tbuckley/cabot-search huggingface dataset:
Impact of oral glutamine intake on the cycle numbers of adjuvant FOLFOX treatment administered in low and high risk colon cancer patients.
Authors: Yousuf Al-Farhat, Ildiko Schipp, Auth Peter, Arpad Boronkai
Journal: Journal of Clinical Oncology (2018)

e15691 Background: Impact of the preventive oral glutamine intake on the development of peripheral neuropathy (PN) was examined along with adjuvant (adj) FOLFOX applied in high and low risk colon cancer patients. The study was carried out in the Dep. of Oncology, County Hospital of Tolna, Hungary Methods: The patients examined were divided into two groups. Control (C) group: neurological examination and consequent treatment of grade-2 PN observed between 08/Jan/2008 – 01/Sep/2012. Preventive (P) group: 33 patients were provided with oral glutamine supplement twice daily along with the adj FOLFOX protocol from the first cycle, between 01/Jan/2013 – 01/Sep/2016. We compared the median cycle number of FOLFOX treatment applied in the two study groups, making a comparison with the respective results of the high (T4, N: ≥ 4) and low risk patients of the IDEA trial Results: Histological parameters of the C/P groups were: T2: 2/6, T3: 19/18, T4: 14/9 and N1: 16/22, N2: 19/11, respectively. Distribution according to risk classification: high (23/16) and low (12/17) risk. Median age of the patients were 62,7 versus 62,2 years. The cumulative number of FOLFOX cycles administered for the C/P groups were 312 and 370, the median number was 9,17 and 11,18, respectively. A median of 9,65 versus 11,33 cycles were administered for the high risk patients whilst 8,33 and 10,94 cycles were given to the low risk groups. Comparing the C/P groups, PN occured as follows: grade-1: 14/21 and grade-2: 21/12, respectively. 3-year disease free survival was also evaluated in both populations: 54 % was registered in the C-arm and 75,7 % in the P- arm Conclusions: Preventive administration of oral glutamine resulted in higher numbers of the adjuvant FOLFOX administered and decreased number of severe PN for the patients examined. Half of the patients in the P group were categorized into the high risk population according to the corresponding results of the IDEA trial, requiring the 6-month (12 cycles) duration of adjuvant treatment. Six months of adj FOLFOX treatment can be performed safely along with the preventive application of oral glutamine, without significant risk of any further adverse events or compromising the survival rates.
Involvement of calpain in the neuropathogenesis of Alzheimer’s disease
Authors: Yacoubou Abdoul Razak Mahaman, Fang Huang, Henok Kessete Afewerky,  Tanko Mahamane Salissou Maibouge, Bishwajit Ghose, Xiaochuan Wang
Journal: Medicinal Research Reviews (2018)

Abstract Alzheimer’s disease (AD) is the most common (60% to 80%) age‐related disease associated with dementia and is characterized by a deterioration of behavioral and cognitive capacities leading to death in few years after diagnosis, mainly due to complications from chronic illness. The characteristic hallmarks of the disease are extracellular senile plaques (SPs) and intracellular neurofibrillary tangles (NFTs) with neuropil threads, which are a direct result of amyloid precursor protein (APP) processing to Aβ, and τ hyperphosphorylation. However, many indirect underlying processes play a role in this event. One of these underlying mechanisms leading to these histological hallmarks is the uncontrolled hyperactivation of a family of cysteine proteases called calpains. Under normal physiological condition calpains participate in many processes of cells’ life and their activation is tightly controlled. However, with an increase in age, increased oxidative stress and other excitotoxicity assaults, this regulatory system becomes impaired and result in increased activation of these proteases involving them in the pathogenesis of various diseases including neurodegeneration like AD. Reviewed here is a pool of data on the implication of calpains in the pathogenesis of AD, the underlying molecular mechanism, and the potential of targeting these enzymes for AD therapeutics.
Arginine methylation of EGFR in circulating tumor cells: A new biomarker for predicting resistance to anti-EGFR agents.
Authors: Krittiya Korphaisarn, Chao-Kai Chou, Weiya Xia, Callisia Clarke, Jennifer S Davis, Hsin-Wei Liao, Shadarra Crosby, Shanequa Manuel, Ji Wu, David Menter, Mien-Chie Hung, Scott Kopetz
Journal: Journal of Clinical Oncology (2017)

3590 Background: Arginine methylation of the epidermal growth factor receptor (meEGFR) increases binding affinity of EGF and other EGFR ligands, reduces the efficacy of anti-EGFR agents in vivo, and is reported to have a role in predicting response to anti-EGFR agents. This study aimed to investigate the predictive impact of meEGFR in metastatic colorectal cancer (mCRC) patients (pts) treated with anti-EGFR agents using blood-based testing. Methods: 15 mL of blood were collected from mCRC pts with documented disease progression following anti-EGFR treatment (Rx). Circulating tumor cells (CTCs) were isolated using antibody (ab)-independent micro-fluidic cassette-based technology (Parsortix system), which separates CTCs on the basis of size and deformability. CTCs were identified based on negative staining for CD45ab and positive staining for EpCAMab. meEGFR was identified based on positive staining for me-R198/200ab on CTCs. Associations between meEGFR-CTCs and total CTCs with progression free survival (PFS) were determined by Kaplan-Meier method and compared by the log-rank test. Results: A total of 47 mCRC pts were prospectively included in this study. CTCs were identified in 30 out of 47 cases (64%). Of those 30, meEGFR-CTCs were identified in 19 cases (63%). Mean total CTCs and meEGFR-CTCs counts were 3.6 (range 0-52) and 2.3 (range 0-30) cells per 7.5ml, respectively. There was no association between meEGFR-CTCs and clinic-pathological features (age, sex, tumor site &amp; grade), line of anti-EGFR Rx, previous irinotecan used, or NRAS, BRAF, PIK3CA, and MSI status. However, in RAS wt /BRAF wt mCRC pts, high levels of meEGFR ratio (defined as &gt; 0.25 meEGFR-CTCs per total CTCs) was associated with significantly inferior PFS with anti-EGFR Rx (median PFS 5.4 mo vs. 8 mo, HR 3.4, 95% CI of 1.5-7.9, P = 0.004). By contrast, high levels of total CTCs ( &gt; 3 cells/per 7.5 ml) had no impact on PFS with anti-EGFR Rx. Conclusions: We have successfully isolated CTCs from mCRC pts’ blood using Parsortix system. Elevated levels of arginine methylated EGFR is associated with a shorter PFS with anti-EGFR-based Rx. Assessment of meEGFR-CTCs may provide a “liquid biopsy” biomarker for reduced efficacy from anti-EGFR Rx.
Abstract 10132: Outcomes of Peripheral Vascular Interventions for Lower Extremity Acute Limb Ischemia
Authors: Elica Inagaki, Alik Farber, Denis V Rybin, Gheorghe Doros, Jeffrey Kalish, Mohammad H Eslami, Naomi M Hamburg
Journal: Circulation (2015)

Introduction: Acute limb ischemia (ALI) is increasingly managed with peripheral vascular interventions (PVI). Objective: The objective of our study was to elucidate the clinical outcomes following PVI in patients with ALI. Methods: We identified 365 patients who underwent PVI for lower extremity ALI between 2010 and 2014 in the Vascular Study Group of New England registry. The control group included 1808 patients who underwent PVI for chronic critical limb ischemia (CLI) who were matched (5:1 to ALI) by arterial segment treated (aortoiliac, femoropopliteal, and infrapopliteal). Comparisons of in-hospital and two-year outcomes, including after adjustment for relevant clinical covariates, were made between the two groups. Results: Compared to CLI patients, ALI patients treated with PVI had lower prevalence of comorbidities but were more likely to have had prior ipsilateral revascularizations including PVI and/or leg bypass. ALI patients experienced lower technical success (89% vs 93%, p=0.04), higher rate of distal embolization (5% vs 2%, p=0.001), longer length of stay (6±8 days vs 4±6 days, p&lt;0.001), and higher in-hospital mortality (4% vs 1%, p=0.001). No differences in two-year outcomes were found between the two groups with respect to rates of major amputation (6% vs 6%, p=0.9) and mortality (20% vs 21%, p=0.8). After adjustment for covariates and previous ipsilateral revascularizations, ALI continued to be associated with lower technical success (OR 0.6 [95% CI 0.4-0.8] p=0.008), higher rate of distal embolization (OR 2.7 [95% CI 1.5-4.9] p=0.001), longer length of stay (OR 1.6 [95% CI 1.4-1.8] p&lt;0.001), and increased in-hospital mortality (OR 2.8 [95% CI 1.3-5.9] p=0.007). However, ALI was not associated with major amputation (HR 1.1 [95% CI 0.7-1.8] p=0.6) or mortality (HR 1.2 [95% CI 0.9-1.5] p=0.3) at two-year follow-up. Conclusions: In a large, observational cohort of patients undergoing PVI, those with ALI had more short-term adverse events compared to patients with CLI. However, two-year amputation rates and mortality were similar between ALI and CLI patients.
<i>BRAF</i>, <i>MEK1</i>, <i>AKT1</i> testing by a new diagnostic method to detect point mutations associated with melanoma: <i>CLART CMA BRAF</i>-<i>MEK1</i>-<i>AKT1.</i>
Authors: Maria Jesus Sanz, Marta Sanchez, Jaime Martinez, Gonzalo Garcia, Ines Mora, Nuria Manjon, Yolanda Ruano, Jose Luis Rodriguez-Peralto, Rosario Cospedal, Maria Luisa Villahermosa
Journal: Journal of Clinical Oncology (2016)

e21074 Background: The mitogen-activated protein kinase (MAPK) pathway can be constitutively activated by alterations in specific genes in many cancers. BRAF mutations have been identified approximately 50% of melanoma. V600 mutations increase BRAF kinase activity promoting melanoma growth. Approximately 90% of all identified BRAF mutations are V600E and 5%-12% are V600K amino acid substitutions. Targeted agents that inhibit BRAF kinase activity have improved progression-free survival when used in BRAF mutant melanoma. RAF-MEK-ERK and PI3K-AKT pathways are key players in melanoma progression and drug resistance. CLART CMA BRAF-MEK1-AKT1 is a novel diagnostic assay to evaluate the BRAF V600E/K mutation in order to screen patients for treatment with inhibitor of BRAF kinase activity. Moreover this is able to identify mutations in MEK1 and AKT1 genes that could be related with resistance to inhibitors of BRAF kinase activity. Methods: Specific ARMS-primers and hybridization probes for detecting mutations BRAF V600E and V600K, MEK1 I111S, P124S and E203K, and AKT1 Q79K were designed. Clinical testing was performed using 155 samples which contained the targets of this assay and samples with wild type alleles. The results were cross checked by comparison to Sanger sequencing methodology. Results: Analytical sensitivity was assessed using recombinant plasmids, results ranged in 1000 copies/µl for the most prevalent BRAF V600E mutation. For the rest of mutations in BRAF, MEK1 and AKT1 results ranged in 10000 copies/µl. Mutations BRAF V600E and V600K were analyzed using specific cell lines, the sensitivity were 0.5ng and 5ng respectively. Diagnostic sensitivity data was over 93% for all mutations, and diagnostic specificity data was 100% for all mutations. Conclusions: CLART CMA BRAF-MEK1-AKT1 detects the most prevalent BRAF V600 mutations (V600E/K), MEK1 I111S, P124S and E203K, and AKT1 Q79K mutation, with sensitivity ≥ 93% and reproducibility ≥ 98%, being capable to detect mutations in samples with at least 10% of tumor cells. Our data support the use of this technology for clinical testing prior to selection of the appropriate treatment in melanoma.
B-cell acute lymphoblastic leukemia (B-ALL) in CLL patients treated with lenalidomide.
Authors: Moritz Fuerstenau, Anna-Maria Fink, Carmen Herling, Christian Maurer, Nadine Kutsch, Javier De La Serna, Marta Coscia, Marta Crespo, Francesc Bosch, Thomas Noesslinger, Paolo Ghia, Arnon P. Kater, Matthias Ritgen, Anke Schilhabel, Stephan Stilgenbauer, Eugen Tausch, Kirsten Fischer, Michael J. Hallek, Barbara Eichhorst
Journal: Journal of Clinical Oncology (2018)

7531 Background: The immunomodulatory drug lenalidomide (len) has shown clinical activity in CLL. It has been associated with an increased rate of second primary malignancies (SPM) in multiple myeloma (MM). In MM degradation of transcription factors Ikaros and Aiolos leads to its anti-tumor activity and T-cell activation; in CLL, its mechanism of action has not been determined yet. In our CLLM1 trial, 2 of 56 pts developed BCR-ABL positive B-ALL during or after len maintenance; there were no B-ALL cases in the placebo group. Methods: We screened all phase III trials using len in CLL pts for reported B-ALL cases, obtained reports of B-ALL cases in CLL from the FDA Adverse Event Reporting System (FAERS) and analysed available data for B-ALL cases in five non-len GCLLSG trials in order to estimate the incidence of B-ALL in CLL pts not exposed to len. In the 2 CLLM1 pts, PCR was performed for detection of BCR-ABL before B-ALL diagnosis and clonal relationships of B-ALL and CLL will be assessed by NGS. Results: In 3 phase III trials (CLLM1, CONTINUUM, ORIGIN) evaluating the use of len in CLL, a total of 846 pts were enrolled, 438 receiving len monotherapy. Five out of 438 pts (1,1%) developed B-ALL during treatment (n = 1) or after discontinuation (n = 4). No B-ALL cases were reported in the control groups including 408 pts. Of the 5 pts, 2 received len as firstline and 3 as maintenance therapy, median length of exposure was 32 months (range 15-47), median age at B-ALL diagnosis was 69 years (range 60-82). Both CLLM1 pts were categorized as ‘high risk’ or ‘very high risk’ according to CLL-IPI, 1 pt featuring a TP53 mutation, both with unmutated IGHV. BCR-ABL could not be detected at any time point before ALL diagnosis, clonal relationship of B-ALL and CLL is currently being analysed. In 2015 pts treated within 5 non-len GCLLSG trials, only 2 cases of B-ALL were identified (0,1%); this underscores the assumption that secondary B-ALL is usually a rare event in CLL. Conclusions: According to a large GCLLSG cohort and in accordance with published data on SPM in CLL, B-ALL is a rare event in CLL patients. In CLL patients treated with len either as firstline or maintenance therapy following chemotherapy, an increased number of B-ALL was observed, the reason for this increase is unknown.
Methylomes variation to predict exemestane resistance in advanced breast cancer.
Authors: Xiao-Ran Liu, Ru-Yan Zhang, Hao Gong, Hope S. Rugo, Jian Tie, Lingbo Chen, Yuan Fu, Jianwei Che, Bin Shao, Feng-Ling Wan, Wei-yao Kong, Guo-hong Song, Han-fang Jiang, Guo-bing Xu, Huiping Li
Journal: Journal of Clinical Oncology (2018)

e24029 Background: In estrogen receptor-positive breast cancer patients (pts), more than 30% have primary hormone therapy (HT) resistance while the precise mechanism underlies remain unclear. Our study, for the first time, focused on the relationship between the methylomes variation and the exemestane resistance (EXEr). Methods: All 16 pts received first-line exemestane based HT were prospectively recruited in our center. Blood samples of baseline, first follow-up and disease progression (PD) were collected. Pts (4/16) who had PD within 6 months under exemestane treatment were considered EXEr, otherwise, pts were considered EXE sensitive (EXEs). Circulating tumor DNA derived methylomes was detected using DNA bisulfite treatment followed by the next-generation sequencing. EXEr related differentially methylated regions (DMRs) were screened using Bismark software (Krueger et al, 2011). Results: The median follow-up of present cohort was 19.0 months. The EXEr related DMRs in terms of both methylation density (MD) and methylation ratio (MR) were summarized in table below. During the treatment, demethylation of R6 was a positive predictor for EXEs (AUC=0.95, P=0.011). Meanwhile, the High MR level of R3a at baseline predicts EXEr (AUC=0.93, P=0.016). Using the methylomes variation of R6, we successfully stratified patients in terms of progression free survival (Cutoff=0.5, P=0.013). Similar predictive value was found when using the MR level of R3a at baseline (Cutoff=0.815, P=0.025) Conclusions: Methylomes variation in certain DMRs could predicts EXEr with clinical potential. However, retest of our finding in a larger prospective study are needed in future works. Table 1. Genomic location of DMRs (abbreviation) P value for methylation density P value for Methylation ratio Overlap genes Chr3 [67800000-67999999] (R3a) 0.026 0.049 SUCLG2-AS1 Chr3 [140200000-140399999] (R3b) 0.029 0.038 CLSTN2; CLSTN2-AS1; TRIM42 Chr6 [32400000-32599999] (R6) 0.005 0.013 HLA-DRA; HLA-DRB5; HLA-DRB6; HLA-DRB1 Chr9 [46800000-46999999] (R9) 0.019 0.002 FAM74A1 Chr10 [46400000-46599999] (R10) 0.019 0.034 PTPN20 Chr12 [101200000-101399999] (R12) 0.016 0.041 ANO4 Chr1[149600000-149799999] (R1) 0.026 0.050 LINC00623; LINC00869; LOC103091866
Cancer pain in the emergency department: A multicenter study of the Comprehensive Oncologic Emergencies Research Network.
Authors: Christopher John Coyne, Rebecca Arielle Shatsky, Danielle D Durham, Adam Klotz, Aveh Bastani, Christopher Baugh, Corita Grudzen, Daniel Henning, David Adler, Jason Wilson, Juan Felipe Rico, Daniel Pallin, Sai-Ching J. Yeung, Steven Bernstein, Jeffrey Caterino, Troy Madsen, Richard Ryan, Demetrios Kyriacou, Arvind Venkat, Cielito C. Reyes-Gibby
Journal: Journal of Clinical Oncology (2018)

6541 Background: Despite initiatives to improve cancer analgesia, patients with cancer frequently present to the emergency department (ED) with pain related issues. To our knowledge, no previous studies have investigated how the presence and severity of pain in cancer patients presenting to the ED may relate to morbidity and mortality. This study aims to investigate these associations. Methods: We conducted a multicenter prospective cohort study of patients with active cancer presenting to 18 EDs within the Comprehensive Oncologic Emergencies Research Network (CONCERN) between December 1st, 2016 and June 1st, 2017. We recorded initial, final and highest ED pain scores and used logistic regression to estimate their association with the following outcomes: 30-day mortality, 30-day ED revisits, and 30-day hospital readmissions. Pain was recoded into none (0), mild (1-3), moderate (4-6) and high (7-10). We also recorded demographics and ECOG scores. Results: We enrolled 1075 patients. The cohort was 52% female with a median age of 64. Approximately 70% of patients had pain, while only 48% of patients received an analgesic. 62% reported having home pain medications. The median highest pain score was 5, while the initial and final were 4 and 1, respectively. Of the patients who presented with pain, 64.8% reported improvement prior to discharge, 28.7% reported no change and 6.5% worsened. A high initial pain score was associated with increased 30-day mortality (OR 2.3, 95%CI 1.11-4.87). An ECOG score of 2 was associated with increased 30-day ED revisits (OR 1.7, 95%CI 1.14-2.5) and readmissions (OR 2.2, 95%CI 1.47-3.27). Conclusions: Pain remains a significant issue for cancer patients presenting to the ED, and was present in nearly 3/4 of our cohort. While not all patients received pain medications, we did note a low median final pain score. Severe pain on presentation appeared to be associated with increased mortality. This knowledge may aid physicians when determining ED disposition for those patients with high initial pain scores. An ECOG score of 2 appears to be associated with increased ED revisits and readmission, which may reflect a population in need of more aggressive outpatient symptom management.
Ph 1 study of MRG-106, an inhibitor of miR-155, in CTCL.
Authors: Francine M. Foss, Christiane Querfeld, Youn H. Kim, Lauren C. Pinter-Brown, Basem M. William, Pierluigi Porcu, Theresa Pacheco, Bradley Haverkos, Jennifer DeSimone, Joan Guitart, Ahmad Sami Halwani, Herbert Aaron Eradat, Auris Huen, Anita G Seto, Linda A Pestano, Gilad Shalag Gordon, Diana Escolar, Paul Rubin, William S. Marshall, Jud Williams
Journal: Journal of Clinical Oncology (2018)

2511 Background: MRG-106 is an inhibitor of miR-155, a microRNA with a strong link to CTCL pathogenesis. The goals of this FIH study are to evaluate the safety, tolerability, PK, and efficacy of MRG-106 in mycosis fungoides (MF) patients (pts). Methods: This Ph 1 trial evaluated MRG-106 given via intralesional injection (75 mg/dose), subcutaneous or IV rapid bolus injection, or 2-hour IV infusion (300, 600 or 900 mg/dose). Pts must have MF stage I-III with plaques and/or tumors and could remain on concurrent stable CTCL therapy. Pts received 6 doses (SC/IV) in the first 26 days of the study followed by weekly or bi-weekly doses. Safety was monitored by physical exams, clinical lab tests, and reported adverse events (AEs). Efficacy was assessed by CAILS and by the modified Severity Weighted Assessment Tool (mSWAT). The effect of MRG-106 on quality of life was assessed by Skindex-29. Results: 36 subjects (20M/16F, median age 63 yrs) have been on study for up to 17 months (as of 25Jan2018). No serious AEs have been attributed to MRG-106. Most common AEs in ≥ 15% of subjects were: fatigue, neutropenia, injection site pain, nausea, pruritus, and headache. Two AEs were deemed DLTs: Gr3 worsening pruritus and Gr 3 tumor flare. MTD has not yet been reached. In the SC/IV cohorts, 26/29 evaluable subjects had improvement in mSWAT score. Skin improvements were observed as early as the first assessment (Day 17). Best improvements were after ≥ 1 month. All 8 pts (across all doses with SC or IV infusion) who achieved ≥ 50% reduction in mSWAT and received > 2 treatment cycles, maintained response for ≥ 4 months. 4/5 pts treated at the 300 mg IV infusion dose had ≥ 50% mSWAT improvement. The overall skin response in pts who received MRG-106 as monotherapy or MRG-106 with concurrent stable therapy were not significantly different. Reductions in Skindex-29 total score correlated to reductions in mSWAT score during the treatment phase. Conclusions: These preliminary results suggest that MRG-106 is well-tolerated, has clinical activity, and has potential to impact MF quality of life. These encouraging data support the continued investigation of MRG-106 in this population. The study is expanded to enroll pts with other hematologic malignancies in which miR-155 is elevated and relevant, including CLL, DLBCL, ATLL. Clinical trial information: NCT02580552.