological symptom burden in older adults with newly diagnosed incurable gastrointestinal (GI) cancer. Methods: We prospectively enrolled patients age ≥70 within 8 weeks of diagnosis of incurable GI cancer at Massachusetts General Hospital from 10/2015-11/2016. We used surveys to assess geriatric impairments (Vulnerable Elders Survey-13 [range 0-10, scores ≥3 identify patients with impairments), QOL (EORTC QLQ-C30 [range 0-100, higher scores indicate better QOL]), physical symptoms (Edmonton Symptom Assessment System [range 0-10, higher scores indicate greater symptom burden]) and psychological symptoms (Geriatric Depression Scale, [range 0-15, higher scores indicate greater depression symptoms]). We used descriptive statistics to determine differences in patient characteristics by the presence or absence of geriatric impairments. We used linear regression adjusted for age, employment, cancer type, and comorbidity to examine associations between geriatric impairments, QOL, and physical and psychological symptom burden. Results: We enrolled 50 of 58 (86%) patients approached (mean age = 78.7; 52% with pancreatic cancer). Nearly half (46%) screened positive for geriatric impairments; these patients were older (81.7 vs 76.1, p &lt; .01) and had more comorbid conditions (2.4 vs 1.2, p = .01). On linear regression, patients with geriatric impairments reported worse QOL across all domains (General QOL: B = -28.3, p &lt; .01; Physical: B = -36.8, p &lt; .01; Role: B = -36.8, p &lt; .01; Emotional: B = -30.1, p &lt; .01; Cognitive: B = -17.8, p = .03; Social: B = -39.7, p &lt; .01), higher depression scores (B = 5.1, p &lt; .01) and worse fatigue (B = 4.6, p &lt; .01), drowsiness (B = 4.0, p &lt; .01), appetite (B = 3.8, p &lt; .01), and pain (B = 2.7, p = .02). Conclusions: Older adults with advanced cancer experience considerable unmet supportive care needs, particularly those with geriatric impairments. Future research is needed to assess older patients for geriatric impairments and address their unique palliative and supportive care needs.
Targeting<i>BRAF</i>Mutations in High-Grade Neuroendocrine Carcinoma of the Colon
Authors: Jarred Burkart, Dwight Owen, Manisha H. Shah, Sherif R. Z. Abdel-Misih, Sameek Roychowdhury, Robert Wesolowski, Sigurdis Haraldsdottir, Julie W. Reeser, Eric Samorodnitsky, Amy Smith, Bhavana Konda
Journal: Journal of the National Comprehensive Cancer Network (2018)

Mutations in the RAS/RAF/MEK/ERK pathway leading to constitutive activation and uncontrolled cellular growth have been identified in various human malignancies, making this pathway a target for potential therapeutics. The activating BRAFV600E mutation is one well-characterized oncogenic mutation that has been described and targeted with clinical success in various malignancies, including melanoma and hairy cell leukemia. Although BRAF-directed treatments have yielded clinical benefit in a subset of tumor types, such as melanoma, thyroid cancer, and lung cancer, BRAF inhibition fails to confer a clinical benefit in colon cancer. Identification of patients for whom BRAF inhibition may produce clinically meaningful outcomes is imperative. The incidence of BRAF mutations in neuroendocrine carcinoma (NEC) is estimated to be 5% to 10%. A recent case series demonstrated benefit in targeting the BRAFV600E mutation in metastatic high-grade rectal NECs. Combination BRAF and MEK inhibition is known to yield improved outcomes compared with BRAF inhibition alone in melanoma. This report presents 2 patients with high-grade colorectal NECs who had different responses to treatment with combined BRAF/MEK inhibition after experiencing disease progression through first-line platinum-based chemotherapy. One patient experienced an excellent initial response to therapy before ultimately experiencing progression, and in the other patient initially had stable disease before eventually experiencing progression. These cases highlight the complicated role BRAF mutations play in gastrointestinal NECs, and the need for further research to identify not only patients who may benefit from BRAF-directed therapies but also strategies to avoid development of resistance.
Overall survival (OS) and stem cell transplant (SCT) in patients with FLT3 mutations treated with CPX-351 versus 7+3: Subgroup analysis of a phase III study of older adults with newly diagnosed, high-risk acute myeloid leukemia (AML).
Authors: Bruno C. Medeiros, Donna Hogge, Laura F. Newell, Dale L. Bixby, Scott R. Solomon, Stephen Anthony Strickland, Tara L. Lin, Harry Paul Erba, Bayard L. Powell, Nikolai Alexandrovich Podoltsev, Robert Ryan, Michael Chiarella, Arthur Louie, Jeffrey E. Lancet
Journal: Journal of Clinical Oncology (2017)

e18507 Background: FLT3+ AML patients (pts; 20%-30% of AML pts) often have rapid post-induction relapse, highlighting the need for therapies that improve the bridge to SCT. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). CPX-351 demonstrated efficacy versus 7+3 in a randomized, open-label, controlled phase III trial in pts aged 60-75 years with newly diagnosed, high-risk AML; our analysis investigated outcomes in the subset of FLT3+ pts. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m 2 [C 100 mg/m 2 + D 44 mg/m 2 ] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m 2 /day x 7 days [2nd induction: x 5 days] + D 60 mg/m 2 on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 consolidation cycles. Results: Of the pts who had FLT3 mutations assessed and received study treatment, 22/138 (16%) pts in the CPX-351 arm and 20/136 (15%) pts in the 7+3 arm had baseline FLT3 mutations. AML subtypes in FLT3+ pts were: tAML (19%); AML after MDS with (38%) or without (10%) prior hypomethylating agents; AML after CMMoL (12%); and de novo AML with MDS karyotype (21%). In FLT3+ pts, median OS was longer with CPX-351 (10.25 mo) versus 7+3 (4.55 mo; HR = 0.57 [95% CI: 0.24, 1.33]; P= 0.093) and the rate of CR+CRi was higher (68% vs 25%). A greater number of FLT3+ pts treated with CPX-351 were able to undergo SCT (n = 10/22 [45%]; 4 pts were alive as of this analysis, after a median post-SCT follow up of 692 days [range: 96-769]) compared with 7+3 (n = 2/20 [10%]; neither pt still alive). The on-study safety profile of CPX-351 in FLT3+ pts was comparable to 7+3 and consistent with the overall study population. Serious adverse events were experienced by 7 (32%) FLT3+ pts in the CPX-351 arm and 10 (50%) in the 7+3 arm. Conclusions: CPX-351 demonstrated numerical improvement in median OS in older pts with newly diagnosed, FLT3+ high-risk AML and allowed more pts to undergo SCT. The analysis was limited by small number of pts. Clinical trial information: NCT01696084.
Global Cancer Institute (GCI) multi-disciplinary tumor boards (MTBs) as an educational tool to improve guideline-based cancer clinical practice in low- and middle-income countries (LMICs).
Authors: Jessica St. Louis, Alexandra Bukowski, Rossana Esther Ruiz Mendoza, Carmen Herrero Vincent, Abraham Hernandez Blanquisett, Alphonse G. Taghian, Vered Stearns, Roisin Connolly, Ben Ho Park, Carol Marquez, Kathleen M. Schmeler, Anuja Jhingran, Marcela G. del Carmen, Thomas Christopher Randall, Don S. Dizon, Kathrin Strasser-Weippl, Paul E. Goss
Journal: Journal of Clinical Oncology (2016)

e18007 Background: GCI multi-disciplinary tumor boards (MTBs) are live global telemedicine discussions of patient-based clinical scenarios between oncologists in LMICs and expert oncology specialists in the United States (US) and Western Europe. In the US MTBs are routine and have been shown to improve patient outcomes and patient and family quality of life. GCI launched MTBs in 2012 with a goal of improving cancer patient care in underserved populations worldwide, and also to foster communication and collaboration between oncologists in LMICs and the US/Europe. Methods: During our MTBs oncologists from LMICs present patient scenarios for discussion of optimal anti-cancer clinical management to a panel of community/tertiary care expert oncologists from our global network. During a MTB, three cancer centers/oncologists present challenging patient scenarios, from a LMIC hospital. The patient scenarios are presented in English using a standard PowerPoint template. After presentation of a patient scenario, guideline - or clinical trial-based discussions ensue. Both optimal and best locally available clinical care in low-resource settings are discussed. For educational purposes our MTBs and the associated YouTube recordings of the discussions are archived, and can subsequently be viewed by practicing oncologists/trainees worldwide. References for international guidelines, published and ongoing clinical trials, and other educational resources are also provided to attendees. Results: Since its initiation in 2012, our MTB program has engaged a growing network of hundreds of doctors in 22 countries (Table 1). Conclusions: GCI MTBs are a well-liked educational and networking tool for oncologists in LMICs to improve their clinical practice and research collaborations. GCI continues to expand its MTBs to Latin America, Europe, and Asia. GCI is currently surveying doctors in our network before and after MTBs to measure shifts in clinical practice or decision-making over time. GCI MTB engagement. Year # of Hospitals Engaged # of Doctors Engaged # of Countries Engaged 2012 1 5 1 2013 7 35 4 2014 10 50 6 2015 17 242 9 2016 26 300 22
TCT-206 Hybrid Coronary Revascularization versus Coronary Artery Bypass Graft Surgery in Patients with Multivessel Coronary Artery Disease: A Meta-Analysis
Authors: Ziad SayedAhmad, Fahed Darmoch, Yasser Al-khadra, Mohamad Soud, Homam Moussa Pacha, Amr Idris, Amir Laktineh, Anwar Zaitoun, Amir Kaki, M Chadi Alraies
Journal: Journal of the American College of Cardiology (2018)
Implementation of a telechemotherapy center in the Peruvian jungle to improve patients' quality of life.
Authors: Tatiana Vidaurre, Fernando Valencia, Cindy Elizabeth Alcarraz, Jule Franve Vasquez Chavez, Litol Becerra, Obeth Sanchez, Luis Mas, Silvia P. Neciosup, Henry L. Gómez
Journal: Journal of Clinical Oncology (2017)

6547 Background: Instituto Nacional de Enfermedades Neoplásicas (INEN) is located in Lima (capital of Peru). There are no oncologists in regions like Peruvian jungle. Approximately 6% of medical attentions at INEN are people from this cities; so they must spend money and time to receive their treatment far from their cities. The purpose was to implement a module of outpatient chemotherapy in a non-specialized hospital, located in Peruvian jungle, for chemotherapy administration monitored by oncologists from INEN through the use of information and communication technologies (ICT). Methods: Two working teams were organized by formal agreement between INEN and local authorities to properly implement the infrastructure and to train local staff from December 2014 to November 2015. Questionnaire EORTC QLQ-C30 (v3) was used to assess QoL at the beginning and 3 months later. Results: A chemotherapy room with 18 armchairs, an area with a laminar flow hood to mix drugs at pharmacy, and videoconferencing equipment were implemented in Lamas, San Martin (1100 Km from Lima). Two general practitioners, 3 nurses and a pharmacist from Lamas, were trained during 3 months at INEN. Since November 2015, 31 patients were admitted. They received 181 cycles of chemotherapy in 248 rounds of administration, monitored by teleconference. Additionally 227 videoconference meetings to evaluate patients and to coordinate with local team were performed. Global health status improved from 76.67% to 83.33%. We observed benefit in functional scales, likewise symptoms related to disease did not vary, nevertheless financial difficulties decreased from 33.3% to 6.67%. In terms of money and time, this meant an average saving of $150.00 and 4 hours of travel time. Conclusions: Using ICT, we successfully implemented a tele-chemotherapy module in the heart of Peruvian jungle without harming patients quality of life. They will not need to travel to Lima for receiving their treatment.
Arthrogenic muscle inhibition after ACL reconstruction: a scoping review of the efficacy of interventions
Authors: Bertrand Sonnery-Cottet, Adnan Saithna, Benedicte Quelard, Matt Daggett, Amrut Borade, Hervé Ouanezar, Mathieu Thaunat, William G Blakeney
Journal: British Journal of Sports Medicine (2018)

To determine whether reported therapeutic interventions for arthrogenic muscle inhibition (AMI) in patients with ACL injuries, following ACL reconstruction, or in laboratory studies of AMI, are effective in improving quadriceps activation failure when compared with standard therapy in control groups.A scoping review of the efficacy of interventions was conducted in accordance with the methodological framework of Arksey and O'Malley and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Search terms included 'arthrogenic muscle inhibition', 'quadriceps activation following knee injuries', 'anterior cruciate' or 'knee' combined with 'quadriceps activation', 'quadriceps inhibition', 'corticomotor', 'arthrogenic', 'brain activation' and 'neuroplasticity'. Articles were evaluated for risk of bias using the PEDro (Physiotherapy Evidence Database) criteria. The overall quality of evidence for each intervention was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE).PubMed, EMBASE and Cumulative Index to Nursing and Allied Health Literature databases.Isolated case reports and articles reporting outcomes in patients with chronic disease or major trauma were excluded. All other original research articles were included.780 potential articles were identified. 20 met the inclusion criteria. These studies provided a moderate quality of evidence to support the efficacy of cryotherapy and physical exercises in the management of AMI. There was low-quality evidence for efficacy of neuromuscular electrical stimulation and transcutaneous electrical nerve stimulation, and very low-quality evidence for efficacy of ultrasound and vibration.This scoping review demonstrated moderate-quality evidence for the efficacy of cryotherapy and physical exercises in improving quadriceps activation failure after ACL injury and reconstruction. These therapeutic modalities are therefore recommended in the management of AMI.
Abstract 15702: Oral Anticoagulation Therapy After Radiofrequency Ablation of Atrial Fibrillation and the Risk of Thromboembolism and Serious Bleeding: A Meta-analysis
Authors: Mohit Turagam, Poonam Velagapudi, Madhav Lavu, Sandia Iskandar, Donita Atkins, Sudharani Bommana, Luigi Di Biase, Andrea Natale, Dhanunjaya Lakkireddy, Madhu Reddy
Journal: Circulation (2016)

Background: Many observational and retrospective studies showed safety of discontinuation of oral anticoagulation (OAT) in radiofrequency ablation (RFA) of atrial fibrillation (AF). We performed a meta-analysis comparing the effect on stroke/systemic thromboembolism (STE) and major bleeding events (MBE) in low risk (CHADS2 0-1) and high risk patients (CHADS2 ≥2) who underwent RFA for AF and stopped or continued OAT. Methods: We performed a comprehensive literature search using: OAT, RFA and AF in Pubmed, Ebsco and google scholar databases. The analysis in low risk (LR) patients included a total of 6 studies (4 prospective observational and two retrospective studies) and 7 studies (5 prospective observational and 2 retrospective studies) in high risk (HR) patients comparing STE and MBE between patients who discontinued and continued OAT after RFA for AF. OAT was discontinued at 3-6 months after RFA in all studies. Follow-up duration for studies ranged from 1 to 5 years. Results: Baseline characteristics, p...
Plasma cell-free DNA copy number analysis by low coverage whole genome sequencing to monitor breast cancer relapse in CA15-3 and CEA silent patients.
Authors: Wen-Ming Cao, Huanhuan Zhou, Wang Xiao Jia, Qian Ziliang, Zhan-Hong Chen, Yun Gao, Rong Wang, Wei-Wu Ye
Journal: Journal of Clinical Oncology (2018)

e13036 Background: CA15-3 and CEA are the commonly used serum tumor biomarkers for monitoring breast cancer relapse. However, it is limited by sensitivity. Here we investigated copy number variations (CNVs) of plasma cell-free DNA (cfDNA) by whole genome sequencing (WGS) as a biomarker to monitor breast cancer relapses, especially for CA15-3 and CEA silent patients. Methods: 33 treatment naïve recurrent breast cancer patients were recruited from Zhejiang Cancer Hospital. Blood samples were collected before first-line treatment. 20 plasma samples were collected from healthy volunteers as controls. Plasma cfDNA was sent to WGS with median genome coverage 1.86X (range from 1.03X to 3.17X) by Illumina X10. Sequencing coverage across chromosomes was summarized by samtools, normalized, and followed by segmentation analysis as provided by R package ‘DNACopy’. A significant changed segment was defined by segment size > = 10M and P < = 0.01. Results: Of the 33 recurrent breast cancer, 12 (36.4%) patients were CA15-3 > = 35KU/L. 14 (42.4%) patients were CEA > = 5ng/ml. Plasma cfDNA CNVs showed high consistency in these groups. The consistency rates were 91.7% (11/12), 92.9% (13/14) and 88.9% (16/18) in CA15-3+, CEA+ and CA15-3- and/or CEA+ groups. The other 15 samples were serum tumor biomarker CA15-3 < 35KU/L and CEA < 5ng/ml. Of them, significant plasma cfDNA CNVs were found in 75.0% (12/16) of patients. The results indicated that cfDNA CNVs analysis might be a useful tool to monitor cancer relapse for tumor biomarker negative patient. Taking together, significant CNVs were found in 84.9% (28/33) of breast cancer patients’ plasma cfDNA samples, which was higher than that of serum tumor biomarkers CEA and CA153 (proportion test, P value < 0.01). No significant CNV was found in 20 health control samples. Further analysis identified frequent CNVs on chromosome 8, 20, 1q, 17, 7p, 3q and 12, which were detected in 24 (72.7%), 18 (54.5%), 16 (48.5%), 11 (33.3%), 10 (30.3%), 7 (21.2%) and 6 (18.2%) breast cancer patients, respectively. Conclusions: It is feasible to use cfDNA CNVs by low coverage WGS for monitoring breast cancer early recurrence, especially in those tumor biomarker silent patients.
Varying prognostic impact of molecular subtype among young patients with de novo stage IV breast cancer: A population-based cohort study.
Authors: Rin Ogiya, Naoki Niikura, Yasuaki Sagara, Yutaka Tokuda
Journal: Journal of Clinical Oncology (2018)

e13090 Background: Younger patients with early stage breast cancer have been reported to have worse prognosis compared to older patients while reverse relationship has been demonstrated in stage IV breast cancer. We aimed to determine clinicopathologic features of young patients with stage IV breast cancer and the overall survival (OS) difference stratified by molecular subtypes. Methods: We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results database from 2010 to 2014. We included patients (age 19-59 years) diagnosed with stage IV breast cancer. The patients were divided into two groups, young age ( < 40 years) and middle-aged (40-59 years). Molecular subtypes were classified as: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, HR+/HER2+, HR-/HER2+ and HR-/HER2-. We used log-rank test and Cox proportional hazards model adjusting for potential confounders to examine the OS between groups and repeated the analysis with stratification by molecular subtypes. Results: Among the 6,337 patients with stage IV breast cancer, 955 patients were young age and 5,382 patients were middle-aged. Patients in the young age group were more likely to be black (23% vs. 20%) and to have grade III tumors (40% vs. 32%) compared to patients in the middle-aged group. During a median follow-up period of 17 months from the date of diagnosis, there were 2,641 (42%) death events. Patients in the young age group experienced significantly longer survival than patients in the middle-aged group; the median OS was 45 and 33 months in young age and middle-aged group, respectively (hazard ratio, 0.75; 95%CI, 0.66-0.84). In the subgroup analysis with stratification by molecular subtypes, patients in the young age group experienced significantly longer survival than patients in the middle-aged group only in HR+ subtypes (HR+/HER2-: hazard ratio 0.70; 95%CI, 0.58-0.84; and HR+/HER2+: hazard ratio 0.57; 95%CI, 0.40-0.80). Conclusions: The OS in patients with stage IV breast cancer was significantly longer in young age compared to middle-aged, only in HR+ subtypes. Further study is warranted to investigate what factors in HR+ subgroup extend the prognosis.