tbuckley/cabot-search huggingface dataset:
Abstract 12229: Bundle Branch Reentrant Ventricular Tachycardia: Novel Genetic Mechanisms in a Life-Threatening Arrhythmia
Authors: Jason D Roberts, Michael H Gollob, Charlie Young, Sean P Connors, Chris Gray, Stephen B Wilton, Martin S Green, Dennis W Zhu, Kathleen A Hodgkinson, Annie Poon, Qiuju Li, Nathan Orr, Anthony S Tang, George J Klein, Julianne Wojciak, Joan Campagna, Jeffrey E Olgin, Nitish Badhwar, Vasanth Vedantham, Gregory Marcus, Pui-Yan Kwok, Rahul C Deo, Melvin M Scheinman
Journal: Circulation (2016)

Introduction: Bundle branch reentrant ventricular tachycardia (BBRVT) is a life-threatening ventricular arrhythmia occurring secondary to macroreentry within the His-Purkinje system. Although classically associated with dilated cardiomyopathy, BBRVT may also occur in the setting of isolated, unexplained conduction system disease. Hypothesis: Idiopathic BBRVT may be secondary to genetic mutations associated with conduction system disease. Methods &amp; Results: We identified 6 cases of BBRVT associated with normal biventricular size and function from 6 centers across North America. Study participants were screened for mutations within pre-specified genes linked to cardiac conduction system disease. Putative culprit mutations were identified in 3 of 6 cases, including 2 in SCN5A (Ala1905Gly [novel] and c.4719C&gt;T [splice site mutation]) and 1 in LMNA (Leu327Val [novel]). Biophysical analysis of mutant Ala1905Gly Na v 1.5 channels in tsA201 cells revealed significantly reduced peak current density and positive shifts in the voltage-dependence of activation consistent with a loss-of-function. The SCN5A c.4719C&gt;T splice-site mutation has previously been reported as disease causing in 3 cases of Brugada syndrome, while the novel LMNA Leu327Val mutation was associated with a classic laminopathy phenotype. Following catheter ablation, BBRVT was non-inducible in all cases and no clinical recurrences were observed during follow-up. Conclusions: Our investigation into apparent idiopathic BBRVT has identified the first genetic culprits for this life-threatening ventricular arrhythmia. This provides further insight into its underlying pathophysiology and emphasizes that conduction system disease, in the absence of ventricular dilation, serves as a sufficient substrate for BBRVT. Our findings also highlight BBRVT as a novel genetic etiology of unexplained sudden cardiac death that can be cured with catheter ablation.
Dabrafenib in pediatric patients with <i>BRAF</i> V600–positive high-grade glioma (HGG).
Authors: Darren R Hargrave, Lucas Moreno, Alberto Broniscer, Eric Bouffet, Isabelle Aerts, Nicolas Andre, Wei-Ping Violet Shen, Anne-Isabelle Bertozzi-Salamon, Kenneth J. Cohen, Ira J. Dunkel, Mark W. Kieran, Andrej Lissat, Mark W. Russo, Kohinoor Dasgupta, Lillian Tseng, Bijoyesh Mookerjee, Birgit Geoerger
Journal: Journal of Clinical Oncology (2018)

10505 Background: The BRAF V600 mutation constitutively activates the MAPK/ERK pathway and is an oncogenic driver in many tumor types, including pediatric brain cancers. There are limited effective therapies for patients (pts) with HGG, ≈ 5% of whom have BRAF V600 alterations. The kinase inhibitor dabrafenib (which targets BRAF V600) demonstrated tolerability in pediatric pts across tumor types in a dose-escalation (ESC) cohort of a phase I/IIa study (Kieran et al, ASCO 2015; NCT01677741). Here we report preliminary analyses in this study of safety and clinical benefit with dabrafenib in pts with HGG across the ESC and disease-expansion (EXP) cohorts. Methods: Pts aged 1 to < 18 y with BRAF V600–positive HGG who had refractory or progressive disease after receiving ≥ 1 standard therapy were treated with dabrafenib (2 equal daily doses) either in the ESC cohort or with the recommended dose of 5.25 mg/kg/d (pts < 12 y) or 4.5 mg/kg/d (pts ≥ 12 y) in the EXP cohort. Measurable disease was not required. Primary objectives were safety and tolerability, and secondary objectives included tumor response and pharmacokinetics. Tumor response was reported by independent review (IR) and investigator assessment (INV) using RANO criteria. Exploratory analyses included independent histopathological review and tumor biology analysis (eg, mutation, methylation status). Results: Pts (n = 31) were treated with dabrafenib across the ESC (n = 8) and EXP (n = 23) cohorts. Median age was 14 y (range, 3 - < 18 y). Across both cohorts (n = 31), the most frequent AEs (any causality) were fatigue (48%), vomiting (42%), and headache (39%). Grade 3/4 AEs occurred in 12/31 pts (39%). No on-treatment deaths occurred. Median duration of exposure was 22 wk (range, 4-225 wk), and 10/31 pts (32%) had treatment ongoing. ORR by IR was 45% (14/31, with 3 CRs), and ORR by INV was 32% (10/31, with 4 CRs). By IR, median duration of response was 7.7 mo (95% CI, 3.0 mo-not estimable) and 13/19 pts with measurable lesions (68%) achieved a maximum tumor reduction of ≥ 50%. Tumor mutational and methylation analyses are ongoing. Conclusions: Dabrafenib was well tolerated in pediatric pts with BRAF V600–positive HGG, and a number of durable objective responses demonstrate the potential for clinical benefit. Clinical trial information: NCT01677741.
Is 18F-FDG-PET/CT a good MRD marker in patients with multiple myeloma? Comparison and correlation with biochemical markers/flowcytometry.
Authors: Uday Yanamandra, B.R. Mittal, Man Upadesh, Arun Reddy, Praveen Sharma, Kanhaiya Agarwal, Alka Khadwal, Gaurav Prakash, Neelam Varma, Subhash Varma, Pankaj Malhotra
Journal: Journal of Clinical Oncology (2016)

8029 Background: Multiple myeloma is a heterogenous disorder with varied responses to chemotherapy. The response criteria are defined based on biochemical assays, bone marrow (BM) examination, flowcytometry and molecular assays. Lately PET/CT is employed in MRD analysis. We aimed at studying the correlation of 18F-FDG-PET/CT with various biochemical markers, bone marrow plasma cells, and flowcytometry MRD analysis as a cross-sectional comparison at a given time point in patients post myeloma therapy. Methods: This is a single-center non-interventional study as part of PIPET-M trial. Patients of multiple myeloma underwent 18F-FDG-PET/CT, biochemical evaluation including (SPEP, UPEP, SIFE, SFLC, β2M, LDH) and BM examination (for plasma cells percentage and flowcytometry for MRD) as part of end of treatment analysis. Patients were included after induction chemotherapy, pre-autologous transplant (within 30 days) or post-transplant (Day 100) for analyzing efficacy of therapy. PET- positivity was based on the PIPET-M staging (A validated staging system developed by the authors). Results: A total of 72 patients were screened of which 52 patients underwent PET/CT, biochemical evaluation including (SPEP, UPEP, SIFE, SFLC, β2M and LDH) and bone marrow examination. Concurrent flowcytometry for MRD was done only in 11 patients. PET positivity had no relation with the pre transplant biochemical markers (SPEP, UPEP, SIFE) [χ2 - (1, 53)-0.34, p-0.56; (1, 52) - 2.18, p-0.14; (1, 52) – 0.32, p-0.57 respectively] or BM plasma cell percentage (p-0.64). In PET positive patients, β2M and LDH were higher (p - 0.032), whereas SFLC ratio though higher was not statistically significant (p-0.61). There was a good agreement between PET positivity and MRD by flowcytomtery (Cohen’s κ - 0.662, p < 0.001). Conclusions: 18F-FDG-PET/CT is a good marker for MRD analysis with good agreement with flowcytometry and disease activity markers such as β2M/ LDH. Its poor correlation with SPEP, UPEP, SIFE and BM plasma cell percentage can be secondary to undetectable levels of these markers in many patients (~ 84%) after therapy. A comparison of these markers for prognosticating PFS/OS is further warranted. Clinical trial information: U1111-1177-8850, REF/2015/12/010356.
Increased medication costs for filaggrin-related eczema and asthma
Authors: P. Soares, K. Fidler, J. Felton, R. Tavendale, A. Hövels, S.A. Bremner, C.N.A. Palmer, S. Mukhopadhyay
Journal: British Journal of Dermatology (2018)

Eczema and asthma are common chronic diseases. Eczema affects 15‐20% of schoolchildren and 2‐10% of adults while asthma affects 16‐18% of the UK population. Almost three‐quarters of children with early onset eczema, a severe and persistent form of eczema, will develop asthma in later life. The filaggrin gene helps produce a protein that creates a protective barrier on the skin against the entry of outside substances that trigger allergies. About 1 in 10 people carry a change in the filaggrin gene and this results in the production of defective protein that can no longer help maintain this skin barrier. This UK study aimed to find whether filaggrin mutations were associated with increased prescribing of medication for eczema and asthma and /or an increased number of asthma exacerbations (i.e. worsening) and whether this translated into different healthcare costs. The study shows that children with eczema and asthma carrying this gene change have substantially increased needs for both eczema and asthma medication through most of their childhood. Children with asthma carrying the gene change were also more prone to suffer asthma attacks over a nine‐year period, enhancing both hospital and human costs of the disease. It follows that a simple ‘spit’ gene test, that can be done anytime in life, including at birth or early childhood, could help predict long‐term healthcare costs and the long‐term risk of more severe disease for individuals with common chronic conditions such as eczema and asthma. Children and adults with filaggrin gene mutations may benefit from targeted treatment regimes, such as daily use of emollients from birth, which could lead to cost savings for healthcare systems and improvements in disease control and quality‐of‐life.
Abstract A002: Comparison of circulating microRNAs in plasma before and after radical prostatectomy among men treated for prostate cancer
Authors: Alicia C. McDonald, Jay D. Raman, Jing Shen, Jason Liao, Manish Vira
Journal: Cancer Research (2018)

Abstract Introduction: MicroRNAs (miRNAs) have been linked to advanced prostate cancer; however, their role as circulating biomarkers of prostate cancer (PC) status has yet to be determined. We examined whether circulating miRNAs in plasma could be employed as biomarkers of disease among men treated for PC by radical prostatectomy (RP). Methods: Men with clinically localized PC scheduled for a RP were recruited. Demographics, medical history, clinical information, pre-RP blood, and post-RP blood within 1 year after RP were collected. Pre- and post-RP blood were processed into plasma and the expression of the 16 most statistically significant PC circulating miRNAs in plasma identified from our previous study (miR- 381, 34a, 523, 365, 122, 375, 1255b, 34b, 450b-5p, 639, 885-5p, 1260, 150, 378, 671-3p, 148a) were examined using real-time PCR. Wilcoxon signed ranked test was used to compare the median expression of these miRNAs between pre- and post-RP plasma. Results: There were 29 men, aged 43 to 77 years, included. Majority were white men (79.3%). The median preoperative serum PSA was 6.3 ng/mL. Majority had a pathologic Gleason score of 7 (3+4) (56%) and a pathologic tumor stage of T3 (60.7%). There was no statistically significant difference in miRNA expression between pre- and post-RP plasma. Conclusion: No difference in miRNA expression before and immediately after RP was observed, possibly due to the lack of impact of tumor removal on miRNA expression and the timing of plasma collections. Future studies that examine post-RP plasma miRNA expression over time with PC recurrence are warranted. Citation Format: Alicia C. McDonald, Jay D. Raman, Jing Shen, Jason Liao, Manish Vira. Comparison of circulating microRNAs in plasma before and after radical prostatectomy among men treated for prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A002.
Clinical characteristics, demographics, and outcomes in hormone-receptor (HR+) positive metastatic breast cancer (MBC) patients treated with palbociclib.
Authors: Chrystal Ann Landry, Maya Dimitrova, Meng Ru, Eleonora Teplinsky, Amy Tiersten
Journal: Journal of Clinical Oncology (2018)

e13027 Background: The PALOMA-1 and PALOMA-3 studies demonstrated a significant progression-free survival (PFS) advantage for palbociclib (P) with letrozole or fulvestrant compared to these therapies alone. As patients allowed to participate in clinical trials do not mirror our heterogeneous patient population, application of these results is limited. We sought to further evaluate response to therapy in our diverse patient population. Methods: A retrospective review identified 58 patients treated with P for HR+ MBC after its FDA approval between January 1st, 2015 and October 1st, 2016 at our center in East Harlem, NY. Records were reviewed and clinical characteristics for each patient were analyzed. Results: The median age was 62 (range 34-84); 22.4% were ≥ age 70. Our cohort was 25% African American, 62.5% Caucasian, and 12.5% Asian American. 70.7% of patients were on an aromatase inhibitor and 29.3% were on fulvestrant. 48.3% had received prior chemotherapy. Median follow up was 18.2 months (95% CI 14.7, 20.2 months). Median event-free survival (EFS) was 11.0 months (5.3, 16.9 months). A partial response or better on imaging (34.5%) was associated with better EFS (HR 0.44 (0.22, 0.91) p = 0.027). Toxicity rate was 87.9%; 44.8% were ≥ grade 3. While toxicity (including ≥ grade 3) was not associated with worse OS or EFS, development of anemia was associated with worse EFS. An increase in MCV of > 10fL (HR 0.18 (0.09, 0.36) p < 0.001) and utilization of G-CSF support for neutropenia (HR 0.20 (0.05, 0.89) p = 0.035) were associated with better EFS. While age ≥70 was associated with worse OS (HR 4.03 (1.16, 14.00) p = 0.028), no difference in EFS or toxicity was observed including when neutropenia and anemia were evaluated independently. There was no difference in OS or EFS based on race or ethnicity. Conclusions: Our data confirm significant improvement in EFS in a real-world patient population with no differences based on race, extreme age, or general development of toxicity. Improved EFS seen with G-CSF support and increase in MCV warrant further investigation. A review of pathologic correlates as potential biomarkers of response based on these clinical results is underway.
Evaluation of clinical outcomes by analysis of mutations in tumor tissue and circulating plasma DNA using next-generation sequencing (NGS) from STEAM, a prospective, randomized, multicenter study in metastatic colorectal cancer (mCRC).
Authors: John J. Lee, John F. Palma, Lijing Yao, Alexander F. Lovejoy, Stephanie Yaung, David Zhang, Nasiema Wingate-Pearse, May Yau, Carolyn Williams, Monica Pimentel, Abraham Munoz, Katrina Mayol, Christoph Mancao, Alan Nicholas, Nicolas Sommer, Johanna C. Bendell, Herbert Hurwitz, Ulrich Peter Rohr
Journal: Journal of Clinical Oncology (2017)

11510 Background: STEAM (NCT01765582) assessed the efficacy and safety of concurrent (c) and sequential (s) FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for first-line treatment of mCRC. Methods: The AVENIO ctDNA Expanded Kit (Research Use Only) was used to assess somatic mutations in 77 cancer-related genes by NGS in tissue, and both pre- and post-induction plasma samples (n = 182, 150 and 118 respectively) from STEAM. Four mutation classes including single-nucleotide variants (SNVs), indels, copy number amplifications (CNAs) and fusions were identified. SNVs and indels were called in tissue and plasma at allele frequencies of 5% and 0.25% respectively. Results: Overall concordance of mutations in pre-induction plasma with tissue was 83%. Concordance for the seven most mutated genes ranged from 91.5%-100%. In pts with matched samples (n = 118), RAS WT pts showed significantly longer progression-free survival (PFS) in both cFOLFOXIRI-BEV (A) and sFOLFOXIRI-BEV (B) arms versus FOLFOX-BEV (C), using genotyping of either tissue or plasma. This was not seen in RAS MUT pts. In contrast, TP53 WT showed no significant treatment differences while TP53 MUT showed longer PFS for cFOLFOXIRI-BEV versus FOLFOX-BEV. A list of mutation frequencies for all samples, as well as hierarchical clustering analysis of tissue mutations will be presented. Conclusions: The AVENIO ctDNA Expanded Kit identified mutations in 77 cancer-related genes, in both plasma and tissue, with high overall concordance. Compared to FOLFOX-BEV, longer PFS was observed for c- or s- FOLFOXIRI-BEV in RAS WT pts and for cFOLFOXIRI-BEV in TP53 MUT pts, irrespective of sample type. These results are hypothesis generating and require further clinical validation. Clinical trial information: NCT01765582. [Table: see text]
The role of modified FOLFIRINOX regimen in unresectable advanced pancreatic cancer: A retrospective clinical study.
Authors: Yuan Qian, Song Zheng, Changku Jia
Journal: Journal of Clinical Oncology (2017)

e15709 Background:Pancreatic cancer was the fourth leading cause of death from cancer in the United States in 2015, with a 5-year survival rate only 6%.More than 85% of patients has an unresectable disease at diagnosis for most patients remain asymptomatic. This population including locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC). Gemcitabine has been the standard treatment option for these patients for more than a decade, with a median overall survival nearly 6 months. In 2011, the phase 3 randomised controlled trial(PRODIGE 4/ACCORD 11) reported that FOLFIRINOX regimen had a significantly improved OS,PFS and a predominant ORR in patients with metastatic disease.FOLFIRINOX, as an encouraging regimen, its actual higher adverse events rate in clinical practice should not be underestimated, especially the grade 3/4 neutropenia and sensory neuropathy. The aim of our study is to explore whether a modified FOLFIRINOX regimen with the decrements of oxaliplatin and irinotecan had maintained efficacy and decreased grade 3/4 adverse events rate for the advanced pancreatic cancer. Methods:Retrospectively collected data of all patients carrying a diagnosis of advanced pancreatic cancer at the department of medical oncology, Hangzhou First People’s Hospital and Hangzhou cancer hospital between January 2014 and September 2016.The endpoint were overall survival, objective response rate and grade 3/ 4 adverse events. Results:Among 21 patients who received median 5(1-12) cycles modified FOLFIRINOX regimen,15 of total patients received this regimen for more than 4 cycles (71.4%). The median overall survival of MPC patients in this study is 12.6 months (95% CI, 6.2 months to 19 months). The objective response rate was 42.9%, with partial remission in 9 cases, stable disease in 8 cases and progression disease in 4 cases. Totally 8 patients had grade 3/4 adverse events, the most frequent were neutropenia (14.3%), neuropathy (14.3%) and diarrhea (9.5%). No chemotherapy-related death occurred. Conclusions:mFOLFIRINOX regimen in this study has maintained efficacy for its high objective response rate and an improved safety profile in patients with advanced pancreatic cancer.
Early outcomes of a high-risk cohort in pancreatic cancer surveillance.
Authors: Maria Fernanda Montiel, Pompeyo Rafael Quesada, Margaret Dunseith, Eduardo Vilar Sanchez, Manoop S. Bhutani, Michael Paul Kim, Matthew H. G. Katz, Anirban Maitra, Maureen E Mork, Banu Arun, Sarah A. Bannon, Florencia McAllister
Journal: Journal of Clinical Oncology (2018)

e16258 Background: By 2030 pancreatic cancer will become the third leading cause of cancer related death in the United States. Genetic evolution studies have suggested the existence of a window of opportunity to improve clinical outcomes by intercepting pre-malignant lesions. This study reports the outcome of pancreatic cancer surveillance in a cohort of PDAC High Risk patients followed at The University of Texas MD Anderson Cancer Center (MDA) between 2015-2018. Methods: The MDA PDAC High-Risk Clinic (MDA-PCHRC) performs surveillance based on risk stratification. The first patient screened under this methodology was seen on March 2015 and this study reports 36 months of surveillance from the date of the first high-risk consult. The referred patients are risk stratified into mild, moderate, and high-risk groups. PDAC risk stratification criteria include PDAC family history, diabetes, chronic pancreatitis and germline mutations with higher susceptibility to PDAC. Patients in the moderate or high-risk category get annual screening with blood markers (CA 19-9, fasting glucose, hemoglobin A1C, amylase, lipase) and magnetic resonance imaging/ cholangiopancreatography (MRI/MRCP). The high-risk group also receives an endoscopic ultrasound (EUS) at baseline. We evaluate the methodology and yield of premalignant lesions in the MDA-PCHRC. Results: A total of 121 patients have been referred to our clinic during this time period. From this group, 71 patients completed at least one cycle of baseline surveillance. Currently, we have identified 4 side branch duct IPMNs, 4 simple cysts and 9 imaging findings of pancreatic parenchymal changes. There has been 1 duodenal neuroendocrine tumor, 1 pancreatic neuroendocrine tumorlet, and 1 high grade IPMN as per biopsy findings. Conclusions: Early results show that screening at the MDA-PCHRC with EUS, MRI/MRCP, and laboratory markers is safe and can detect premalignant lesions. However, further follow up is warranted to thoroughly assess the efficacy of pancreatic cancer screening in a high-risk populations. Moreover, patients followed in our clinic are enrolled into a Prospective Cohort and their biospecimens (blood and urine) are prospectively collected for future biomarkers validation.