tbuckley/cabot-search huggingface dataset:
Efficacy and safety of cobimetinib (C) combined with vemurafenib (V) in patients (pts) with <i>BRAF</i><sup>V600</sup> mutation–positive metastatic melanoma: analysis from the 4-year extended follow-up of the phase 3 coBRIM study.
Authors: Brigitte Dreno, Paolo Antonio Ascierto, Grant A. McArthur, Victoria Atkinson, Gabriella Liszkay, Anna Maria Di Giacomo, Mario Mandalà, Lev V. Demidov, Daniil Stroyakovskiy, Luc Thomas, Luis De la Cruz-Merino, Caroline Dutriaux, Claus Garbe, Isabelle Anne Rooney, Jessie J. Hsu, Erica Park, Antoni Ribas, James M. G. Larkin
Journal: Journal of Clinical Oncology (2018)

9522 Background: The coBRIM study demonstrated that first-line C+V improved progression-free (PFS) and overall survival (OS) compared with placebo (P)+V in pts with BRAFV600-mutated advanced melanoma. We report updated survival outcomes and safety after extended follow-up. Methods: coBRIM was a double-blind, multicenter study in which 495 patients were randomized to receive C (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle; n = 247) or P (n = 248) in combination with V (960 mg twice daily). PFS and OS were primary and secondary endpoints, respectively. Results: At database closure, median follow-up duration for the overall intent-to-treat population was 18.6 months (range, 0.5–55.1 months); 176 pts (71%) in the C+V arm and 190 pts (77%) in the P+V arm had discontinued the study, with the most common reason being death (C+V = 148 pts [60%]; P+V = 162 pts [65%]). Median PFS among pts receiving C+V was 12.6 months (95% confidence interval [CI], 9.5–14.7 months) vs 7.2 months (95% CI, 5.6–7.5 months) in pts receiving P+V. Median OS among pts receiving C+V was 22.5 months (95% CI, 20.3–28.8 months) vs 17.4 months (95% CI, 15.2–20.5 months) in pts receiving P+V. A greater proportion of pts receiving C+V were alive at 1, 2, 3 and 4 years vs pts receiving P+V (Table). Median duration of treatment in the C+V arm was 9.0 months (range, 0.1–53.1 months) for C and 9.2 months (range, 0.3–53.3 months) for V. Pts in the P+V arm had a shorter median duration of treatment of 5.6 months (range, 0.2–43.9 months) for P and 5.7 months (0.2–53.2 months) for V. Grade 3/4 adverse events (AEs) were reported in 75% and 61% of pts in the C+V and P+V arms, respectively. Grade 5 AEs were reported in 2% of pts in each study arm. A larger proportion of pts discontinued C+V (19%) versus P+V (10%) due to AEs. Conclusions: Extended follow-up of the phase 3 coBRIM study confirmed the survival benefit of C+V over P+V. No new safety signals were observed. Clinical trial information: NCT01689519. Landmark OS, % (95% CI) C+V P+V 1-year 74.5 (68.9–80.1) 63.8 (57.6–70.0) 2-year 49.0 (42.5–55.6) 39.0 (32.7–45.4) 3-year 38.5 (32.1–44.9) 31.1 (25.0–37.2) 4-year 34.7 (28.4–41.0) 29.2 (23.1–35.2)
Prognostic implications of TAMs in colorectal cancer hepatic metastases.
Authors: Matthew Reilley, Sreyashi Basu, Riham Katkhuda, Nicolle Patterson, Tenghui Chen, Jorge M Blando, David Menter, Dipen M. Maru, James Patrick Allison, Scott Kopetz, Padmanee Sharma, Michael J. Overman
Journal: Journal of Clinical Oncology (2017)

3574 Background: A limited understanding of the immune microenvironment of mismatch repair-proficient metastatic colorectal cancer (mCRC) impedes efforts to develop effective immunotherapy treatments for the majority of CRC patients. Liver metastatic disease is common and associated with poor outcomes. While T-cell infiltration of liver metastases positively correlates with survival, most mCRC patients do not benefit from checkpoint-blockade therapy. Tissue associated macrophages (TAMs) have been associated with an immune suppressive environment, but their prognostic role in mCRC is largely unknown. Methods: Comprehensive analysis of gene expression and immunohistochemistry (IHC) in 25 microsatellite stable (MSS) untreated liver metastatectomy (LM) specimens was performed. Clinical outcomes including recurrence, immunologic data, and tumor microsatellite status were evaluated and correlated. Results: Principal component analysis of immune and cancer pathway related genes were performed and compared with recurrence status. All samples were confirmed MSS. There were distinct differences in gene expression between patients who remained disease free and those who recurred. Among immune related genes CXCL5, IRF4, IL6R, TNF, CTLA4, ICOS, and ARG1 were relatively over-expressed in non-recurrent tumors, while PPARG, AIRE, and EPCAM were over-expressed in recurrent tumors (FDR 0.2, p &lt; 0.05). Cibersort analysis predicts a significantly higher number of M2 versus M1 macrophages regardless of recurrence status (p &lt; 0.05), with an approximate M1:M2 ratio of 1:2 and a higher total number of M1/M2 macrophages in tumors that recur. On IHC, an average of 29% of cells per sample expressed macrophage marker CD68. Relatively fewer CD3, CD4, and CD8 T cells were observed with average infiltration rates of 7.4%, 3.6%, and 2.6% respectively. Conclusions: CRC liver metastases demonstrate evidence of a large TAM population with significant M2 component and a smaller T cell population. A greater number of TAMs appear to correlate with recurrence, while a more immunogenic phenotype correlates with lower recurrence risk.
Abstract 17784: Self-expandable Transcatheter Aortic Valves Programs In Centres Without On Site Cardiac Surgery: Data From A Multicentre Registry
Authors: Juan G Cordoba-Soriano, Jesus Jimenez-Mazuecos, Jessica Roa-Garrido, Jose F Diaz Fernandez, Gonzalo Gallego-Sánchez, Antonio Gutierrez Diez, Pastor Perez-Santigosa, Lorenzo F Hernando, Francisco J Sánchez-Burguillos, Javier Botas, Rosa Lazaro, Jesus Herrero-Garibi, Francisco Valencia-Serrano, Javier Robles
Journal: Circulation (2016)

Introduction: Current European and American guidelines recommend TAVI procedures only in centres with on site cardiac surgery, due to the possibility of the neediness for emergent open-surgery conversion. The improvements of technology and the higher experience of implant centres have become this scenario in an anecdotal possibility, mainly with the self-expandable devices. Methods: We assess the features and the course of patients undergoing TAVI in six centres without on site cardiac surgery but with the possibility for transfer to a reference centre for urgent cardiac surgery. All procedures were accepted by each heart-team with participation of each cardiac surgeons of reference. VARC-2 criteria were used. Results: A total of 210 patients (81.7 ± 5 years; 48% male; mean STS score 5.1 ± 3%; mean EUROSCORE 18.1 ± 10%, 11% porcelain aorta) were included in this prospective registry. The mean distance from the cardiac surgery centre of reference was 66 Km (0.2-154 Km). The 26% of the procedures were perfo...
Association of baseline and longitudinal low neutrophil-lymphocyte ratio (NLR) and high lymphocyte counts (LCs) with progression-free survival (PFS) and overall survival (OS) in real world advanced non-small cell lung cancer (aNSCLC) patients (pts) treated with nivolumab (nivo) or pembrolizumab (pembro).
Authors: Stephanie Labomascus, Ibtihaj Fughhi, Andrew McDonald, Philip D. Bonomi, Marta Batus, Mary J. Fidler, Sanjib Basu, Jeffrey Allen Borgia
Journal: Journal of Clinical Oncology (2018)

e21020 Background: High baseline neutrophil to lymphocyte ratio (NLR) is associated with inferior OS for patients with stage III/IV NSCLC pts treated with nivo or pembro. This study evaluates potential relationships between baseline and longitudinal NLR and absolute LCs with PFS and OS in aNSCLC pts on nivo or pembro. Methods: Patients with stage III/IV NSCLC who received at least one cycle of nivo or pembro between January 2015 and January 2017 were identified in our pharmacy database. Pt demographics, longitudinal leukocyte counts, treatment start date, date of progression, and last follow-up were recorded. OS and PFS were assessed by log-rank tests and Cox proportional hazard analysis. Time-dependent Cox model based analyses were used to assess association with longitudinal NLR and LCs. A cutoff of NLR 5.0 was used for NLR. Results: The study included 162 aNSCLC pts. Median age 68 yrs, male/female 40.1%/59.9%. NLR > 5.0 was associated with inferior PFS longitudinally. Median PFS values were: baseline NLR > 5/ < 5 = 2.1/3.9 mos (p = 0.03), at 6 wks NLR > 5/ < 5 = 2.6/6.1 mos (p = 0.003), at 12 wks NLR > 5/ < 5 = 3.8/7.1 mos (p = 0.03). NLR > 5.0 was similarly associated with inferior OS at the same intervals. In time-dependent analyses, NLRs as a continuous variable were associated with inferior PFS (HR 1.03, p = 0.02) and OS (HR 1.05, p < 0.001). Longitudinal analyses of LCs as a continuous variable showed that higher LCs over time were associated with superior PFS (HR 0.49, p = 0.0083) and OS (HR 0.357, p = 0.006). Conclusions: Low baseline and longitudinally lower NLRs are associated with longer PFS and OS in aNSCLC pts on nivo or pembro. High baseline and longitudinally higher LCs were associated with superior PFS and OS in the same group. While NLRs and LCs may merely be prognostic indicators, it’s possible that they reflect a patient’s ability to mount an immune response. They may also be useful in guiding strategies to overcome immunotherapy resistance.
Disparities in treatment-related financial burden and recurrence in a diverse sample of colorectal cancer survivors.
Authors: Jean A. McDougall, Matthew P. Banegas, Charles Wiggins, Ashwani Rajput, Vi Kien Chiu, Kristina Flores, Anita Kinney
Journal: Journal of Clinical Oncology (2017)

e18067 Background: The high cost of cancer care creates adverse financial consequences for cancer patients, impacting adherence to treatment, clinical outcomes, and quality of life. Prior studies estimate that 40% of colorectal cancer (CRC) patients experience treatment-related financial burden. This study aims to identify factors associated with financial burden and evaluate its relationship with cancer recurrence. Methods: This cross-sectional study identified individuals diagnosed with stages I-III CRC between 2001 and 2012 through the statewide New Mexico Tumor Registry. A comprehensive survey was administered in 2014. Participants were considered to have experienced financial burden if they reported any treatment-related debt accumulation, bankruptcy filing, other financial sacrifices, or inability to pay medical bills. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Results: Among the 277 CRC survivors who participated in this study, 40% identified as Hispanic and 39% lived in a rural area. Financial burden was reported by 43% of CRC survivors. In a model adjusted for age at diagnosis, sex, race, ethnicity, education, and years since diagnosis, participants who spoke a mixture of English and Spanish (OR: 3.5, 95% CI: 1.3-9.5), those with low health literacy (OR: 2.4, 95% CI: 1.2-4.7), and those with public insurance (OR: 2.2, 95% CI: 1.2-4.4) were more likely to report financial burden. Ethnicity and rural status were not independently associated with financial burden. Six percent (n = 16) of participants experienced a CRC recurrence. Survivors who reported financial burden were 4-times as likely to experience a recurrence (OR: 4.3, 95% CI 1.1-17.7) as those who did not report financial burden. Conclusions: Language, low health literacy, and public insurance may increase the likelihood that CRC survivors experience financial burden. These disparities are alarming given the observed association between financial burden and CRC recurrence. Larger, prospective studies are needed to confirm the association between financial burden and recurrence and to identify potential intervention targets.
Abstract 15198: Infarct Size in Patients on Chronic Statin Therapy Undergoing Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction
Authors: Nicola Cosentino, Sarah Cortinovis, Valentina Milazzo, Mara Rubino, Angelo Cabiati, Monica De Metrio, Marco Moltrasio, Gianfranco Lauri, Gianluca Pontone, Giancarlo Marenzi
Journal: Circulation (2015)

Introduction: Statin pre-treatment has been reported to have a cardio-protective effect in patients undergoing elective or urgent percutaneous coronary intervention (PCI). However, data on ST-elevation myocardial infarction (STEMI) patients undergoing primary PCI are still controversial. Hypothesis: We prospectively evaluated the effect of chronic statin therapy on infarct size (IS), myocardial salvage index (MSI), and micro-vascular obstruction in consecutive STEMI patients undergoing primary PCI. Methods: Two-hundred-thirty STEMI patients (mean age 61±11 years, 183 men) who underwent primary PCI were evaluated with cardiac magnetic resonance (CMR) imaging during hospitalization (median 4 days after primary PCI). In all patients, we measured peak troponin I level, while IS, MSI, and micro-vascular obstruction were determined by CMR. Results: Fifty (22%) patients were on chronic statin therapy and showed a significantly lower troponin I peak value when compared to patients without prior statins (54±47 vs. 88±106 ng/ml; P=0.02). At CMR evaluation, IS related to the index event was significantly smaller (12.5±11.5 vs. 18.5±18.5 grams,P=0.05), and MSI was higher (0.68±0.25 vs. 0.52±0.30; P=0.01) in patients with prior statin therapy. Micro-vascular obstruction was also less frequent (10% vs. 20%; P=0.14) in this group. At multivariable analysis, prior statin therapy remained significantly associated with IS and MSI (P=0.05 and P=0.02, respectively). No significant association was observed between index IS and LDL-cholesterol levels at hospital admission in the entire population (P=0.91). Moreover, no relationship between IS or MSI and statin dose (r=-0.10, P=0.56 and r=0.10, P=0.55, respectively), and length of statin treatment (r=-0.06, P=0.71 and r=0.29; P=0.10, respectively) was found. Conclusions: The results of the present study demonstrated that prior statin therapy is associated with significant smaller IS and higher MSI in patients presenting with STEMI and treated with primary PCI. Whether these preliminary findings will translate into a potential therapeutic strategy warrants further research.
PTH-041 Prospective study of the diagnostic yield from 20g FNB needle in routine upper GI and HPB lesions
Authors: Nazar Aslam, Elaenor Liu, Sameer Shaktawat, Venkat Mahesh
Journal: Endoscopy (2018)

<h3>Introduction</h3> Improvements in the EUS FNA and FNB needle design and optimisation of tissue acquisition techniques have resulted in better diagnostic yield (DY). In addition, recently there has been considerable interest in histological processing of tissue acquired using newer 'core' FNA needles. At BSG 2016 we provided preliminary data on DY of tissue acquired using standard FNA needle. We hereby present data on yield of 20G Cook EchoTip Procore<sup>TM</sup> FNB needle. <h3>Aim</h3> To compare the diagnostic yield of 20G FNB needle and compare the incremental yield of histological over cytological preparation of tissue acquired. <h3>Methodology</h3> Prospective non-blinded randomised study. All patients undergoing EUS guided FNA/FNB from January 2016 to January 2018, for all upper GI and HPB lesions were included. FNB was performed using Cook Echotip Procore 20GTM needle, Olympus EU-ME2TM processor and linear echoendoscopes was used. All patients had 2 or 4 passes done with the same needle, specimens from each pass were randomly collected in BD Cytorich<sup>TM</sup> or Formalin. Each preservative had either 1 or 2 passes of material. Only C5 malignancy diagnosis from the primary pathologist or from second expert opinion with MDT acceptance was considered positive for cancer, other non-malignant conditions was considered as positive for statistical purposes only when clear diagnosis was offered by pathologist. <h3>Results</h3> In total, 147 patients had EUS guided sampling and 111 patients had EUS FNB with 20G FNB needle. 68 M: 43 F. Average age was 66.7 years (±11.3). Of these, 102 had samples both for cytology and histology. Final diagnosis was made in 92 (90.2%) patients. Pancreatic cancer was seen in 52 (51%) patients, cholangiocarcinoma in 7 (6.7%), NET/GIST in 11 (10.8%), Lymphoma in 11 (10.8%), malignant nodes in 6 (5.9%), other cancers (e.g. rhabdomyosarcoma) in 6 (5.9%), benign (e.g. chronic pancreatitis, autoimmune pancreatitis, paraganglioma, reactive nodes etc) in 8 (7.7%), and no diagnosis was made in 10 (9.8%). Histological processing provided answers in 87 (78.3%) patients with combined cytological and histological processing providing diagnosis in the rest of 15 (13.5%) with overall diagnostic yield of 91.9% (102 patients). <h3>Conclusion</h3> Our study results show that adequate samples can be obtained for histological processing with Cooke Procore<sup>TM</sup> FNB needles with good cumulative diagnostic yield (92%) and significant diagnostic yield from preferentially processing samples for histological assessment rather than standard cytology, possibly due to better preservation of tissue architecture and cell morphology. Limitations include non-specialist reporting cytopathologist and non-randomised retrospective design.
Self-management in prostate cancer survivors: A randomized controlled trial.
Authors: Ted A. Skolarus, Tabitha Metreger, Hyungjin Kim, Robert L. Grubb, Jeffrey R. Gingrich, Hui Zhu, Soohyun Hwang, John D Piette, Sarah T. Hawley
Journal: Journal of Clinical Oncology (2018)

5011 Background: The purpose of this randomized trial was to compare a personally-tailored symptom management intervention consisting of 4 automated telephone assessments and tailored education for improving symptom self-management among prostate cancer survivors to usual care (1 non-tailored newsletter about symptom management). We hypothesized improved symptom self-management and prostate cancer quality of life following the intervention. Methods: A total of 556 prostate cancer survivors experiencing symptom burden were recruited from April 2015 to February 2017 across 4 sites. Participants were randomized to intervention (n = 278) and usual care (n = 278) groups as reported in our protocol. Our primary outcome was symptom burden assessed via patient report 5 months after enrollment using the EPIC-26 instrument. Secondary outcomes included psychosocial outcomes and domain-specific changes according to intervention participants’ primary symptom area (urinary, bowel, sexual, general). We used multivariable regression analysis to evaluate intervention impact on outcomes. Results: The mean age of prostate cancer survivors was 66.7 years and the majority was treated with radiation therapy (56.7% vs. 46.2% surgery). The 5 month primary outcome assessment was completed by 89% of participants. There were no baseline differences across groups. At 5 months, we observed differences between groups in urinary domains (irritative - 61.8 control vs. 63.4 intervention, adjusted mean difference (aMD) 2.6, p = 0.07; obstructive - 74.5 control vs. 77.4 intervention, aMD 2.6, p = 0.07) with no significant differences in other outcomes. Intervention participants choosing urinary (crude mean difference (cMD) irritative 3.0; p = 0.09, obstructive 6.1; p < 0.01), bowel (cMD 9.1; p = 0.08), and sexual (cMD 5.6; p < 0.01) domains as their primary focus area reported improvements at 5 months. Participants reported high satisfaction with the intervention. Conclusions: A personally-tailored, automated telephone symptom management intervention for prostate cancer survivors was feasible and led to differences in urinary and sexual health symptoms in this randomized trial. Self-management of treatment-related side effects appears warranted. Clinical trial information: NCT01900561.
Tetrahydrouridine-decitabine for non-cytotoxic epigenetic therapy of NSCLC to enhance immunotherapeutic effect of anti-PD1 in vivo.
Authors: Kai Kang, David S. Schrump, Anish Thomas, Kurt Alex Schalper, Yogen Saunthararajah, Vamsidhar Velcheti
Journal: Journal of Clinical Oncology (2017)

11552 Background: NSCLC response to anti-PD1 therapy is ~20%, largely because most NSCLC avoids immune-recognition in the 1 st place, e.g., by epigenetics to suppress neo-antigen expression. DNA methyltransferase (DNMT1) mediates this repression and is depleted by decitabine (Dec). Unfortunately Dec has trivial distribution into solid cancer tissues because of rapid deamination by cytidine deaminase (CDA). Therefore, to improve tissue-distribution of Dec with the low Cmax/long Tmax profile needed for DNMT1-depletion without cytotoxicity, we combined Dec with a CDA inhibitor tetrahydrouridine (THU). Methods: C57/BL6 mice were inoculated with LL3-luc cells via tail vein. After documentation of lung invasion by live-imaging, mice (n = 5/group) were randomized to PBS, THU-Dec (10/0.1 mg/kg sc 3×/wk), anti-PD1 (5 mg/kg ip q5d, DX400 from Merck) or THU-Dec/anti-PD1 combination. Antigen presentation, PD, MDSCs, and T-cells were measured in blood and tumor. Results: THU-Dec or anti-PD1 alone decreased tumor by imaging and increased survival, however, THU-Dec/anti-PD1 combination extended median survival the most and completely regressed tumor in 2/5 mice (median survival days PBS 37, THU-Dec 56, anti-PD1 62, THU-Dec/anti-PD1 77). Rechallenge of cured mice with LL2-luc confirmed immune-memory effect, with no engraftment vs expected engraftment in controls. Consistent with the pharmacologic rationale, THU-Dec produced &gt; 2-fold more DNMT1-depletion in tumor vs PBS. Consistent with non-cytotoxic effect, absolute lymphocyte counts were preserved with THU-Dec, while numbers of G-MDSC decreased (2.9 k/µL PBS vs 0.3 k/µL THU-Dec/anti-PD1, p &lt; 0.01). Expression of neoantigens MAGE-A1 and MAGE-A3 increased &gt; 4-fold with THU-Dec vs PBS (p &lt; 0.01). THU-Dec/anti-PD1 increased tumor infiltrating lymphocytes 6-fold vs PBS (p &lt; 0.01) and decreased regulatory T-cells 2.5-fold vs PBS (p &lt; 0.01). IFNγ expression in tumor increased 2.4-fold with THU-Dec/anti-PD1 vs PBS (p &lt; 0.01). Conclusions: THU-Dec/anti-PD1 produced marked survival improvements and cures in tumor-bearing mice, scientific validation of our clinical trial NCT02664181 combining THU-Dec/nivolumab in 2 nd line for NSCLC.