tbuckley/cabot-search huggingface dataset:
E-cigarette use among patients of smoking-related cancers in the United States.
Authors: Oladimeji Akinboro, Rawad Elias, Stanley Madu Nwabudike, Oluseyi Balasire, Jamie S. Ostroff
Journal: Journal of Clinical Oncology (2018)

10052 Background: The prevalence of e-cigarette use, and its impact on smoking cessation, among cancer survivors in the United States is unknown. We sought to estimate the prevalence of e-cigarette use, and examine its associations with cigarette smoking and quit attempts among survivors of smoking-related cancer survivors in the United States. Methods: We obtained data from the 2014-2016 annual cycles of the National Health Interview Survey. Our study sample comprised 2,561 adults with self-reported lifetime histories of at least one smoking-related cancer. We calculated the prevalence rates of e-cigarette use among survivors of smoking-related cancers. Using a multivariable logistic regression model, we examined independent associations of cigarette smoking history with e-cigarette use while adjusting for sociodemographic and other patient variables that were associated with e-cigarette use from the bivariate analyses. Survey weights were applied in estimating the population-based prevalence rates, odds ratios (OR), and 95% confidence intervals (CI). Results: The prevalence of e-cigarette use among survivors of smoking-related cancers was 3.31% (95% CI 2.39%, 4.56%). Those aged 18-44 years had the highest rates of e-cigarette use of any age group (7.26%; 95% CI 2.80%, 11.72%; p-value for age: < 0.001). No associations were seen between e-cigarrete use and gender, race, presence of other smoking-related comorbidities, or duration of survival. Current cigarette smokers were 31 times as likely as never smokers to use e-cigarettes (OR 31.48; 95% CI 4.54, 218.16). Among current smokers, no association was seen between e-cigarette use and either the number of quit attempts or smoking cessation counselling by health professional in the prior year. Conclusions: E-cigarette use was highest among current smokers and relatively young survivors of smoking related cancers. The lack of association between e-cigarette use and smoking quit attempts supports observations that e-cigarettes do not increase smoking quit rates. This is concerning, and highlights the need for further studies to define the impact of e-cigarette use on smoking cessation, and long-term outcomes of survivors of smoking-related cancers.
Safety and pharmacodynamics of the DRD2 antagonist ONC201 in advanced solid tumor patients with weekly oral administration.
Authors: Mark N. Stein, Jyoti Malhotra, Usha Malhotra, Ann W. Silk, Nancy Chan, Lorna Rodriguez-Rodriguez, Joseph Aisner, Robert Aiken, Jenna Newman, Evita Sadimin, Tracie Saunders, Melissa Frankel, Aparna Kareddula, Wafik S. El-Deiry, Rohinton Tarapore, Joshua E. Allen, Joseph R. Bertino, Steven K. Libutti, Janice M. Mehnert, Andrew Zloza
Journal: Journal of Clinical Oncology (2018)

2595 Background: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy in preclinical cancer models via induction of the CHOP/DR5-mediated integrated stress response pathway and caspase-dependent apoptosis. In addition to cytotoxic effects in tumor cells, DRD2 antagonism can induce the activation of NK and other immune cells. The first-in-human trial of ONC201 previously established a recommended Phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a Phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics with weekly oral administration of ONC201. Methods: Patients ≥18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of ONC201 with weekly oral administration, which was subsequently confirmed in an 11-patient dose expansion cohort. Results: A total of 20 patients were enrolled: 3 at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. Pharmacokinetic profiles were consistent with every three week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 were detected, along with intratumoral induction of integrated stress response (CHOP/DR5), apoptosis (TUNEL) and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effector molecules was higher in patients who received ONC201 once every week versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions: Weekly, oral ONC201 is well-tolerated and results in prolonged stable disease, intratumoral apoptotic signaling and enhanced immunostimulatory activity that warrants further investigation. Clinical trial information: NCT02250781; NCT02324621.
Tyrosine kinase inhibitor (TKI) cessation in advanced non-small-cell lung cancer (aNSCLC) for improved detection of EGFR-mutated (EGFRm) circulating tumor DNA (ctDNA).
Authors: Samer Tabchi, Stephanie Forte, Raafat Alameddine, Aline Khazaka, Marie Florescu, Xiaoduan Weng, Mustapha Tehfe, Normand Blais
Journal: Journal of Clinical Oncology (2018)

e21064 Background: First/second generation EGFR-TKI are eventually met with therapeutic failure in EGFRm aNSCLC, but treatment continuation beyond initial progression can delay the need for second line therapy by a median of ~ 3 months. In this context, osimertinib was shown to be effective in T790M mutated EGFR, which occurs in > 50% of cases. T790M detection within ctDNA is convenient but has suboptimal sensitivity. The goal of this study is to determine whether temporary TKI cessation - beyond initial progression - would allow for increased plasma detection of EGFR mutations. Methods: EGFRm aNSCLC patients who were still on a TKI beyond initial progression were enrolled. TKI was withheld on day 0. Blood samples were drawn and the NCCN-FACT FLSI-17 questionnaire (version 2) was administered on days 0 and 6±1. Semi quantitative measurements of EGFR mutations within plasma samples were obtained using the cobas EGFR Mutation Test v2. Descriptive statistics were reported and paired t-test was used to compare differences in ctDNA yield and quality of life after TKI cessation. Results: 33 patients were enrolled in 2017. Median age was 71 years (46 - 87). 75.8% were women. Median time to progression on first/second generation TKI was 19.76 mo (0.3 - 46). Temporary TKI cessation was safe with no tumor flares reported. Questionnaire scores indicate a trend towards improved quality of life one week after TKI cessation (p = .08). Baseline EGFR and T790M mutations were detected within ctDNA in 63.6% and 27.3% of cases, respectively, with 33.3% and 19% of the detection occurring on only one of the two test days for both respective mutations. The yield of detection was significantly higher after TKI cessation for the baseline mutation (mean semi-quantitative index 5.2±6.2 on d0 and 6.1±6.4 on d6/7; p = .043) but not for T790M (p = .46). Conclusions: Our data suggest that TKI cessation can lead to increased shedding of ctDNA in sensitive cells. In contrast, drug withdrawal may not impact the shedding of ctDNA in resistant clones. Irrespective of drug withdrawal, a strategy of repeat testing appears more sensitive in the detection of tumoral mutations than performing this assay only once.
Comparative effectiveness study of first-line pemetrexed-platinum doublet chemotherapy with or without bevacizumab for Chinese patients with advanced non-squamous non-small-cell lung cancer.
Authors: Xiaoyou Li, Li Wang, Yi Wen, Meiqi Shi
Journal: Journal of Clinical Oncology (2018)

e21053 Background: Bevacizumab plus platinum-based doublet chemotherapy is recommended by NCCN as a category 1 regimen and is widely used for advanced NS-NSCLC. In China, one of the most common first-line chemotherapy for NS-NSCLC is pemetrexed-platinum doublet (Pem-Pt), but the evaluation of bevacizumab plus Pem-Pt (B+Pem-Pt) is limited. This study describes real-world effectiveness of B+Pem-Pt in Chinese NS-NSCLC patients. Methods: From Jan 2012 to Mar 2017, patients with advanced NS-NSCLC receiving Pem-Pt or B+Pem-Pt were retrospectively collected. The effectiveness outcomes included median PFS and/or ORR of the overall population, the patients with malignant pleural effusion (MPE) or brain metastasis (BM), and those receiving maintenance therapy (MT) with or without bevacizumab. Results: Among 236 patients meeting selection criteria, 96 received B+Pem-Pt versus 140 received Pem-Pt. Comparing to Pem-Pt, the Pem-Pt+B regimen led to a longer median PFS (11.0 vs. 6.6 months, HR, 0.59; 95%CI, 0.42-0.83; P< 0.0001), and a higher ORR (63.5% vs. 20.8%, OR = 7.1, 95%CI, 3.73-13.54) in the overall population. The patients chose MT with bevacizumab showed a longer median PFS (11.6 vs. 7.2 months; P < 0.001) than those chose non-bevacizumab MT. The significant effectiveness of Pem-Pt+B was demonstrated in patients without MPE or BM, and improved trends of Pem-Pt+B were likewise observed in patients with MPE or BM (Table 1). The safety profile was acceptable, with no observation of hypertension, proteinuria, severe bleeding, nor any new unexpected findings. Conclusions: These real-world data confirmed the superiority of bevacizumab plus pemetrexed-platinum doublet in Chinese advanced NS-NSCLC patients, with acceptable adverse effects. Table 1. Comparison of PFS between B+Pem-Pt and Pem-Pt in subgroups. Median PFS (Months) HR (95% CI)* P # BM YES 0.84 (0.41,1.71) 0.45 B+Pem-Pt 7.8 Pem-Pt 5.9 NO 0.51(0.34,0.78) 0.001 B+Pem-Pt 11.0 Pem-Pt 7.3 MPE YES 1.08 (0.56,2.08) 0.71 B+Pem-Pt 9.7 Pem-Pt 7.2 NO 0.47 (0.31,0.72); < 0.0001 B+Pem-Pt 13.1 Pem-Pt 6.2 * Multivariate Cox regression analysis # Log-Rank test
An innovative approach by Nabi Akram Hospital in Iran's Khonj Town to bring women for a health checkup event with a focus to identify women with risk factors for breast cancer.
Authors: Atefeh Raoufi, Adnan Ahmadiazad, Zahra Sarraf, Rashin Modi, Esmael Karimi, Mi'araj Ahmadiazad, Mohammad Shahbazi
Journal: Journal of Clinical Oncology (2016)

e17029 Background: Women breast cancer mortality is a major issue, with adverse consequences on the family members left behind globally and Iran is no exception. In fact, the overall cancers rates have significantly increased in Iran over the past decades; the women breast cancer in particular. It has been documented that the prevalence of breast cancer is one third of all cancers and that the rate of breast cancer mortality in Iran increased from 3.93 in 2006 to 4.92 per hundred thousand in 2010 and it is on rise. What has not been document is can innovative screening approaches in a conservative town-culture society, where the word cancer scares people, save lives? This clinical pilot project aimed at answering this very question empirically. Methods: To attract women to the Nabi Akram Hospital, presence of a team of healthcare providers, including a professionally established gyn-oncologist was announced in Khonj, a strategically located town in southern Iran that provides healthcare services to a huge urban- and rural-based population. Using the Millions Women Study (MWS) breast cancer questionnaire, 26 women (mean age of 41) were screened. Results: Fifty four percent of the participating women had never been screened for breast cancer. Three cases were identified as at risk for breast cancer. One case of breast cancer was recorded, and several cases of chronic diseases (HTN and diabetes) were identified. These cases were scheduled for treatments/chronic disease managements. Conclusions: Innovative and culturally sensitive approaches can bring women for a general health checkup without mentioning the word cancer and in the process gynecological cancer screening instruments (such as MWS instrument) can be utilized to identify women at risk for cancers, breast cancer in particular. With this pilot project's successful outcomes and the established community trust and interests in such services, some 30,000 women will be screened in 2016.
Evaluation of liquid biopsies for molecular profiling in untreated patients with stage III/IV non-small cell lung cancer (NSCLC).
Authors: Benjamin Besse, Jordi Remon, Ludovic Lacroix, Laura Mezquita, Cecile Jovelet, Karen Howarth, Vincent Plagnol, Clive D. Morris, Chloe Pannet, Claudio Nicotra, Emma Green, Jean-Charles Soria
Journal: Journal of Clinical Oncology (2017)

11540 Background: Molecular profiling is limited by tumour heterogeneity and access to sufficient tissue for comprehensive analysis. Circulating tumour DNA (ctDNA) can be used as a minimally-invasive liquid biopsy for mutation detection, quantification and monitoring for personalised treatment strategies. Methods: We recruited 110 patients into a prospectively-designed study for Stage III/IV NSCLC patients intended to initiate 1 st line platinum-based chemotherapy. Blood collections (10ml K2-EDTA) were performed prior to treatment and analysed by InVision (enhanced tagged-amplicon sequencing) using a 34-gene panel. Tissue biopsies, when available, were analysed by NGS (Ion-Torrent, Sanger) for concordance analysis. To evaluate correlation with outcome, repeat blood collections were performed in selected patients. Results: 110 NSCLC pts were included (61% male, 14% never-smoker, and 70% adenocarcinoma). ctDNA profiling detected mutations in 83 pts (79%). TP53 (44%), KRAS (17%), STK11 (18%; 11/19 with KRAS/STK11) and EGFR (10%) were the commonest abnormalities detected. Additionally, MET (6%), ERBB2 (6%), PIKC3A (6%) and BRAF (4%) mutations and EGFR, MET, ERBB2 amplifications were detected in 2% of patients, respectively. 20% of the mutations detected in ctDNA were observed at &lt; 0.5% allele fraction, with 6% between 0.03%-0.25% AF. Tissue was available in 44 pts; somatic mutations were detected in 73%. Tissue &amp; liquid concordance was 92.3%. 10 pts (23%) reported as tissue negative had a positive liquid biopsy. 33 advanced NSCLC patients were evaluated for longitudinal serial ctDNA monitoring up to cycle 4 of chemotherapy; the ratio of mutated molecules between D1 and D42 was significantly correlated with change in RECIST 1.1 measurement at D42 (p-value = 0.002625 CI 95% 0.298, 0.875). Conclusions: ctDNA can be used as a ‘liquid biopsy’ for molecular profiling of NSCLC patients to detect clinically relevant and actionable mutations when tissue biopsy is unavailable. Liquid biopsies can be used longitudinally and may provide an early surrogate for response evaluation by radiographic RECIST.
Thrombopoietin receptor–independent stimulation of hematopoietic stem cells by eltrombopag
Authors: Yun-Ruei Kao, Jiahao Chen, Swathi-Rao Narayanagari, Tihomira I. Todorova, Maria M. Aivalioti, Mariana Ferreira, Pedro M. Ramos, Celine Pallaud, Ioannis Mantzaris, Aditi Shastri, James B. Bussel, Amit Verma, Ulrich Steidl, Britta Will
Journal: Science Translational Medicine (2018)

Eltrombopag stimulates multilineage hematopoiesis through intracellular iron chelation.
P04.09 MicroRNA analysis of the invasive margin of Glioblastoma reveals druggable therapeutic targets in lipid metabolism pathways
Authors: H Alfardus, M de los Angeles Estevez Cebrero, J Rawlinson, A Lourdusamy, R Grundy, A McIntyre, S Smith
Journal: Neuro-Oncology (2018)

Heterogeneity of gene expression in Glioblastoma (GBM) has been recently recognised as a key feature involved in therapy resistance with invasive cells remaining after surgery and displaying unique molecular features. The dysregulation of small non-coding RNAs known as microRNAs (miRNAs) can disrupt gene regulatory networks and contribute to GBM development. However, the intra-tumour heterogeneity of miRNA expression in GBM has not yet been investigated. Global miRNA expression profiling was performed in 45 GBM surgical specimens sampled from the tumour necrotic core, proliferative rim and the invasive margin. Gain-of-function studies were conducted using transfection of selected mature miRNAs into GBM cell lines. Global metabolomic profiling by liquid chromatography coupled with electrospray mass spectrometry (LC-ESI-MS) and gene expression assays were used to identify molecular targets regulated by miRNAs in GBM cells. Transwell assays were performed to examine the migration and invasion effects of inhibiting targets expression. Evaluation of targets expression in tumour tissue samples was performed by qRT-PCR, flow cytometry and immunohistochemical analysis. We identified two significantly upregulated miRNAs in the invasive margin compared to the core and the rim of the tumour. Integrated metabolomic and gene expression analysis revealed that these miRNAs may act synergistically to target key enzymes involved in fatty acid oxidation (ACOX1 and CPT2) and lipoprotein uptake and secretion (LDLR). ACOX1, CPT2 and LDLR were found to be expressed at lower levels in the core and the rim relative to the invasive edge samples. The pharmacological inhibition of CPT2 and LDLR resulted in a significant reduction in GBM cell invasion. Our finding indicates that lipid metabolism may present a possible vulnerability of GBM invasive margin. Understanding the function of miRNAs in regulating lipid homeostasis in GBM may provide novel avenues for GBM therapy.
A nonrandomized confirmatory phase III study of sublobar surgical resection for peripheral ground glass opacity dominant lung cancer defined with thoracic thin-section computed tomography (JCOG0804/WJOG4507L).
Authors: Kenji Suzuki, Shunichi Watanabe, Masashi Wakabayashi, Yasumitsu Moriya, Ichiro Yoshino, Masahiro Tsuboi, Tetsuya Mitsudomi, Hisao Asamura
Journal: Journal of Clinical Oncology (2017)

8561 Background: The optimal mode of surgery for peripheral ground glass opacity (GGO) dominant lung cancer (LC) defined with thoracic thin-section computed tomography (TSCT) remains unknown. Methods: We conducted multi-institutional confirmatory phase III trial to evaluate the efficacy and safety of sublobar resection for peripheral GGO dominant LC. Mode of surgery is basically wedge resection, and segmentectomy is allowed when surgical margin is insufficient ( &lt; 5 mm) or histological invasiveness. LC with maximum tumor diameter (MTD) ≤ 2.0 cm and with consolidation tumor ratio ≤ 0.25 based on TSCT were registered. The primary endpoint was 5-year relapse-free survival (RFS). The planned sample size was 330, with the expected 5-year RFS of 98%, threshold of 95%, one-sided α of 5% and power of 90%. Survival analyses were performed using the Kaplan-Meier method and their confidence intervals were estimated by Greenwood’s formula. Results: Between May 2009 and April 2011, 333 pts were enrolled from 51 institutions. The primary endpoint, RFS was estimated on 314 pts who underwent sublobar resection. Median age was 62 (range 24 - 79) and 104 were smokers. Median MTD on lung window was 1.20 cm (0.53 - 2.00). Median MTD of consolidation was 0 (0.00 - 0.48). Operative modes were 258 wedge resection and 56 segmentectomy. Histological diagnosis were 310 adenocarcinomas, 27 precancerous lesions, and 14 non-neoplastic lesions. Median pathological surgical margin was 15 mm (0 - 55). Grade 2 or higher postoperative complications based on CTCAE v3.0 were observed in 119 (37.9%), and Grade 3 in 17 (5.4%), without any Grade 4 or 5. The 5-year RFS was 99.7% (95% CI, 97.7 - 100.0%), which met the primary endpoint. There was no local relapse. The ratio of FEV1.0 change between preoperative and one year after surgery over preoperative value ranged -37% to +49% with a median of -5%. Conclusions: Sublobar resection, mainly wedge resection, offered sufficient local control and RFS for peripheral GGO dominant LC on TSCT. Sublobar resection should be the first choice of mode of surgery if surgical margin is enough preserved. Clinical trial information: 000002008.
Screening the potential long-term survivors among stage IV breast cancer patients from Asian: A multi-center prognostic nomogram based on real-world data.
Authors: Jianli Zhao, Ying Wang, Kai Chen, Yunfang Yu, Junrong Jiang, Xiao Lin, Yaping Yang, Herui Yao
Journal: Journal of Clinical Oncology (2018)

e13093 Background: Accurate prediction of survival in a newly diagnosed stage IV breast cancer patient is one of the most difficult challenges that physicians face. This study aimed to develop a nomogram to predict the overall survival(OS) of newly diagnosed stage IV breast cancer patients from Asian. Methods: From the institution’s database, we collected data of 368 stage IV breast cancer patients as a training set to establish nomogram that calculated the predicted probability of survival at different time point: 1, 2, and 3 years for overall survival. The nomogram was independently validated with 210 patients with stage IV breast cancer from two other institutions using concordance index(C-index), calibration plots and risk group stratifications. Results: The median overall survival was 33.6 months and 31.4 months in the training dataset and the validation dataset, respectively. The initial primary tumor stage(p = 0.027), the molecular subtype of metastatic lesions(p < 0.001), the disease-free survival(p = 0.024), presence of brain metastasis(p = 0.041), and especially the tumor burden of metastasis disease(local recurrence, oligo-metastatic disease, or multiple-metastatic disease, p < 0.001), were significantly associated with OS, and were included in the prognostic nomogram. The developed nomogram had a C-index of 0.77(95%CI 0.71-0.84) and 0.71(0.60–0.82) in the training and the validation sets, respectively. The predicted survival using the nomogram is well correlated with actual OS, which showed by the ideal calibration plots. The nomogram was able to stratify patients into different risk group, the median OS for patients with total score less than 2 and for patients with total score higher than 15 were 69 months and 18 months, respectively. Conclusions: We have constructed a novel prediction nomogram that can guide the physicians to select personalized treatment options and also help patients to obtain more clear insights into their future outcomes. Furthermore, this nomogram can be a valuable tool to screen long-term survivors who can be potential candidates for more intensive multi-disciplinary management to achieve long-term clinical remission.