tbuckley/cabot-search huggingface dataset:
Tumor-related symptoms (TRS) assessment in patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with gefitinib or erlotinib: Preliminary results of an observational study.
Authors: Giovanni Mansueto, Filomena Narducci, Silvia Quadrini, Lucia Mentuccia, Roberta Grande, Isabella Sperduti, Teresa Gamucci
Journal: Journal of Clinical Oncology (2013)

e20619 Background: Edmonton Symptoms Assessment Scale (ESAS) is a validated tool in palliative care, which evaluates physical symptoms through a numeric scale (0-10). Symptoms improvement as a predictive factor for response rate (RR) in pts with advanced NSCLC treated with tyrosine-kinase inhibitors (TKIs) has not yet been evaluated. To this purpose, we performed an observational retrospective study. Methods: Pts with advanced NSCLC treated with gefitinib or erlotinib were eligible. Primary outcome was the association between treatment response and tumor-related symptoms (TRS) (pain, asthenia, dyspnea) improvement. ESAS was performed at day 1 and 14 of each 28-d cycle. Symptoms' scores were divided into: not clinically relevant (0-4, NCR) and clinically relevant (5-10, CR). Sample size estimation was 115 to 165 pts to be needed for the expected difference in the primary outcome. Differences between symptoms' groups were analyzed with the paired-data McNemar-test. All the associations were estimated using the Chi-Square test. Kaplan-Meier method was used for survival calculation. Uni- and multivariate survival analysis were carried out using the Cox regression model. Results: Here we report data about 73 consecutive pts; median age: 69 years, males 68%, ECOG PS 0-1 86%, smokers 68%, EGFR-mutated 22%. Treatment was gefitinib (23%) or erlotinib (77%). RR: RC/RP 14%, SD 20%, PD 66%. Median follow-up was 7 months. 63% of pts had at least one CR TRS at baseline. Among these pts, a significant reduction (p&lt;0.0001) of TRS during treatment was observed (Table). Our preliminary data show a significant association between dyspnea/asthenia and RR (p=0.01). At the multivariate analysis, TRS improvement correlates with both PFS and OS. Also related with survival were PS, EGFR status (PFS) and RR (OS). Conclusions: Our preliminary data show that TRS improvement is significantly associated with treatment response and appears to be a prognostic factor during treatment with TKIs. [Table: see text]
Periodontal disease prevalence in patients treated with tamoxifen.
Authors: Marisa Isabel Brusca, Marcelo Blanco Villalba, Jose Grandinetti, Juan Pablo Re, Alejandra PINI, Guillermo Juan Streich, Emiliano Molinas, Carlos Gonzalez Palacios, Marina Paula Bramajo
Journal: Journal of Clinical Oncology (2013)

e11600 Background: Periodontal diseases arise from inflammatory diseases involving the periodontal connective tissue as a common factor. Estrogen produces inflammatory changes that worseness the periodontal preexistent status; and alters the microbiologic environment acting as a nutrient. The objective of this study is to determinate the relation between the treatment with tamoxifen and the prevalence of periodontal disease in women with breast cancer. Methods: Observational study. Sample: 70 postmenopausal patients, distributed in the following groups: Group 1 (N: 17) patients with breast cancer diagnosis and treated with tamoxifen less than one year; Group 2 (N: 18) patients with breast cancer and treated with tamoxifen for 1 to 2 years; Group 3 (N: 18) patients with breast cancer and treated with tamoxifen for 2 to 5 years; Group 4 (N:17) patients with breast cancer that have finalized their treatment with tamoxifen. A poll was performed between these patients, a periodontal scale and a mouth hispid was performed. Microbiologic standard tests were performed for Candida and also molecular biologic tests. Results: Group 1: health: 0%, severe periodontal diseases: 22% Group 2: health: 0% severe periodontal disease: 25% Group 3: health: 25% severe periodontal disease: 10% Group 4: health: 35% severe periodontal disease: 5%. Microbiologic cultives: presence of Candida albicans, tropicalis, parapsilosis, dubliniensis and glabrata. The maoyor variety of species were isolated from Group 1. Conclusions: The time frame with Tamoxifen treatment shows differences in the Periodontal status and reveals differences in the growth of Candida species because a decrease in number and species of yeast, this means an additional benefit in the studied population. We believe it is important to run this study with larger populations in order to determine the benefits of the treatment with Tamoxifen.
Epidemiology, risk factors, and outcomes in malignant bowel obstruction.
Authors: Maria Vieito, Nieves Martinez Lago, Marta Carmona Campos, Carmela Rodriguez Lopez, Francisco J. Barón, Sonia Candamio, Isabel Galrisa Neto, Rafael Lopez
Journal: Journal of Clinical Oncology (2013)

e20708 Background: Malignant bowel obstruction is a complex syndrome that needs a multidisciplinary management and a better definition of prognostic risk factors. Methods: Information of patients with known history of cancer, admitted for a first episode of suspected malignant bowel obstruction, between 2008 and 2010 with consultation by a medical oncologist or palliative care specialist was reviewed and epidemiological variables like sex, age, localization, histology, and clinical stage treatments received, presence of infiltrating abdominal tumors, and peritoneal carcinomatosis were recorded at diagnosis and at the time of admission. Results: The basal characteristics of the 115 patients are resumed in the Table. At admission patients had in their majority known stage IV disease (75%) with previous evidence of peritoneal carcinomatosis in 63% of cases and of intra abdominal infiltrating masses in 49%, but only half of the patients were receiving active chemotherapy. Nearly all patients presented symptoms like pain (98%) and nausea (91%), followed by vomit and abdominal distension and a deterioration of their performance score (9% PS0-1, 43% PS2, 33% PS3, 13% PS4). Palliative prognostic index (PPI) altered items were mainly oral intake (64%) and edema (21%). They were treated with antisecretors (octreotide 58%, butylscopolamine 26%), anti-emetics, (ondasetron 65%, metoclopramide 46%) neuroleptics (60%), corticosteroids (59%) and analgesics (opioids in 66%). Conclusions: The episode of obstruction could be resolved in a median of 12 days in more than half of our patients(59%), this led to an acceptable rate of outpatient management of 61%, nerveless the prognosis of this patients is still very poor. with a median survival from the moment of obstruction of only 42 days and a rate of reobstruction of 52%. [Table: see text]
Abstract 670: Molecular basis of the idling state uncovers vulnerabilities suitable to sequential targeting in melanoma
Authors: Corey E. Hayford, Bishal B. Paudel, Leonard A. Harris, Keisha N. Hardeman, Darren R. Tyson, Vito Quaranta
Journal: Cancer Research (2019)

Abstract Recent published work from the lab identified a novel “idling” population state in the response of BRAF-mutant melanoma cancer cell lines to BRAF inhibition. The idling state is marked by a long-term net-zero proliferation rate in drug treatment, resulting from a balance of division and death events within isogenic clonal populations. We hypothesize that the idling state is equivalent to stable disease in patients that experience short-term tumor reduction on targeted therapy (e.g. tumor stops growing or shrinking but is still capable of rebound). Specifically, the idling state may be a prelude to resistance as a reservoir for genetic modifications that lead to tumor rebound. It is therefore critical to understand the molecular mechanisms underlying the idling state, since they may point to exploitable treatment vulnerabilities. Here, we have characterized the idling state in several isogenic clonal lineages isolated from the melanoma SK-MEL-5 cell line across several biological scales, including genomics, transcriptomics, metabolism, and cell morphology. Consistently across these measurements, these lineages converge to a molecularly homogeneous phenotype, which we consider to be an idling state molecular signature. Prominent in this signature are genes involved in metabolism redox balance and neuronal cell differentiation. This convergence appears to be a property of many cell lineages in the SK-MEL-5 parental population, since they were observed in barcoded lineages at approximately the same abundance pre- and post-treatment. When treating cells in the idling state with drugs that target the convergent molecular signature, we observe remarkable cell death and a significant drug effect compared to untreated cells. Together, we propose that these data reflect a non-selective convergence mechanism to tolerate drug treatment. We expect idling state drug vulnerabilities may inform sequential drug treatment strategies that exploit convergence mechanisms and reduce the number of cells that could acquire genetic resistance modifications. It may also shed light on the mechanism to achieve complete remission for melanoma patients in the clinic. Citation Format: Corey E. Hayford, Bishal B. Paudel, Leonard A. Harris, Keisha N. Hardeman, Darren R. Tyson, Vito Quaranta. Molecular basis of the idling state uncovers vulnerabilities suitable to sequential targeting in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 670.
Attention-Deficit/Hyperactivity Disorder and Mortality Risk in Taiwan
Authors: Vincent Chin-Hung Chen, Hsiang-Lin Chan, Shu-I Wu, Meng Lee, Mong-Liang Lu, Hsin-Yi Liang, Michael E. Dewey, Robert Stewart, Charles Tzu-Chi Lee
Journal: JAMA Network Open (2019)

Few studies have investigated levels of mortality in patients with attention-deficit/hyperactivity disorder (ADHD), and findings have been inconsistent and lacking information on specific causes of deaths.To investigate the association between ADHD and causes of death in Taiwan.A nationwide population-based cohort study was conducted using a cross-national Taiwanese registry. The ADHD group comprised 275 980 individuals aged 4 to 44 years with a new diagnosis between January 1, 2000, and December 31, 2012. All individuals with ADHD were compared with 1 931 860 sex- and age-matched controls without ADHD.The association between ADHD and mortality was analyzed using a Cox regression model that controlled for sex, age, residence, insurance premium, outpatient visits, congenital anomaly, intellectual disability, depression disorder, autism, substance use disorder, conduct disorder, and oppositional defiant disorder. The analysis of suicide, unintentional injury, homicide, and natural-cause mortality was performed by a competing risk adjusted Cox regression controlling for other causes of mortality and potential confounding factors.Data on mortality from all causes, suicide, unintentional injury, homicide, and natural causes collected from a national mortality database.There were 275 980 individuals with ADHD and 1 931 860 comparison individuals without ADHD in this study. Sex and age at index date were matched. The mean (SD) age was 9.61 (5.74) years for both groups. Most of the participants were male (209 406 in the ADHD group; 1 465 842 in the non-ADHD group; 75.88% for both groups). A total of 4321 participants from both cohorts died during the follow-up period (15.1 million person-years), including 727 (0.26%) from the ADHD group and 3594 (0.19%) from the non-ADHD group. Of those who died, 546 (75.1%) in the ADHD group and 2852 (79.4%) in the non-ADHD group were male. After adjusting for potential confounders, compared with the non-ADHD group, patients with ADHD showed higher overall mortality (adjusted hazard ratio, 1.07; 95% CI, 1.00-1.17) and higher injury-cause mortality from suicide (adjusted hazard ratio, 2.09; 95% CI, 1.62-2.71), unintentional injury (adjusted hazard ratio, 1.30; 95% CI, 1.10-1.52), and homicide (adjusted hazard ratio, 2.00; 95% CI, 1.09-3.68). No increased risk of natural-cause mortality was observed after adjustment.In this study, ADHD was associated with higher injury-cause mortality, particularly that due to suicide, unintentional injury, and homicide. Although the risk of injury mortality was significantly higher in patients with ADHD than in the non-ADHD group, the absolute risk of mortality was low.
Characterization of the exposure-response relationship leading to recommendations for dosing optimization in a new drug application review.
Authors: Jun Yang, Nitin Mehrotra, Hong Zhao, Ruthann Marie Giusti, Suzanne Demko, Patricia Keegan, Brian Booth, Nam Atiqur Rahman
Journal: Journal of Clinical Oncology (2013)

2510 Background: On November 29 2012, the U. S. FDA approved cabozantinib (COMETRIQ) for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). Drug-related toxicity was common at a dose of 140 mg once daily across Phase 1 to Phase 3 trials submitted in this NDA. During the review of this application, these safety findings raised the question whether the optimal cabozantinib dose was selected for the treatment of MTC. Exposure-response (E-R) analyses were performed to assess the appropriateness of the cabozantinib dose. Methods: The data were obtained from an international, multi-center, randomized (2:1), placebo-controlled trial enrolling 330 patients with metastatic MTC. To account for variable exposure levels due to dose modification and inter-individual pharmacokinetic variability, average exposure (Starting Dose*Dose intensity/individual CL/F) was used as the exposure metric in the E-R analyses. The relationships between cabozantinib exposure and progression free survival (PFS), and selected safety endpoints including diarrhea, palmar-plantar erythrodysesthesia (PPE) syndrome and time to dose modification (TTDM) were evaluated. Results: Kaplan-Meier analyses of PFS for each quartile of average cabozantinib exposure suggest that patients with lower exposure and those with higher exposure may have equivalent PFS, comparatively. The multivariate Cox proportional analysis identified individual patient’s clearance as a significant covariate for prediction of TTDM with a hazard ratio of 1.95 (95% CI [1.47-2.59]), suggesting that patients with higher exposures required dose modification earlier than patients with lower exposures. The results of the E-R analyses may be difficult to interpret due to the high rate of dose modification. Nevertheless, these results indicate that a lower dose may be as effective with improved tolerability. Conclusions: The E-R analyses along with the observed safety and efficacy data in the clinical trials led to an FDA requirement to conduct a post marketing clinical trial to evaluate the safety and efficacy of a lower cabozantinib dose.
Susceptibilities to N-ethyl-N-nitrosourea-induced transplacental carcinogenesis in LEC, LEA and F344 rats.
Authors: Keisuke Izumi, Takeshi Tsuchigauchi
Journal: Cancer Research (2004)

3204  In our studies, the Long-Evans Cinnamon (LEC) rat, an animal model of Wilson’s disease and helper T cell deficiency, is susceptible to: 1) N-diethylnitrosamine (DEN)-induced liver carcinogenesis, and 2) N-methyl-N-nitrosourea (MNU) and azoxymethane (AOM)-induced colon carcinogenesis, but resistant to: 3) DEN, MNU and N-nitrosobis(2-hydroxypropyl)amine (BHP)-induced lung carcinogenesis, and 4) N-butyl-N-(hydroxybutyl)nitrosamine (BBN)-induced bladder carcinogenesis. N-Ethyl-N-nitrosourea (ENU) is a potent carcinogen of the nervous system. In the present study, we studied the ENU-induced transplacental carcinogenesis in male and female LEC, Long-Evans Agouti (LEA) and F344 rats (n=21). ENU was dissolved in 0.1 M citrate buffer (pH 6.0) and given to pregnant rats as a single s.c. injection at a dose of 60 mg/kg body weight on the 17th day after conception. All surviving animals were killed at 30 weeks of age and examined histologically. Six of male and 10 of female LEC rats died of hepatic injury at 15-19 weeks. None of LEC rats developed the tumors of the central and peripheral nervous system. In male and female LEA rats, the incidences of the nervous system tumors were 14/21 (67%, P
O024 Human memory TH17 cell populations change into anti-inflammatory cells with regulatory capacity upon exposure to active vitamin D
Authors: W Dankers, N Davelaar, JP van Hamburg, J van de Peppel, EM Colin, E Lubberts
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Introduction</h3> In autoimmune diseases such as rheumatoid arthritis (RA), an important therapeutic goal is to normalise the imbalance between pro- and anti-inflammatory cells. This imbalance is illustrated by elevated levels and activity of memory CCR6 +Th17 cell populations, such as Th17 and Th17.1 cells, in RA patients compared to healthy controls. Therefore, modulating these cells to become anti-inflammatory could contribute to restoring the immunological balance. <h3>Objectives</h3> The active vitamin D metabolite 1,25(OH)<sub>2</sub>D<sub>3</sub> is known to inhibit pro-inflammatory cytokine production by CCR6 +Th memory cells. Therefore, we investigated whether 1,25(OH)<sub>2</sub>D<sub>3</sub> can induce an anti-inflammatory phenotype in these memory T cells. <h3>Methods</h3> CCR6 +Th memory cells, excluding Tregs, were sorted from treatment-naïve early RA patients or healthy controls and cultured with or without 1,25(OH)<sub>2</sub>D<sub>3</sub>. Effects were analysed using microarray, RT-PCR, ELISA or flow cytometry. Functional properties were assessed via suppression and chemotaxis assays. <h3>Results</h3> 1,25(OH)<sub>2</sub>D<sub>3</sub> inhibits pro-inflammatory cytokines such as IL-17A, IL-17F and IL-22 in CCR6 +Th memory cells from both healthy controls and RA patients. This is accompanied by induction of anti-inflammatory factors, including IL-10 and CTLA4. Interestingly, these formerly pathogenic cells suppress proliferation of autologous CD3 +T cells, similar to classical Tregs. Importantly, the modulated memory cells still migrate towards the site of inflammation, modelled by synovial fluid, and retain their suppressive capacity in this environment. <h3>Conclusions</h3> Committed pro-inflammatory IL-17A-producing CCR6 +Th memory cells can become anti-inflammatory cells with functional regulatory capacities upon exposure to active vitamin D. This process can contribute to restoring the immunological balance and inhibiting synovial inflammation in RA. <h3>Disclosure of interest</h3> None declared
Optimal patient selection for CPT-11 chemotherapy in colorectal cancer: Quantitative prediction of tumor response and overall survival using expression data of novel marker genes
Authors: H. Takemoto, N. Tomita, K. Murata, M. Fukunaga, S. Okamura, M. Ohue, H. Ishida, K. Tanimoto, K. Hiyama, M. Nishiyama
Journal: Journal of Clinical Oncology (2009)

e14529 Background: Unlike the toxicity, none of the critical prediction markers of CPT-11 efficacy has been validated to date. With a hypothesis that expression analysis of a set of the key drug sensitivity genes could allow us to predict the therapeutic response, we identified potent marker genes for CPT-11 in in vitro, conducted this prospective study attempting to develop a prediction formula of efficacy using the expression data (2006 ASCO, 2006 ESMO), and demonstrated the latest prediction formula of the best tumor response (BTR), time to treatment failure (TTP), and the overall survival after CPT-11 chemotherapy (OS). Methods: Seven genes identified as possible marker genes for CPT-11 (SN-38)- AMD1, CTSC, EIF1AX, FLJ13089 , DDX54, PTPN2, and TBX3-, and 5 other possible marker genes (ABCG2, CYP3A4, MGMT, POR, and TOP2A) that had already been known as drug sensitivity determinants and selected by our in vitro screening process, were studied. CPT-11 was intravenously administered on Days 1, 8, and 15, every 4 weeks in chemo-naive patients with stage IV colorectal cancer after palliative operation. Tumor samples were collected at surgery and tumor response was evaluated by RECIST. Results: All of the 44 enrolled patients were assessable for BTR (% of initial tumor size), TTP (day), and OS (day) in the clinical study, and we successfully developed the best linear model for each, which converted the quantified expression data of the 7 selected genes into objective BTR, TTP, and OS. We used 20, 16, and 15 tumor specimens and constructed potent prediction formulae for BTR (r=0.9420), TTP (r=0.7103), and OS (r=0.8406), respectively. Utility-confirmation analyses using another 16, 10, 13 clinical samples appeared to show that the formulae could predict BTR (r=0.6491, p=0.007) and OS (r=0.7947, p=0.011). We also fixed the best linear models using 5 other known marker genes, but they had less advantage in prediction. Conclusions: Despite limited data, our developed formulae using the 7 novel genes would provide advantages in prediction of individual response to CPT-11. Based on the positive results of this study, we have initiated a large scale validation study of the formula. [Table: see text]
Genomic landscape of neutrophilic leukemias of ambiguous diagnosis
Authors: Haijiao Zhang, Beth Wilmot, Daniel Bottomly, Kim-Hien T. Dao, Emily Stevens, Christopher A. Eide, Vishesh Khanna, Angela Rofelty, Samantha Savage, Anna Reister Schultz, Nicola Long, Libbey White, Amy Carlos, Rachel Henson, Chenwei Lin, Robert Searles, Robert H. Collins, Daniel J. DeAngelo, Michael W. Deininger, Tamara Dunn, Than Hein, Marlise R. Luskin, Bruno C. Medeiros, Stephen T. Oh, Daniel A. Pollyea, David P. Steensma, Richard M. Stone, Brian J. Druker, Shannon K. McWeeney, Julia E. Maxson, Jason R. Gotlib, Jeffrey W. Tyner
Journal: Blood (2019)
Skeletal-related events (SREs), baseline comorbidity, and survival among elderly patients (pts) with metastatic (M1) prostate cancer (PCa) in SEER-Medicare.
Authors: Ebere Onukwugha, Candice Yong, C. Daniel Mullins, Brian S. Seal, Arif Hussain
Journal: Journal of Clinical Oncology (2013)

e16027 Background: The prevalence of comorbidities increases with age in older men diagnosed with M1 PCa. However, the relationship between comorbidities, PCa, SREs, and mortality is not well understood. Methods: We analyzed pts aged 66+ diagnosed with M1 PCa between 2000 and 2007 from the linked Surveillance, Epidemiology, and End Results (SEER) and Medicare dataset. Pts surviving at least 30 days post-diagnosis were identified and followed until death or censoring in December 2009. Pathologic fracture, spinal cord compression, and bone surgery were identified from Medicare claims based on three measures: 1) SRE claim occurred after claims with a bone metastasis (BM) ICD 9 code; 2) BM ICD 9 code directly coincided with SRE claim; 3) SRE was not anchored to BM. Cox proportional hazards regression models controlled for demographic and clinical factors, including interaction terms involving indicators for comorbidities. Regression models were estimated using all-cause and PCa-specific mortality as outcomes. Results: Application of inclusion/exclusion criteria resulted in 7,062 pts. PCa-specific and all-cause mortality were 54% and 80% at a median (mean; min; max) follow up of 609 days (837; 30; 3,653). The proportion with any SRE was 17% (Measure 1), 9.7% (Measure 2), and 17.1% (Measure 3). Joint tests indicated statistically significant interaction terms using Measure 1 for PCa-specific mortality and Measure 3 for all-cause mortality. The adjusted hazard ratio (AHR) and 95% confidence interval (CI) on the SRE indicators are shown in the Table. Conclusions: The association between SREs and death among elderly M1 PCa patients is affected by comorbidities. [Table: see text]