tbuckley/cabot-search huggingface dataset:
Is surgical resection justified for hepatocellular carcinoma with portal vein tumor thrombus? A systematic review and meta-analysis.
Authors: Li-Yang Sun, Lei Liang, Jiong-Jie Yu, Ju-Dong Li, Xin-Fei Xu, Wen-Tao Yan, Bing Quan, Jia-He Wang, Zhen-Li Li, Jun Han, Hao Xing, Han Wu, Han Zhang, Zheng Wang, Chao Li, Ming-Da Wang, Meng-Chao Wu, Feng Shen, Tian Yang
Journal: Journal of Clinical Oncology (2018)

e16111 Background: The prognosis of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) is very poor. According to the BCLC treatment recommendations, sorafenib or other palliative treatment (PT) is recommended as the first-line therapy when it happens. In real world, however, a significant number of selected patients with HCC and PVTT suffered from surgical resection (SR). Methods: PubMed, Embase, Medline and Cochrane library were searched for studies comparing SR with PT (including TACE, sorafenib, etc.) for HCC with PVTT, which were published before September 2017. Results: 4,810 patients from 7 studies were enrolled in this meta-analysis, which divided into the SR group (n = 2,344) and the PT group (n = 2476). When compared with the PT group, the pooled hazard ratio (HR) for the 1, 3 and 5-year OS rates of the SR group were 0.56 (95% CI 0.52–0.60, P = 0.03), 0.56 (95% CI 0.53–0.59, P < 0.001) and 0.55 (95% CI 0.54–0.57, P < 0.001). For subgroup analysis, when compared with the mere TACE group, the pooled HR for the 1, 3 and 5-year OS rates of the SR group were 0.54 (95% CI 0.43–0.67, P = 0.81), 0.75 (95% CI 0.65–0.87, P = 0.25) and 0.76 (95% CI 0.67–0.88, P = 0.25). Conclusions: This meta-analysis demonstrated SR had better OS than TACE or other palliative therapy for HCC with PVTT. SR may be suitable as the first-line treatment for selected patients with resectable HCC and removable PVTT.
Using circulating tumor DNA analysis to depict genomic profiles and predict survival outcomes in patients with small-cell lung cancer.
Authors: Jinghui Wang, Jingying Nong, Yuhua Gong, Shuai Sun, Yuting Yi, Yan-Fang Guan, Ling Yang, Hongyan Jia, Shucai Zhang, Xuefeng Xia, Xin Yi, Zhongxing X. Liao
Journal: Journal of Clinical Oncology (2017)

8567 Background: Small-cell lung cancer (SCLC) accounts for approximately 15% of lung cancers. Most patients have extensive-stage disease with widespread metastases and poor survival. Understanding the molecular mutation profile of each SCLC patient would allow precision treatment and improved clinical outcome. However, tumor tissues from surgery are not available for most SCLC patients and biopsy specimens are often have limited quantities. Several studies have provided evidence of circulating tumor DNA (ctDNA) in detecting somatic variants of multiple solid tumors. This study evaluated utility of ctDNA to depict genomic profiles and predict survival outcomes in SCLC patients. Methods: 22 Plasma samples were obtained before initial treatment from 22 patients with SCLC enrolled between 2012 and 2016. Targeted-capture deep sequencing was performed to identify somatic variants in 465 cancer-related genes. Genomic mutation profiles were described and the clinical implications were further analyzed. Results: Tumor DNA can be detected in all 22 plasma samples collected from patients with SCLC. In total, 340 variants were identified, and the mean and median mutation rate were 6.3 and 6.6 per Mb. TP53 and RB1 are the most frequently mutated genes, detected in 90.9% (20/22) and 59.1% (13/22) patients, respectively. Further analysis showed that high ctDNA fraction in cell-free DNA (cfDNA) was associated with heavy tumor burden (R = 0.7, p = 0.0017). Moreover, patients with high ctDNA fractions (ctDNA fraction &gt; = 18.3%) had poor progression free survival (PFS) (HR, 17.2; p = 0.0019). The median PFS of patients with high versus low ctDNA fractions was 5.2 months (95% CI 4.6 to 5.8 months) versus 10.0 months (95% CI 9.3 to 10.7 months), respectively. Conclusions: In this study, ctDNA analysis offers a promising way to depict the molecular profile in patients with SCLC. Moreover, these findings highlight the potential clinical utility of ctDNA to predicate clinical outcome in SCLC.
Abstract 18217: Adult Height, Lifestyle and Healthy Aging
Authors: Wenjie Ma, Kaitlin Hagan, Qi Sun, Eric B Rimm, Lu Qi
Journal: Circulation (2016)

Introduction: Adult height has shown directionally diverse associations with several age-related diseases including cardiovascular disease and cancer, as well as mortality. However, it remains unknown how height is associated with overall health and well-being among populations who have survived to older age, and whether lifestyle modulates such relations. Methods: The current analysis consisted of 52,134 Nurses’ Health Study (NHS) participants without chronic diseases in 1980 and whose health status was updated until 2012. Current height was inquired at NHS study enrollment in 1976. Healthy aging was defined as being free of 11 major chronic diseases and having no reported impairment of subjective memory, physical impairment, or mental health limitations. Results: Of all eligible study participants, 6,877 (13.2%) were classified as healthy agers. After adjustment for demographics and lifestyle factors, we observed an 8% (95% confidence interval [CI]: 6% to 11%) decrease in the odds of healthy aging per s...
Detection of HRD gene mutations and copy number changes in cfDNA from prostate cancer patients.
Authors: Chris Raymond, Jenny Hernandez, Reynolds Brobey, Yue Wang, Kristy Potts, Kavita Garg, Lee Lim, Dan DiPasquo, Mark Li, Mehdi Dehghani, Robert J. Amato
Journal: Journal of Clinical Oncology (2017)

e16546 Background: Recent genomic surveys of prostate cancer have identified somatic mutations in metastatic castration-resistant prostate cancer (mCRPC). In this study, we examined mCRPC patients for AR aberrations and mutations in the HRD (homologous recombination DNA-repair) pathway which may confer platinum or PARP inhibitor sensitivity. Methods: A novel targeted-hybrid-capture NGS assay capable of identifying deleterious mutations, copy number amplification and gene copy loss, was applied to circulating, cell-free DNA (cfDNA) extracted from plasma samples from 20 mCRPC patients. Samples were collected between 3/2010 – 10/2015 and stored at -20C. The gene panel used in the assay included AR and several genes in the HRD pathway — ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, NBN, PALB2, and RAD51. Sequencing libraries created with the cfDNA extracted from 2.8-4 mLs of plasma had an average unique read coverage depth of 2282 genome equivalents (range 445 – 5136, median 2181). Results: Somatic variations were observed in 17 of the 20 samples analyzed. Copy number variation (CNV) was observed in 11 samples. AR amplification, linked to resistance to abiraterone and enzalutamide, was observed in 30% (6) of samples. Canonical AR ligand binding domain mutations, such as T787A and L702H were also detected. ATM, BRCA1, BRCA2, HDAC2, and FANCA gene deletions were also detected, as well as frameshift, nonsense, and other deleterious mutations in HRD genes. Significant CNV in multiple genes was observed in at least 5 patient samples. Mutations were detected across the entire collection date range, speaking to the robustness of cfDNA. Conclusions: Non-invasive tumor mCRPC genotyping appears to be feasible. The ability to detect HRD gene alterations suggests cfDNA testing may be suitable for the detection of HRD pathway defects and overall genome instability.
Results of PROSPECT: A randomized phase 3 trial of PROSTVAC-V/F (PRO) in men with asymptomatic or minimally symptomatic metastatic, castration-resistant prostate cancer.
Authors: James L. Gulley, Michael Borre, Nicholas J. Vogelzang, Siobhan Ng, Neeraj Agarwal, Chris C. Parker, David William Pook, Per Rathenborg, Thomas W. Flaig, Joan Carles, Neal D. Shore, Liddy Chen, Christopher Ryan Heery, Winald R. Gerritsen, Frank Priou, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2018)

5006 Background: PRO is a PSA-targeted, poxvirus-based cancer vaccine using a heterologous prime-boost regimen comprising a recombinant vaccinia vector prime followed by 6 booster doses with the recombinant fowlpox vector. PROSPECT was designed as a confirmatory trial of a prior randomized phase 2 trial (RandPh2) that showed 8.5 months prolongation of median OS (25.1 m PRO vs 16.6 m Placebo (Pbo)) (Kantoff, JCO 2010; 28:1099) Methods: Double-blind randomization to one of the following 3 arms: PRO+Pbo (V), PRO+GM-CSF (VG), or Pbo+Pbo (P). Stratified per PSA < or ≥ 50 ng/mL and LDH < or ≥ 200 U/L. Primary Endpoint: OS. Secondary endpoints: Alive without event at 6 months (AWE-6) and Safety. Results: Between Dec 2011 and Jan 2015, 1297 pts were randomized in 15 countries. Demographics: mean age: 71 (SD: 8.25), ECOG PS0/1-2: 74%/26%, mean PSA: 74.5 (SD:209). Site of metastasis: bone 74.7, lymph node 15.7, visceral 8.4%. The 3rd interim analysis was held in Sep 2017, after reaching 80% of the expected deaths, and the DMC recommended closure of the study on grounds of futility. The K-M OS curves showed a substantial overlap between the 3 arms and the planned statistical analysis showed statistically non-significant differences. Median OS was 34.8, 33.9 and 34.7 months for V, VG and P arms respectively. Two comparisons were prespecified: V vs P and VG vs P, and the HR were 1.02 (p = 0.40) and 1.03 (p = 0.66) respectively. No benefit was seen in the secondary endpoint AWE6. Although 91% of patients experienced AEs of any grade, and 65% experienced injection site reactions, only 5.8% lead to premature discontinuation of treatment. Conclusions: PROSPECT failed to confirm an OS benefit observed in a prior RandPh2. Of interest, OS observed in all arms was approximately one year longer than anticipated based upon historical controls, likely related to improved standard of care since study enrollment began in 2011. Clinical trial information: NCT01322490.
Abstract 21202: 5-Aminolevulinic Acid Combined With Sodium Ferrous Citrate Ameliorates Post Cardiac Ischemia/Reperfusion Injury via Regulating Inflammatory Cytokines
Authors: Yu Oimatsu, Koichi Kaikita, Masanobu Ishii, Yasuhiro Izumiya, Kenichi Tsujita
Journal: Circulation (2017)

Post ischemia/reperfusion injury (I/R) reduces beneficial effect of restoration of coronary flow in the setting of acute myocardial infarction. Heme oxygenase-1 (HO-1) is inducible enzyme, and plays a crucial role in reaction against for oxidative stress, inflammatory, and apoptosis. Previous studies reported that HO-1 could reduce the infarct size after ischemia/reperfusion injury (I/R). 5-aminolevulinic acid (5-ALA) is known to be a naturally occurring metabolic precursor of heme, and 5-ALA combined with ferrous iron can induce HO-1 in various cells. In this study, we investigate the protective effect of 5-ALA pretreatment after I/R using mice model. Male C57/BL 6J mice (8-12 weeks of age and weighing 21-26 g) were pretreated with 100 mg/kg 5-ALA/HCL and 157 mg/kg sodium ferrous citrate or placebo 48, 24, 1 h before I/R, and underwent 50 minutes of left coronary artery occlusion followed by 24 h reperfusion. Infarct area (IA), area at risk (AAR), and area of left ventricle (LV) were determined by 5% Evans blue and 1% triphenyltetrazolium chloride (TTC) double staining after 24h reperfusion (Figure [A]). Pretreatment of 5-ALA group significantly reduced IA/AAR compared to the placebo group (34.0% [28.1 - 37.6%] VS 51.7% [45.8 - 54.0%], p= 0.001, n=6, Figure [B and C]). Real time PCR assay after 24h reperfusion showed that expression of mRNA of TNF-α (p=0.040), IL-1β(p=0.024), MMP-9 (p=0.011) and BNP (p=0.046) were significantly lower in 5-ALA group than that in placebo group. These findings suggested that 5-ALA pretreatment regulated inflammatory reaction after I/R. The beneficial effect of 5-ALA could be related with HO-1 induction. In conclusion, pretreatment of 5-ALA combined with ferrous iron could play a protective role after I/R by attenuating inflammatory reaction.
Abstract 11983: Delayed Inhalation of Hydrogen Mitigates Neurological Dysfunction in a Porcine Model of Cardiac Arrest and Cardiopulmonary Resuscitation
Authors: Zhengfei Yang, Tao Yu, Cai Wen, Xiaozhu Zhai, Mary Ann Peberdy, Joseph P Ornato, Wanchun Tang
Journal: Circulation (2016)

Introduction: Immediate inhalation of hydrogen (H 2 ) has been demonstrated to improve post-resuscitation (PR) neurological dysfunction. However, early applying inhaled H 2 is not practical especially in out of hospital cardiac arrest because of the safety issue. In the present study, we investigated the effects of delayed treatments with H 2 on post resuscitation neurological function in a porcine model of prolonged cardiac arrest (CA). Hypothesis: Delayed inhalation of H 2 mitigates neurological dysfunction after resuscitation in a CA porcine model. Methods: Eighteen male domestic pigs weighing 39±2 kg were utilized. Ventricular fibrillation (VF) was induced electrically and CPR was initiated after 10 mins of untreated VF. All the animals were resuscitated successfully and randomized into two groups immediately following resuscitation: delayed inhalation of H 2 (DH group, N=9) or inhalation of room air (C group, N=9). Animals in the DH group were ventilated with 2% H 2 /21% oxygen from 2h post resuscitation (PR) to PR 4h. Serum levels of S100B and neuron-specific enolase (NSE) were measured by ELISA at baseline and PR 360 min. The neurological deficit score (NDS) and survival were evaluated daily for a total of 72 hours. Results: Better survival duration and NDS at 24h, 48h and 72h were observed in the DH group animals compared with those of the C group (Table). The serum levels of S100B and NSE were significantly lower in the DH group when compared with the C group (Figure). Conclusion: Delayed treatment of H 2 mitigates neurological injury and improves neurological dysfunction after resuscitation.
Salinomycin reduces the viability of circulating epithelial tumor cells (CETCs) and tumorspheres cultured from circulating cancer stem cells (cCSC) and may potentially prevent progression in patients with solid cancer.
Authors: Monika Pizon, Dorothea Schott, Katharina Pachmann, Ulrich Pachamnn, Norbert Szalus
Journal: Journal of Clinical Oncology (2017)

e23143 Background: Recently the hypothesis has been proposed that a more aggressive subpopulation of circulating tumor cells, circulating cancer stem cells are the source of metastatic spread from the primary tumor. These cells are considered to be responsible for treatment relapse and have therefore become a major target in cancer research. The antibiotic Salinomycin has been shown to reduce the expression of markers for stemness and spheroid-forming ability. In this study, we evaluated the cytotoxic effect of salinomycin on CETCs and tumorspheres cultured from cCSC. Methods: 20 patients with solid tumors in different stages of disease were included. The determination of CETCs and cCSC was performed using maintrac method and tumorsphere forming assay, respectively. To evaluate the cytotoxic effect of salinomycin on CETCs and spheroids they were exposed to different concentrations of salinomycin in short time culture for different periods of time. Results: 80% of patients had detectable CETCs but sphere formation was observed in 95% of solid cancer patients. Growth of spheroids was detected also in patients without CETCs. The number of tumorspheres increased significantly with tumor progression. Treatment with salinomycin showed an 80% reduction in spheroid formation compared with control. Salinomycin reduced the viability of spheroids in a dose–dependent manner. Salinomycin had stronger cytotoxic effect on CETCs in non-metastatic as compared to metastatic patients (median of dead CETCs 85% vs. 34%, p &lt; 0.001). Patients without chemotherapy responded better to salinomycin treatment than patients after several lines of chemotherapy (median of dead CETCs 87%vs.35%, p &lt; 0.001) Conclusions: Using a method for cultivation of tumorspheres from blood of cancer patients and an effective in vitro platform for screening anti-cancer stem cells drugs was developed. Thus it could be shown that salinomycin targets not only more differentiated circulating cancer cells but also cancer stem cells from peripheral blood. It may evolve as a novel and promising therapeutic strategy for future cancer treatment
Exome sequencing of ovarian cancer patients to identify variants predictive of sensitivity to chemotherapy.
Authors: Assaad Semaan, Kristin Delfino, Andrew Wilber, Kathy Robinson, Laurent Brard, Shaheen Riadh Alanee
Journal: Journal of Clinical Oncology (2016)

e17079 Background: Studies have found that genetic determinates can predict response to chemotherapy in some cancer patients. However little is known about ovarian cancer. By using exome sequencing, potential alleles predictive of sensitivity to cisplatin treatment could be enriched. Methods: The study group was comprised of 22 sensitive and 6 patients resistant to adjuvant chemotherapy containing a platinum drug. Sensitivity was defined as disease free survival greater than 6 months. We compared the exome sequences of sensitive vs. resistant patients using next-generation sequencing. Single nucleotide variants (SNVs) associated with sensitivity to platinum drugs was identified using Ingenuity Variant Analysis. Results: Mean age was 58.36 years for sensitive, and 58.17 years for resistant patients. All patients were white except for one African American patient in the sensitive group. Whole exome sequencing identified 33 SNVs unique to sensitive and 9 variants unique to resistant patients that are associated with response to chemotherapy. Three genes were significantly mutated in sensitive vs. resistant patients. IGF1R was mutated in 59% sensitive and 0% resistant patients (14 variants, p-value 1.247 E-2), LRP2 was mutated in 54% sensitive and 0% resistant patients (12 variants, p-value 3.196 E-2), and NCAPD2 was mutated in 50% sensitive and 0% resistant (7 variants, p-value 4.71 E-2). AFF1 was mutated in 50% resistant and 0% sensitive (3 variants, p-value 3.2 E-3), BRCA2 was mutated in 50% resistant and 0% sensitive (3 variants, p-value 2.4 E-3), and PRKDC was mutated in 50% resistant and 0% sensitive (3 variants, p-value 2.9 E-3). Conclusions: Using exome sequencing to identify novel variants that may be predictive of sensitivity to treatment is one approach to overcoming the statistical limitations of genome wide studies. Here we successfully identified variants unique to treatment sensitivity in patients receiving platinum drugs for ovarian cancer. With validation of these variants it is possible that new markers predictive of patient response may be identified.
Clinical development of 4SC-202, a combined epigenetic inhibitor of HDAC class I and LSD1, to overcome anti-PD-1 refractoriness and increase efficacy of checkpoint inhibition.
Authors: Frank Hermann
Journal: Journal of Clinical Oncology (2017)

e14096 Background: Checkpoint inhibitor (CI) like anti-PD(L)-1 antibodies are a breakthrough innovation, but a high unmet medical need remains for a large proportion of patients not responding. Low mutational load, microsatellite stability and a non-inflamed tumor microenvironment have been described as negative predictive factors. A promising approach to increase the benefit from anti-PD(L)-1 treatment is to alter the tumor microenvironment to a more immune-inflamed phenotype by combination assets. Epigenetic modulation has been reported as one key determining factor in shaping the immune microenvironment and compounds altering these processes, like histone deacetylases (HDAC) inhibitor in particular offer a promising approach. Methods: We report preclinical results from the small molecule compound 4SC-202, an orally available clinical stage epigenetic inhibitor, specifically targeting HDAC class I and lysine-specific demethylase LSD1. Results: 4SC-202 has shown the ability to elicit a variety of immune modulating effects on tumors and their microenvironment by enhancing the expression of tumor associated antigens as well as MHC and co-stimulatory molecules. Combination treatment of 4SC-202 with CI in syngenic mouse models showed a strong synergistic effect leading to enhanced tumor reduction when compared to 4SC-202 or checkpoint inhibitor treatment alone. Importantly, 4SC-202 strongly increased the number of tumoricidal cytotoxic T cells (CTL) without affecting the viability of activated T cells. Conclusions: Anti-PD(L)-1 refractory/non-responding patients remain a population with a high unmet medical need, increasing in number over time. Advanced melanoma is the model tumor for immunotherapy in general and CI in particular. Based on the strong preclinical rationale, we hypothesize that the addition of 4SC-202 to anti-PD-1 treatment may lead to increased immunogenicity of the tumor, an inflamed tumor microenvironment and subsequent clinical benefit in anti-PD-1 refractory/non-responding melanoma patients. The “SENSITIZE” study is intended to proof this concept in a phase Ib/II clinical trial.
Outcome of patients undergoing delayed debulking surgery (DDS) in advanced ovarian cancer (OC).
Authors: Shanthini M Crusz, Dhivya Chandrasekaran, Saurabh Phadnis, Michael John Delvin, Mary Quigley, Melanie E Powell, Arjun Jeyarajah, David Oram, Alexandra Lawrence, Naveena Singh, Ranjit Manchanda, Elly Brockbank, Rowan E Miller
Journal: Journal of Clinical Oncology (2018)

e17530 Background: There are limited data evaluating the outcomes of DDS in women with advanced OC receiving 6 cycles of neoadjuvant chemotherapy (NACT). Methods: Retrospective analysis of patients with advanced OC who were deemed not suitable for primary surgery or interval debulking surgery (IDS) after 3 cycles of NACT, but underwent DDS following 6 cycles of NACT between 2004 and 2016 at Barts and The London Hospital, UK. Results: Twenty-nine patients underwent DDS. Median age was 60 (IQR 51-66). 34% (10/29) had stage 3C and 59% (17/29) had stage 4 disease. The majority (97%) had high grade serous histology. 4/29 (14%) received single-agent carboplatin, 20/29 (69%) received carboplatin/paclitaxel, 4/29 (14%) received carboplatin/paclitaxel/avastin and 1/29 (3%) other combination. Reasons for patients being unsuitable for IDS following 3 cycles of NACT were disease in anatomical sites deemed unresectable in 90% (26/29) and unfit for surgery in 10% (3/29). 28% (8/29) of patients underwent upper abdominal surgery. Complete cytoreduction (R0) was achieved in 57% (17/29) and R1 resection ( < 1cm residual disease) in 24% (7/29). 21/29 (72%) patients received 2 cycles of adjuvant chemotherapy following surgery. Of the 26 patients who have documented recurrence, the median progression free survival (PFS) was 17 months (95% CI 13.7, 20.2). Median overall survival (OS) was 36 months (95% CI 21.0, 51.0). Conclusions: Despite limited numbers, the OS data for patients undergoing DDS is promising and whilst we have no direct comparison group, the OS compares favourably to patients with advanced OC who do not undergo surgery at any stage (18 months, Marchetti et al 2017). Prospective studies are required to confirm the benefit of DDS in patients whose disease is not amenable to IDS.