tbuckley/cabot-search huggingface dataset:
Exosome liquid biopsies of NSCLC patients for longitudinal monitoring of ALK fusions and resistance mutations.
Authors: Kay Brinkmann, Daniel Enderle, Claudia Flinspach, Lisa Meyer, Johan Skog, Mikkel Noerholm
Journal: Journal of Clinical Oncology (2018)

e24090 Background: Molecular profiling of mutations in NSCLC patients is of increasing relevance for direction of targeted therapy. Assessing such biomarkers directly from plasma overcomes hurdles associated with biopsies, including significant risk and difficulties to monitor molecular changes longitudinally. Here we applied molecular testing for detection of EML4-ALK fusions and ALK resistance mutations in exosomal nucleic acids from plasma of lung cancer patients. In a prospective cohort of ALK-positive patients the longitudinal monitoring of response to treatment by liquid biopsies in correlation to routine diagnostics was investigated. Methods: In an accredited laboratory the ExoDx Lung(ALK) test was used for variant-specific detection of EML4-ALK from exosomal RNA of patient plasma using a validated qPCR panel. In parallel, ALK resistance mutations were analyzed on exosomal RNA as well as cfDNA using our ExoLution Plus platform that simultaneously isolated exosomal RNA and cfDNA. 11 ALK exon23-based mutations were analyzed by ExoDx NGS platform. Samples were collected at baseline as well as longitudinally throughout treatment. Results: To date, EML4-ALK fusion qPCR was tested on 144 longitudinal samples of 52 patients. In parallel, 35 samples derived from 29 patients were sequenced for ALK mutations. ExoDx Lung(ALK) test was able to detect ALK fusions on exosome RNA in 50% of patients at baseline. 98% of the samples collected during objective response or stable disease were negative by ExoDx Lung(ALK), indicating that lack of exosome ALK fusions in plasma is a sign of response. The ALK resistance mutation panel was performed on two patients with PD, and both were detected positive for ALK resistance mutations, L1196M (variant 1) and G1202R (variant 3), respectively. Conclusions: Biomarker analysis from plasma exosomes represents a valuable diagnostic tool to track ALK-positive patient responses longitudinally. Variant-specific detection of ALK fusions on exosomal RNA and resistance mutations was closely correlated to disease control in the clinic and can be used for accompanying targeted therapy.
Phase II trial of high-dose melatonin oral gel for the prevention and treatment of oral mucositis in H&amp;N cancer patients undergoing chemoradiation (MUCOMEL).
Authors: Alicia Lozano, Jordi Marruecos, Jordi Rubió-Casadevall, Nuria Farre, Antonio Lopez-Pousa, Jordi Giralt, Isabel Planas, Beatriz Cirauqui, M. Lanzuela, Rosa Morera, Ane Escribano, Jaime Gomez-Millan, Maria Dolores Toledo, Gonzalo Vazquez Masedo, Luis Cascallar, Pedro Grima, Vicente Valenti, Cristina Tarrago, Ramon Bosser, Ricard Mesia
Journal: Journal of Clinical Oncology (2018)

6007 Background: Severe Oral Mucositis (SOM) is one of the most significant adverse events (AE) in H&N cancer patients undergoing concurrent chemo/bio-radiotherapy. The objective of the trial is to evaluate the safety and efficacy of melatonin (MLT) oral gel in the prevention and treatment of oral mucositis (OM) in H&N cancer patients. Methods: Multicenter, prospective, randomized, double-blind, placebo-controlled study. Eligible patients were randomly assigned (1:1 ratio) to receive 3% MLT or matching placebo (PLC) oral gel. Patients received once daily (5 days/week) IMRT radiation therapy (total dose ≥ 66 Gy). Concurrent systemic treatments were cisplatin Q3W or cetuximab Q1W. All patients received concomitant standard symptomatic treatment for OM. Efficacy analyses were performed on a mITT population (patients receiving at least one medication dose) or ITT. Efficacy endpoints were either RTOG or NCI CTCv4, G3-4 oral mucositis (SOM) and G2-4 ulcerative oral mucositis (UOM). Comparison of incidence rates of SOM/UOM: Fisher exact test; comparison of duration of SOM/UOM: U Mann-Whitney test. Results: 84 patients (ITT: 42 MLT/42PLC; mITT: 40 MLT/39 PLC) were included. Most frequent tumor sites were oropharynx (n = 38; 45%) and oral cavity (n = 24; 29%). Concurrent systemic treatments were cisplatin (n = 54; 64%) or cetuximab (n = 30; 36%). Efficacy results in the mITT population (incidence) and ITT (duration) Clinical trial information: NCT02630004. No relevant differences for AEs between groups or for overall response rate after 2 months of IMRT completion. Conclusions: Treatment with MLT oral gel resulted in a consistent trend to a lower incidence and shorter duration of SOM as well as a significantly shorter duration of UOM. These benefits were more marked in the subgroup of patients receiving cisplatin. These results warrant further clinical development. Scale Median duration in SOM/UOM patients (days) SOM Incidence (%) SOM UOM MLT PLC p value MLT PLC p value MLT PLC p value Overall NCI 50 67 0.17 17 22 0.21 39 58 0.004 RTOG 53 64 0.36 18 24 0.11 42 49 0.06 RTOG or NCI 57 79 0.05 - Cisplatin NCI 41 64 0.09 20 24 0.82 35 52 0.03 RTOG 37 61 0.16 12 19 0.41 38 52 0.03 RTOG or NCI 44 78 0.02 - Cetuximab NCI 62 63 1.00 7 21 0.07 51 75 0.12
The Acute Stroke Care Revolution
Authors: S. Andrew Josephson, Hooman Kamel
Journal: JAMA (2018)

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Association between duration of somatostatin analogs (SSAs) use and quality of life in patients with carcinoid syndrome in the United States based on the FACT-G instrument.
Authors: Daniel M. Halperin, Lynn Huynh, Jennifer L Beaumont, Beilei Cai, Todor Totev, Rachel Bhak, Mei Sheng Duh, Francis Vekeman, Maureen Neary, David Cella
Journal: Journal of Clinical Oncology (2017)

e15693 Background: Carcinoid syndrome (CS) results from the secretion of bioactive amines by functional neuroendocrine tumors. The only FDA-approved agents to treat carcinoid syndrome symptoms (CSS) are SSAs. This study assessed the association of duration of SSA use and quality of life (QoL) among patients with CSS usingthe validated Functional Assessment of Cancer Therapy-General (FACT-G) instrument. Methods: Patients with CSS in the US were recruited by NCAN for a two-part online, anonymous survey (~6 months apart). The first survey was fielded between July-October 2016 and results are reported here. Eligible patients were ≥18 years old with CSS and received either SSA or non-SSA treatment for CSS control. The survey consisted of demographic, clinical and QoL questions, including FACT-G. Descriptive and multivariable regression analyses, adjusting for demographic and clinical characteristics, were performed to assess predictors of FACT-G QoL scores. Duration of SSA use was categorized into quartiles ( &lt; 2.7, 2.7-4.42, 4.43-8.0, and &gt; 8.0 years). Results: Among 117 patients who completed the first survey, 76.9% were female and 87.2% Caucasian with a mean age of 58.0 years. A predominant number of patients (98.3%) received SSAs in the past month. The mean ± SD FACT-G total score was 67.6 ± 20.0 (possible range: 0-108), lower than that of the general US population (80.1 ± 18.1). The mean ± SD duration of SSA use was 6.1 ± 4.7 years. Descriptive analysis suggested that patients receiving SSA treatment for &gt; 8 years had higher (better) FACT-G subscale and total scores than reference group &lt; 2.7 years. Multivariable models showed that FACT-G total score was 11.3 points ( P= 0.033) higher for patients treated with SSA &gt; 8 years compared to those treated for &lt; 2.7 years. Similar patterns were observed for two FACT-G subscales - Physical Well Being and Functional Well Being. Conclusions: The duration of SSA use was positively associated with QoL benefit among CS patients. This may be explained by long-term effectiveness of SSAs or selection bias favoring patients with more indolent disease. Future studies will be needed to distinguish between these possibilities.
Influence of age on overall survival of patients with hepatocellular carcinoma after hepatic resection.
Authors: Jian-Hong Zhong, Jun-Tao Tan, Bang-De Xiang, Le-Qun Li
Journal: Journal of Clinical Oncology (2016)

e15595 Background: The suitability of hepatic resection for older patients remains controversial. This study aimed to investigate whether age influences overall survival of patients with hepatocellular carcinoma (HCC) after resection. Methods: Records of 1,132 patients with HCC after hepatic resection were retrospectively reviewed. Overall survival (OS) was compared between younger and older patients based on five cut-off ages (30, 40, 50, 60, and 70 years). Results: Across all patients, OS was 89.7 % at 1 year, 67.7 % at 3 years, and 47.7% at 5 years. OS was similar between younger and older patients at all cut-off ages (all P > 0.1), but OS was marginally lower among patients > 70 years old than those ≤ 70 (P = 0.090). Multivariate analyses identified several risk factors for lower OS: preoperative serum albumin < 35 g/L, alanine aminotransferase > 80 U/L, fetoprotein ≥400 ng/mL, presence of esophagogastric varices or macrovascular invasion, incomplete/absent tumor capsule, tumor size > 10 cm, tumor number ≥3, and major hepatectomy. Conclusions: Age does not influence the prognosis of patients with HCC after hepatic resection. Older patients should be considered for curative resection if remnant liver volume and liver function are adequate.
Racial Disparities in CD34+ Cells and Their Influence on Cardiovascular Repair
Authors: Doris A. Taylor, James T. Willerson
Journal: Circulation Research (2018)

Tahhan et al 1 report racial disparities in the frequency of several circulating subsets of CD34+ progenitor cells (CPCs) in patients with cardiovascular disease.They further show that race is an independent predictor of CPC frequency, even when 2 populations are adjusted for cardiovascular risk factors.The authors evaluated the role of CPCs, their mobilization after acute myocardial infarction (AMI), and their predictive value after infarction in blacks compared with whites. Article, see p 467In unadjusted data in this study, CD34+ CPCs and CD34+/ CXCR4+ (C-X-C motif chemokine receptors) cell counts were significantly lower in the peripheral blood of blacks. 1 When the data were adjusted for cardiovascular risk factors, black race was found to be an independent determinant of CD34+, CD34+/CXCR4+, CD34+/CD133+, and CD34+/KDR+ cells in the peripheral blood.Furthermore, with the onset of AMI, the frequency of CD34+ cells was reduced further in blacks and appeared to be predictive of mortality.Although the differences in cell frequencies between blacks and whites in this study are small (14%-17%) after adjusting for age, sex, and cardiovascular risk factors, the abnormally low frequency of these cells in the circulation after AMI suggests that the changes may be physiologically meaningful.This is supported by the finding that the reduction in CD34+ cells was an indicator of increased mortality in blacks after a myocardial infarction.The authors also reported that CD34+ cell numbers were associated with lower levels of matrix metalloproteinase-9, which may suggest a possibility for a difference in remodeling after AMI.This article highlights that patient race is an additional demographic along with previously reported baseline characteristics, such as age and sex that may contribute to changes in circulating progenitor cell numbers, and suggests that racerelated changes in endogenous cell-mediated repair may play a role in racial disparities in cardiovascular disease outcomes in a similar manner as other environmental and lifestyle-related risk factors (eg, smoking, hypertension, body mass index).
Phase Ib study of regorafenib (rego) and PF-03446962 (PF) in patients with refractory metastatic colorectal cancer (mCRC) (REGAL).
Authors: Jeffrey Melson Clarke, Gerard C. Blobe, John H. Strickler, Hope Elizabeth Uronis, Yousuf Zafar, Michael Morse, Evan Dropkin, Leigh Howard, Margot O'Neill, Christel N. Rushing, Donna Niedzwiecki, Hollie Watson, Christy Arrowood, Herbert Hurwitz
Journal: Journal of Clinical Oncology (2016)

e15013 Background: PF is a fully human, IgG2 monoclonal antibody to activin receptor like kinase 1 (ALK1). ALK1 is highly expressed on proliferating endothelial cells and critical to transforming growth factor- β mediated tumor angiogenesis. Rego is an anti-angiogenic tyrosine kinase inhibitor approved for use in mCRC and GIST. Preclinical evidence suggests greater anti-angiogenic effects with combined ALK1 and VEGF inhibition. Methods: We conducted a phase Ib clinical trial of the novel combination of rego + PF in mCRC pts, utilizing a standard 3+3 trial design with an expansion cohort. Key eligibility included chemotherapy refractory mCRC, ECOG 0-1, and indication for rego. The primary objective was to define maximum tolerated dose (MTD) and the recommended phase 2 dose (RPTD) of rego + PF. 3 dose levels (DL) of PF were planned at 3, 4.5, and 7 mg/kg IV every 2 weeks, with starting dose level (DL1) at 4.5 mg/kg. Rego was dosed at 120 mg PO daily for 21 days of 28 day cycle. Results: 11 pts were enrolled across 2 dose levels with 7 pts in DL1 and 4 pts in DL-1. Enrollment was stopped early due to reprioritization of the PF development program. Median prior lines of therapy = 3 (2 - 4). Due to infusion reactions in the first 2 pts, diphenhydramine was used before the doses of PF in the remaining 9 pts. 2 pts experienced DLT in DL1 due to dose reductions leading to < 75% of planned dose intensity for grade (gr) 2 fatigue and gr 2 hand-foot syndrome (HFS). 2 pts were non-evaluable for DLT due to early disease progression. One gr 5 pelvic infection occurred in DL1. Among the 11 patients treated, treatment related AE included HFS (n = 4), abdominal pain (n = 3), fatigue (n = 4), anorexia (n = 3), dehydration (n = 3), and infusion reaction (n = 3). Of the 6 patients evaluable for response, there were no partial or complete responses; stable disease was seen in 2 pts (33%), and progressive disease in 4 pts (66%). Median progression free survival and overall survival were 2.0 mo (0.92-9.5) and 7.2 mo (1.2-NA), respectively. Conclusions: This is the first clinical trial to evaluate the combination of targeted VEGF and ALK1 inhibition. The study was terminated before determination of the MTD and RPTD. DLT was seen with PF at 4.5 mg/kg and rego at 120 mg. Clinical trial information: NCT02116894.
Abstract 18414: Could Tolvaptan Prevent the New Onset of Atrial Fibrillation After Cardiac Surgery?
Authors: Yuichiro Kishimoto, Yoshinobu Nakamura, Yoshikazu Fujiwara, Shingo Harada, Takeshi Ohnohara, Satoru Kishimoto, Tomohiro Kurashiki, Motonobu Nishimura
Journal: Circulation (2016)

Introduction: Atrial fibrillation (Af) occurs frequently after cardiac surgery and not only prolongs hospitalization but also influences the prognosis. Tolvaptan (TV) has a strong diuretic effect, ...
Serial FDG-PET to predict response, time to skeletal related events, and survival in patients with bone-dominant metastatic breast cancer.
Authors: Jennifer M. Specht, Lanell Peterson, Alena Novakova, Janet N O'Sullivan, Finbarr O'Sullivan, Andrew Shields, Susan Montgomery, Hannah M. Linden, Julie Gralow, Georgiana Kehr Ellis, Vijayakrishna K. Gadi, William E. Barlow, Robert K Doot, Erin K Schubert, Lisa K Dunnwald, Lawrence MacDonald, Paul Kinahan, David A. Mankoff
Journal: Journal of Clinical Oncology (2016)

11569 Background: Response to therapy in bone lesions can be difficult to assess. In this prospective study, FDG-PET was used to assess TTP, SRE and survival (OS) in patients (pts) starting a new therapy for bone-dominant metastatic breast cancer. Methods: Pts underwent an FDG-PET prior to starting new therapy and again at approximately 4 months. FDG static images were analyzed quantitatively using the maximum standardized uptake value (SUVmax) of up to 5 most dominant lesions. Response was determined by clinical follow-up data exclusive of PET results. Results: 29 pts (mean age 55, range 33-91) completed both FDG scans. At 35.5 mos median follow-up, 26/29 patients died from their disease (90%). Median OS was 32.7 mos (range 6-87). 27/29 (93%) pts had disease progression; median TTP was 5.7 mos (range 2.1-29.4); and 18/29 (62%) had an SRE; median time to SRE 6.5 mos (range 0-86.3). By univariate analysis, absolute change in the mean SUVmax between scans was not prognostic for TTP, SRE or OS. In multivariable analysis, after adjusting for presence of an elevated tumor marker and SUVmaxat baseline FDG-PET,a one standard deviation (2.6 units) reduction in SUVmax (averaged over tumor sites) at the second scan was associated with a 35% reduction in the risk of progression (p = .04). An increase of 5.9 SUV units was associated with a 70% increase in risk of progression. Absolute change in SUVmax from baseline, and initial higher SUVmax were associated with earlier time to SRE (p = .001, < .001, respectively). An increase of 5.9 SUV units over measured tumor sites was associated with more than a doubling of the risk of death (p = .01). The average difference between SUVmax at baseline and second scan was not significantly associated with OS (p = .13). Conclusions: Changes in SUVmax over the course of treatment in pts with bone-dominant breast cancer predicted TTP and SRE, but were of borderline significance in OS. High baseline SUVmax was associated with shorter time to SRE, shorter TTP and poorer OS. These results demonstrate a role for FDG-PET in assessing bone-dominant breast cancer response to therapy and support the use of FDG-PET as a response measure in future clinical trials. Support: 5R01CA124573-05
Bone metastasis to predict treatment response rate and overall survival of patients with metastatic melanoma.
Authors: Yesung Lee, Natasha Masub, Todd Wechter, Judy Zhong, Una Moran, Farbod Darvishian, David Polsky, Russell S. Berman, Richard L. Shapiro, Jeffrey S. Weber, Iman Osman, Anna C. Pavlick, Melissa Wilson
Journal: Journal of Clinical Oncology (2018)

e21585 Background: Substantial numbers of metastatic melanoma patients (approximately 40%) develop bone metastases (M-bone), yet the impact of M-bone on response to systemic therapy and overall survival (OS) is not adequately studied. We examined responses of patients with M-bone to systemic and bone-directed therapy and effect of M-bone on survival. Methods: Unresectable stage III and stage IV melanoma patients prospectively enrolled at NYU (2002 – 2017) were examined. We compared metastatic patients with M-bone (n = 198) to those without M-bone (n = 265) and analyzed their progression free survival (PFS) and OS using Kaplan Meier survival analysis. Cox multivariate analysis was performed to determine if M-bone was an independent predictor of survival. Results: Patients with M-bone were associated with an increase in tumor infiltrating lymphocytes (p < 0.001), axial location of the primary melanoma (p < 0.001), and more advanced stages (stage III and IV) at initial diagnosis (p = 0.005) compared to patients without M-bone. In multivariate Cox analysis, patients with M-bone had worse OS that was independent of performance status, LDH, and number of metastatic sites (HR = 1.38, p = 0.047). Among patients who received targeted therapy, M-bone remained an independent predictor of worse OS (HR = 1.96, p = 0.048). There was also a trend towards worse OS in patients who received immunotherapy (p = 0.066). Treatment with bone directed therapy did not have significant impact on bone specific PFS. Conclusions: The microenvironment of bone may contribute to the significant negative impact of M-bone on treatment outcome. More studies are needed to better understand the mechanisms behind these clinical outcomes considering the expected increased overall survival of metastatic melanoma patients in the new era of effective targeted and immune therapies.
Serum amphiregulin in colorectal carcinoma and the correlation with liver metastasis.
Authors: Chawalit Chayangsu, Virote Sriuranpong
Journal: Journal of Clinical Oncology (2016)

e15078 Background: Amphiregulin (AREG) is one of the epidermal growth factor receptor (EGFR) ligands and play important roles in several tumor progression and metastasis. Upregulations of AREG in colonic carcinoma tissue have been shown to correlate with depth of tumor invasion, nerve invasion and liver metastasis. We sought to investigate a correlation of serum AREG in colorectal cancer with clinicopathological parameters and liver metastasis. Methods: Colorectal cancer patients who came to receive treatment at King Chulalongkorn Memorial Hospital during August 2013 to March 2014 were enrolled. We collected baseline serum prior to start any therapy and stored till analysis. Serum AREG was measured by ELISA using Human Amphiregulin DuoSet (R&D Systems, Minneapolis, MN). The correlation between each independent clinicopathological characteristics and serum AREG was analysed. Results: There were 120 patients enrolled to current analysis which included 78 patients (65.5%) with stage I-III and 41 patients (34.5%) in advanced stage. In advanced disease group, the median level of serum AREG was 31.55 pg/mL, which was higher than those of the localized disease group 15.48 pg/mL, p = 0.001. With correlation analyses, serum AREG higher than 25 pg/mL (high serum AREG) had significantly correlate with liver and peritoneal metastasis (p < 0.001). Additionally, high serum AREG had significant correlation with more poor differentiated/mucinous histolgical grade (p = 0.014), M1 (p = 0.001), lymphovascular invasion (p = 0.016) and perineural invasion (p < 0.001). Conclusions: High serum AREG ( > 25 pg/mL) has correlation with liver and peritoneal metastasis and has a potential impact as a prognostic marker in colorectal carcinoma.