tbuckley/cabot-search huggingface dataset:
ERS Clinical Research Collaborations: underpinning research excellence
Authors: Chris Brightling, Celine Genton, Werner Bill, Tobias Welte, Mina Gaga, Elise Heuvelin, Guy Brusselle
Journal: European Respiratory Journal (2018)

<b>The ERS Clinical Research Collaborations (CRCs) programme provides support to projects in different areas of respiratory medicine, to build and maintain pan-European and/or global collaborations. CRC applications can be submitted annually by October 15.</b>http://ow.ly/34s730lxgnw
Genetic variation in TET3 and survival in metastatic colorectal cancer (mCRC) from FIRE-3, TRIBE, and MAVERICC clinical trials.
Authors: Stephen B. Gruber, Stephanie Schmit, Marilena Melas, Chenxu Qu, Volker Heinemann, Sebastian Stintzing, Alfredo Falcone, Fotios Loupakis, Christoph Mancao, Shu Cao, Chiara Cremolini, David V Conti, Wu Zhang, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

3575 Background: Patients enrolled in FIRE-3, TRIBE, and MAVERICC clinical trials for mCRC were genotyped using Illumina Oncoarray to identify predictive and prognostic biomarkers. Here we report results of a genome-wide association study (GWAS) of overall survival (OS) and progression-free survival (PFS) in 790 patients from 3 clinical trials. Methods: DNA samples from patients of European descent (≥80% estimated European ancestry) treated on all arms of FIRE-3, TRIBE, and MAVERICC were genotyped on the Infinium OncoArray through the Colorectal Transdisciplinary (CORECT) Study. We performed a GWAS of directly genotyped markers with a minor allele frequency ≥ 1% (403,467 SNPs) in 790 patients with mCRC from three trials (FIRE-3 n = 235, TRIBE n = 320, MAVERICC n = 235). Cox proportional hazards regression adjusted for age, sex, principal components for global ancestry, and trial was performed in R using GenABEL to identify associations between genetic variants and OS and PFS. Subgroup analysis by study arm, sex, and primary location was performed. Bonferroni correction for the number of independent genetic markers was applied to minimize false positives. Results: Males were 514 (65.1%) and females were 276 (34.9%) of the patients meeting eligibility criteria and genotype data passing QC. The median OS was 21.0 months and median PFS was 9.2 months. Genomic control lambda values for OS = 1.03 and PFS = 1.03 showed minimal population stratification. One SNP, rs7597070 on 2p13.1 within an intron of TET3, was significantly associated with OS and exceeded the Bonferroni correction threshold for genome-wide significance < 1.67E-07. The A allele (MAF = 0.016) was associated with increased OS versus the T allele (HR = 0.29; 95% CI, 0.19-0.45; P-value = 5.9E-08). Suggestive evidence also supported an association with PFS (HR = 0.53 (A allele); 95% CI, 0.34-0.81; p = 3.4E-03). The frequency of the A allele was 1.6% in our European patients, 10% in East Asians and 42% in Africans in the 1000 Genomes data. Conclusions: Our data identify a new promising prognostic biomarker for OS and PFS among patients with mCRC, and population genetic differences may contribute to disparities in survival by ancestry.
Impact of flexible assessment schedules on treatment effect bias in pragmatic clinical trials.
Authors: Ariel B. Bourla, Elizabeth Sweeney, Christina M. Parrinello, Amy Pickar Abernethy, Sandra D. Griffith
Journal: Journal of Clinical Oncology (2018)

e14519 Background: Traditional clinical trials in Oncology require radiology assessments to be performed within a rigid timeframe that is burdensome and not indicative of real world practice. Pragmatic clinical trials may incorporate a more flexible schedule of radiographic assessments reflective of usual care patterns. However, there is concern that this could introduce surveillance bias, particularly if the schedules differ systematically between treatment arms. We aimed to understand the impact of flexible scanning schedules on treatment effect estimates. Methods: We conducted simulations to estimate the impact of flexible assessment schedules on determining clinical evidence of progression in metastatic breast cancer (mBC). We investigated two scan assessment schedules, one traditional and one more flexible, and within each schedule we tested ‘window sizes’ of every 12 weeks +/- 1, 2, 3 and 4 weeks. To simulate a worst-case scenario, we set the scan frequencies to be systematically different by arm. Simulation parameters were based on the mBC literature and retrospective electronic health record data. We used a representative range of hazard ratios (HR) and baseline progression-free survival (PFS) rates. Results: Using any of the window sizes in either of the assessment schedules resulted in only a small amount of bias in the treatment effect estimates. Among all HR settings in the simulation, the median bias ranged from -.01 to .10 (-1.0% to 5.3% bias). In an example using a flexible assessment schedule and a PFS of 15 months, we saw a lack of effect of scanning interval on treatment effect estimates (Table). Conclusions: Increased flexibility of radiographic assessment has minimal impact on comparative assessment of PFS in simulated randomized mBC clinical trials. A less rigid assessment schedule in the setting of a pragmatic clinical trial could ease patient and physician burden, and produce study results more generalizable to real world clinical practice, without compromising analytic integrity. Window Size True Hazard Ratio 1 1.2 1.4 1.6 1.8 2 +/- 1 week 1.013 1.222 1.412 1.615 1.829 2.018 +/- 2 wks 1.017 1.241 1.421 1.622 1.844 2.034 +/- 3 wks 1.021 1.250 1.432 1.644 1.870 2.056 +/- 4 wks 1.035 1.262 1.447 1.672 1.883 2.083
Survival with nivolumab therapy in recurrent/advanced squamous cell head and neck carcinoma. A single center experience.
Authors: Ana Laura Ortega Granados, Natalia Luque Caro, Juan Francisco Marín Pozo, Facundo Alberti Vargas, Mónica Fernández Navarro, Capilla de la Torre Cabrera, María Ruiz Sanjuan, Nuria Cárdenas Quesada, Miguel Angel Moreno Jimenez, Francisco José García Verdejo, Pedro Sanchez Rovira, Carmen Tirado Bejarano
Journal: Journal of Clinical Oncology (2018)

e18032 Background: All patients diagnosed of advanced or relapsed squamous cell carcinoma of head and neck (SCCHN) are relapsing before a platin-based first line therapy, and then, median overall survival with treatment options available till 2016 is around 6 months. Since CheckMate 141 results, we have evidence of nivolumab activity in this scenario. Methods: We performed a retrospective observational study, including all patients with advanced or recurrent SCCHN treated with nivolumab in our institution (tertiary center in Spain) in a compassionate use program in a year, since June 2016 to June 2017, and followed until January 2018. We included 12 patients, 11 male and 1 female, with a median age of 60.8 years (37-45; 4 patients were older than 65 years). Results: Most frequent tumor site was larynx (50%), followed by oropharynx (18.75%) and hypopharynx (12.5%). Majority of patients (81.25%) were diagnosed in a stage I-III, so they received any local therapy. Most patients received nivolumab as a second line therapy (68.75%); it was used as a third line in 18.75% and as a fourth line in 12.5% of patients. Best response by RECIST criteria was progression in 8.3%, partial response in 41.7%, stabilization in 41.7% and complete response in 1 patient (8.3%). Median overall survival is not reached [NR (26-48 m)], and median duration of therapy was 8.25 months. Median PFS was 8.25 months (6-18), and survival since nivolumab therapy is around 12 months. We did not found any hyperprogression nor severe toxicity; only 3 patients (18.75%) experienced some grade 1-2 toxicity (2 patients xerosis, and 1 patient hypotiroidism). Conclusions: Although our sample is small, we can suggest that therapy with nivolumab is better than other options, in terms of survival and toxicity, so it can be a standard after platinum progression in recurrent or advanced SCCHN
Chemotherapy, acute health care events, and hospice use among stage IV pancreatic cancer patients.
Authors: Yuhua Bao, Renee Maciejewski, Manish A. Shah, Melissa Garrido, Paul K Maciejewski, Holly Gwen Prigerson
Journal: Journal of Clinical Oncology (2016)

6574 Background: For patients with advanced pancreatic cancer, chemotherapy may alleviate cancer-related symptoms and extend lives modestly, but may also result in adverse events that require hospitalization and delay or prevent hospice care. To inform discussions regarding treatment choices, this study assesses the association between chemotherapy use and health care utilization close to end-of-life among patients with Stage IV pancreatic cancer. Methods: Sample included patients in the SEER-Medicare database who were 66 or older when diagnosed with Stage IV pancreatic cancer in 2006-2010 and who died within one year of diagnosis (N = 7,977). To mitigate treatment selection, the analysis excluded 3,537 patients who died very soon (within 60 days of diagnosis) and 615 patients who delayed initiation of chemotherapy ( > 60 days post diagnosis) (Earle et al. 2001 JCO), leading to a final sample of 3,825 patients. Multivariate logistic regressions estimated incremental probabilities of acute inpatient admissions, ER visits, death in a hospital, and hospice care, and, zero-inflated Poisson regression estimated the incremental days of hospice care, associated with chemotherapy. All outcomes were measured within the last 30 days of life. Propensity score (PS) matching (and weighting as a sensitivity analysis) was adopted for all analysis, with PS constructed based on demographics, community socioeconomics, surgery or radiation as part of first course treatment, and comorbidities. Results: Chemotherapy use was associated with an increase in the probability of acute inpatient admissions from 0.29 to 0.45 (AOR = 2.03; p < 0.001), from 0.27 to 0.41 (AOR = 1.93; p < 0.001) for ER visits, and from 0.09 to 0.14 (AOR = 1.68; p = 0.006) for death in a hospital. Chemotherapy was associated with a reduction of 4 hospice days (from 15.7 to 11.5 days, p < 0.05), but not with probability of any hospice care, in the last 30 days of life. Conclusions: At the population level, chemotherapy use among Stage IV pancreatic patients was associated with substantial increases in patients’ encounters with acute care settings and likelihood of dying in a hospital, and reduced days receiving hospice care when patients were near the end of their lives.
In-hospital outcomes of acute myeloid leukemia (AML) patients undergoing allogeneic hematopoietic stem cell transplant (HCT).
Authors: Urshila Durani, William J. Hogan, Mark Robert Litzow, Hassan Alkhateeb, Ankit J. Kansagra, Ronald S. Go
Journal: Journal of Clinical Oncology (2017)

e18091 Background: Allogeneic HCT is a potentially curative option for certain patients with AML. However, in-hospital outcomes and cost haven't been described. We use the NIS, a nationally weighted sample of hospital discharges in the US, to examine these outcomes. Methods: Years 2002-2013 of the NIS were queried for adults with a primary diagnosis of AML undergoing HCT. Mortality, length of stay, hospital charges, and complications were analyzed and predictors of increased charges and mortality were determined with multivariate regression analysis. Results: From 2002-2013 19,965 adults with AML were admitted for HCT. Donor sources included peripheral blood stem cells (PBSCTs) (79%); bone marrow (BMTs) (15%); umbilical cord blood (6%). In hospital mortality was 8%. Major complications included stomatitis (36%), total parenteral nutrition (TPN) (17%), neutropenic fever (14%), bacteremia (12%), mechanical ventilation (6%), and dialysis (3%). Median charges per hospitalization increased (p&lt;0.01) from $161,894 (2002) to $324,765 (2013); median length of stay (27 days) remained stable over time. Multivariable regressions are depicted (Table). Umbilical cord blood transplants were associated with increased mortality (OR 2.25, p&lt;0.01) and charges ($69,105, p&lt;0.01) relative to PBSCTs. Conclusions: This study demonstrates increasing cost of BMT on a national level as well as increased cost and mortality with umbilical cord transplants. [Table: see text]
Effect of the TGFβ induced lncRNA TBILA on non-small cell lung cancer progression by regulating HGAL and binding with S100A7.
Authors: Zhiliang Lu, Nan Sun, Jie He
Journal: Journal of Clinical Oncology (2018)

e24203 Background: Long non-coding RNAs (lncRNAs) play critical roles in multiple cellular processes of non-small cell lung cancer (NSCLC); however, their involvement in transforming growth factor-beta (TGFβ) signal pathway, the critical pathway of tumor cell epithelial-mesenchymal transition and metastasis, remains poorly understood. Methods: RNA-Seq was used to compare the global gene expression patterns of NSCLC cells treated with and without TGFβ1. Dual luciferase reporter assay and ChIP assay were performed to verify the regulation of TBILA by TGFβ. Rapid amplification of cDNA ends, northern blot, RNA Scope and nuclear/cytoplasm fractionation were performed to find out molecular characteristics and subcellular localization of TBILA. TBILA and HGAL expression levels in NSCLC tissues and adjacent tissues were detected by RT-qPCR. Loss and gain of function assay were used to explore the role of TBILA in NSCLC progression in vitro and in vivo. RNA immunoprecipitation and RNA pull down were used to explore TBILA binding proteins. Co-IP, GST pull down and western blot assays were performed to detect activation and alteration of downstream signaling pathways. Results: We observed 423 lncRNAs were upregulated, and 246 lncRNAs were downregulated in TGFβ1-treated cells compared with control cells. And one of the most prominent hits, named as TGFβ-induced lncRNA (TBILA), promoted NSCLC progression and was upregulated in tumor tissues (p < 0.001). Upregulated by TGFβ classical signaling pathway, TBILA promotes HGAL expression by binding with the Smad transcription factor complex, thereby enhancing RhoA activation. In addition, TBILA induces the S100A7-JAB1 pathway by binding with nuclear S100A7 and enhances pro-survival pathways in NSCLC. Moreover, TBILA expression level and invasiveness of NSCLC cells was upregulated by cancer associated fibroblasts culture supernatant. Conclusions: Our findings demonstrate that TBILA acts as key regulator of the TGFβ signaling pathway and revealed that TGFβ plays a role in regulating lncRNAs in NSCLC. TBILA has pleiotropic pro-survival and invasion-metastasis cascade-inducing effects; thus, TBILA may be an effective target in NSCLC treatment.
Self-reported health and access to care among cancer caregivers: Analysis of the 2015 behavioral risk factor surveillance system (BRFSS).
Authors: Emily Castellanos, Sayeh Nikpay
Journal: Journal of Clinical Oncology (2017)

6573 Background: Caregivers play a vital role in the support and treatment of cancer patients. Caregiver well-being can impact patient-perceived quality of care. The study objectives were to compare self-reported health and access to care between cancer caregivers and non-caregivers, and to determine the relationship of caregiving burden to self-reported health and access to care. Methods: We used data from the Caregiver and Core Modules of the 2015 BRFSS, an annual federal survey of health-related behavior, health conditions, and preventive service use. Caregiver burden was assessed by time (hours per week and duration of caregiving) and task (personal care and household management tasks). Measures of self-reported health and access to care between cancer caregivers and non-caregivers were compared using t-test or Chi-Square testing. Associations of caregiver burden with self-reported health and access to care were assessed with linear and logistic regressions. Results: 1,910 cancer caregivers and 84,412 non-caregivers were included. Compared to non-caregivers, cancer caregivers were more likely to report inability to see a physician due to cost (15% vs 9%; p &lt; 0.001), depression (25.0% vs 17.9%; p &lt; 0.001), and poor mental health (mean days per month 5.7 vs 3.1; p &lt; 0.001). Compared to caregivers with low task burden, those with moderate or high task burden reported both more poor mental health days (moderate ß = 1.8, 95% CI 0.5 – 3.1, p = 0.008; high ß = 2.0, 95% CI 0.6 – 3.3, p = 0.004) and increased likelihood of cost barriers (moderate OR 1.6, 95% CI 1.03 – 2.5, p = .035; high OR 1.8, 95% CI 1.2 – 2.9, p = .008). Increased time burden was associated with more poor mental health days (moderate ß = 1.5, 95% CI 0.2 – 2.7, p = .02; high ß = 4.4, 95% CI 3.3 – 5.6, p &lt; .001) but not cost barriers. No differences in insurance, personal health provider, medical check-ups, or self-reported poor physical health were identified. Conclusions: Cancer caregivers are more likely than non-caregivers to report poor mental health, depression, and difficulty seeing a physician due to cost. Caregivers with high caregiving burden are at increased risk of experiencing poor mental health and cost barriers to medical care.
Survivorship experience for patients (pts) with metastatic melanoma (MM) on immunotherapy (IT).
Authors: Julia Elizabeth Lai-Kwon, Chloe Chia Hoey Khoo, Serigne Lo, Donna Milne, Mustafa Abdi Mohamed, Jeanette Raleigh, Kortnye Maureen Smith, Shahneen Kaur Sandhu, Michael Jefford
Journal: Journal of Clinical Oncology (2018)

e21503 Background: IT has significantly improved survival for pts with MM. The experience of long-term responders remains under-studied. We characterised survivorship issues faced by these pts using a cross-sectional survey. Methods: Eligible pts had MM, aged ≥18, ≥ 6 months post initiation of IT, and attained an objective response or stable disease. A 72-item questionnaire including items from validated measures and customised questions covering physical and psychological effects, impact on lifestyle, access to information, satisfaction with care, and availability of supports was administered. The impact of duration on and off IT was assessed. Results: 69/78 (88%) pts [median age 63 (range: 24-88); 42 (61%) male; 10 (15%) with BRAF V600 mutation] responded from Aug-Dec 2017. 50 (72%) had stage IVC disease. 49 (71%) were on 1st line therapy. Pts received single agent anti-PD1 (50, 72%), combined anti-PD1 and anti-CTLA-4 (13, 19%) and anti-CTLA4 (6, 9%). 39 (56%) were still on treatment. Reasons for IT cessation were toxicity (63%) and sustained response following ≥ 24 months of therapy (36%). Long-term toxicity (41, 59%): dermatological (51, 74%), rheumatological (30, 58%) and fatigue (62, 91%) were common. Combined anti-CTLA4 and anti-PD-1 resulted in more long term toxicity compared with anti-PD-1 monotherapy. The prevalence and type of symptoms was similar for pts on IT ( < or > 12 months) and pts who were off IT. Psychological morbidity including anxiety awaiting results (50, 72%), fear of cancer recurrence (56, 81%) and fear of death (44, 64%) was common. Anxiety awaiting results reduced with duration of IT. However, concerns regarding long term toxicity increased. Concern about stopping IT was common (50, 85%). Many pts reported difficulties with domestic tasks (36, 52%) and recreational activities (43, 62%). Most valued a survivorship care plan (SCP) (63, 91%) and screening for other cancers (67, 97%). Conclusions: Understanding the issues faced by long-term responders is essential to optimise pt care. Pts may benefit from routine discussion regarding IT cessation and long term toxicities, tailored psychological support and a SCP.
Cohort profile: African Collaborative Center for Microbiome and Genomics Research (ACCME) study.
Authors: Sally Nneoma Adebamowo, Eileen Dareng, Ayo Famooto, Kolawole Michael Odutola, Rasheed Bakare, Clement Adebayo Adebamowo
Journal: Journal of Clinical Oncology (2016)

5524 Background: Cervical cancer is the second commonest cancer in Africa. Much remains unknown about the prevalence and pathogenicity of human papilloma virus (HPV) types, mechanism of disease and there is a need for new biomarkers for screening programs. Methods: ACCME is a multicenter prospective cohort study of host germline, somatic and HPV genomics and epigenomics, and vaginal microenvironment; and their association with cervical cancer in 10,000 HIV negative women in Nigeria. Data on demography, lifestyle, medical history, serum, germline DNA, HPV genotype and vaginal pH are collected at baseline and during follow-up visits every 6 months. Samples of exfoliated cervical cells are analyzed for high-risk HPV with Roche LINEAR ARRAY and vaginal bacterial composition and abundance are characterized by deep sequencing of barcoded 16S rRNA gene fragments (V4) on Illumina MiSeq platform. Colposcopy and biopsy are conducted on participants with clinical lesions and those with persistent high-risk HPV infections. Results: By January 2016, 10,300 participants had been enrolled unto the cohort. The mean (SD) age of the study participants at baseline was 40 (10) years. Most of the participants were married (76%), attended university (44%) and had professional jobs (37%). All the study participants have had vaginal sex, 17% have had oral sex and only 2% have ever had anal sex. We found 30% of the study participants were HPV positive and 70% were HPV negative. The mean (SD) vaginal pH in the study population was 5.2 (0.5). Further analyses to characterize high-risk HPV types and determine persistence will be conducted at each follow-up visit. Characterization of cervical cytokines and vaginal microbiome are being conducted. Conclusions: ACCME is a paradigm for translational research in biomarker discovery that addresses high impact public health challenges affecting women’s health in Africa and the rest of the world.
The significance of RB expression in malignant pleural mesothelioma in multidisciplinary treatment including extrapleural pneumonectomy.
Authors: Seiji Matsumoto, Toru Nakamichi, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Nobuyuki Kondo, Seiki Hasegawa
Journal: Journal of Clinical Oncology (2016)

e20082 Background: The retinoblastoma (Rb) protein binds E2F transcription factors in the G1 phase to inhibit the activity of the Rb protein, thereby blocks the cell from initiating DNA replication. Rb protein phosphorylation leads to the release of E2F, after which DNA replication is initiated. The purpose of this study was to examine the association between the expression of Rb protein as well as phosphorylated Rb protein, and the prognosis of malignant pleural mesothelioma. Methods: The study subjects comprised 46 mesothelioma patients who underwent multidisciplinary treatment including extrapleural pneumonectomy (EPP) during the period from April 2004 to December 2012. Of the 46 subjects, 35 were male and 11 were female. The mean age was 59.8 years. Histological types were epithelial type (42 cases), biphasic type (2 cases), desmoplastic type (1 case), and small cell type (1 case). Paraffin-embedded surgical samples were immunostained to evaluate expression of the Rb protein and the phosphorylated Rb (p-Rb) protein. The intensity of expression was graded on a scale of 0 to 3+ with 3+ being the highest expression observed (0, negative; 1+,weak; 2+, moderate; 3+, intense). The Kaplan-Meier method was used to calculate survival times after surgery and log-rank tests were used to compare them. Results: Thirty-two patients had Rb protein positive tumours. The median survival time was 39.2 months for expression intensity of 0, 15.1 months for expression intensity of 1+ , 36.3 months for expression intensity of 2+, and 5 months for expression intensity of 3+ (95% CI:6.4-71.9, 13.5-16.7, 2.29-70.4, 0.6-9.34). When samples were divided into a group of samples with intense expression and a group of all the other samples, the median survival times were 36.3 months and 5.0 months, respectively (95% CI:9.4-63.2, 0.65-9.34 p = 0.003). Conclusions: There was no correlation found between the p-Rb protein and the prognosis in 46 mesothelioma patients who underwent multidisciplinary treatment including EPP. Those with intense Rb expression had a poor prognosis. This study suggests that, in multidisciplinary treatment including EPP, Rb could become a target for molecularly-targeted therapy.