tbuckley/cabot-search huggingface dataset:
Perspective study of intensive therapy makes newly diagnosed distant metastatic nasopharyngeal cancer (mNPC) potential curable.
Authors: Tongyu Lin, Mengping Zhang, He Huang, Ying Huang, Chengcheng Guo, Xueying Li, Huangming Hong, Xiaojie Fang, Zhao Wang, Xiaoting Lin, Jia Tian Lin, Chaoyong Liang, Tingzhi Liu, Xiaohong Fu, Shanshan Li, Ying Tian, Dr.Prem Raj Shrestha, Yabing Cao, Linzhu Zhai, Taixiang Lu
Journal: Journal of Clinical Oncology (2014)

e17007 Background: Distant mNPC, commonly treated with platinum-based chemotherapy, is conventionally considered as an incurable disease. We explored the efficacy and survival of cetuximab plus platinum and taxane as induction chemotherapy (IC) followed by CCRT and subsequent maintenance treatment (MT) as 1st-line therapy for mNPC in a perspective study. Methods: Patients (pts) more than 18 ys old with untreated distant mNPC, including initial diagnosis without any prior treatment (IM) and first relapse after radiotherapy (RM), were enrolled in the study. In the pilot treatment group (PTG), pts received IC consisting of cetuximab (initially 400 mg/m2, and then 250 mg/m2 qw), cisplatin (75 mg/m2 q3w), and docetaxel (75 mg/m2 q3w) for a maximum of 6 cycles followed by CCRT (IMRT or tomotherapy to involved primary and cervical fields or bony metastases concurrently with cetuximab and cisplatin) if pts obtained CR/PR after IC, then MT with capecitabine and celecoxib for 3 ys. Contemporaneously, pts treated by other physicians in our center who received platinum-based chemotherapy followed by CCRT according to the NCCN guidelines were considered as control group (CG). Results: 39 pts were enrolled in the PTG from Jul 2006 to Sep 2012 (87% male, median age: 43 ys, 38.5% IM). With a median follow-up time of 23.5 mths, the median OS and PFS were 43.7 mths, 21.0 mths respectively. Subgroup analyses showed pts with IM had a prolonged OS and PFS compared with RM (5yOS: 56.4% vs 32.8%, p=0.021; 5yPFS: 43.2% vs 22.5%, p=0.148). 66 pts in the CG had a poorer survival compared with PTG (5yOS: 13.1%, HR, 0.43, p=0.001; 5yPFS: 5.7%, HR, 0.32, p<0.001). The overall RR of IC was 74% in the PTG and 47% in the CG (p=0.006), which predominately attributed to significant disparity of CR rate (33% vs 3%, p<0.001). No significant differences were observed in the rates of G3/4 AEs during IC between PTG and CG, except for the rate of G3 acne-like rash (10% vs 0%). Conclusions: The favorable increased percentage of pts with newly diagnosed distant mNPC who obtained CR and long-term survival supported a potential curative role for intensive therapy in mNPC. This outcome could be confirmed through further phase III clinical trial.
Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10
Authors: Peng Xiao, Huilun Zhang, Yu Zhang, Mingzhu Zheng, Rongbei Liu, Yuan Zhao, Xue Zhang, Hongqiang Cheng, Qian Cao, Yuehai Ke
Journal: The Journal of Experimental Medicine (2019)

Inflammatory cytokines produced by activated macrophages largely contribute to the pathological signs of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is the predominant anti-inflammatory cytokine in the intestine, and its therapeutic efficacy for IBD has been clinically tested. Nevertheless, how the function of IL-10 is regulated in the intestinal microenvironment remains unknown, which largely hinders the further development of IL-10–based therapeutic strategies. Here, we found that the expression of phosphatase Shp2 was increased in colonic macrophages and blood monocytes from IBD patients compared with those from healthy controls. Shp2 deficiency in macrophages protects mice from colitis and colitis-driven colon cancer. Mechanistically, Shp2 disrupts IL-10–STAT3 signaling and its dependent anti-inflammatory response in human and mouse macrophages. Furthermore, a Shp2-inducing role of TNF-α is unveiled in our study. Collectively, our work identifies Shp2 as a detrimental factor for intestinal immune homeostasis and hopefully will be helpful in the future exploitation of IL-10 immunotherapy for IBD.
The preliminary results of the application of adjuvant chemoimmunotherapy (АCIТ) in the treatment of patients (pts.) with adenocarcinoma (AC) of the lung.
Authors: Sergey P. Pyltsin, Yury N. Lazutin, Gennadiy Z. Sergostyants, Liubov Yu Vladimirova, Igor A. Leyman, Pavel A. Anistratov, Anna P. Charitonova
Journal: Journal of Clinical Oncology (2014)

e18531 Background: Chemotherapy is the standard adjuvant treatment of lung cancer, but it's somewhat ineffective and controversial at the 1 stage of the disease. The authors have developed an original method АCIТ for using Russian recombinant interferon-gamma Ingaron (Pharmaclon. Moscow.), the results of the 2nd phase of clinical trials are presented in this work. Methods: The study included 63 pts. undergoing radical resection of lung about 1-3A stage AC from 2009 to 2011, which randomized into two groups. The 1 group included 33 pts. which received АCIТ after pneumonectomy in regime: carboplatin AUC=5 on d. 1 + etoposide 100 mg/m2 in 1, 3, 5 d.+ Ingaron of 500,000 IU/m2 in 2,4,6 d. of i.v. infusion; after a lobectomy carboplatin is replaced by cisplatin-80 mg/m2 on d. 1. The 2 group consisted of 30 pts. which received chemotherapy in similar regimes, but without the introduction of Ingaron.The interval between cycles was 3 weeks. Registration of adverse events was carried out according to criteria of NCI-CTC 2005, DFS was determined by the method of Kaplan-Meier, differences between groups were compared log-rank test. Results: In the 1 group of three planned cycle ACIT received 28 (84,8%) pts., in the 2nd 27 (90%). Febrile fever in the first group was registered in 23 (36,5%) patients, less 5 (7,9%) observations of temperature rise was accompanied by a shivering. In the 2nd group fever grade (g) 1 was observed in 3 (4,7%) cases. Other symptoms of influenza-like syndrome: artralgia g.1-15 (23,8%), g.2-8 (12,7%); mialgia g.1-13 (20,6%),g.2 -12 (19%) were for 2-3 day after the introduction of Ingaron. Hematological toxicity was mild recorded rarely, does not require the use of special therapy. The analysis of curves with a median follow-up of 26 months revealed a trend to increase the indicators of the 3-year DFS to 25%, 92% in the 1 group compared to 67% in the 2nd (p=,08). Conclusions: Improvement of parameters of the 3-year DFS demonstrates the prospects of further study of chemoimmunotherapy with Ingaron, as a continuation of a set of clinical material and increase of the time of observation that is likely to reveal a statistically significant differences remote results of the treatment.
Cost-utility analysis of routine surveillance imaging of patients in first remission after treatment for diffuse large B-cell lymphoma.
Authors: Scott F. Huntington, Jakub Svoboda, Jalpa Doshi
Journal: Journal of Clinical Oncology (2014)

6526 Background: Surveillance imaging of patients (pts) with DLBCL in first remission (CR1) remains controversial. NCCN guidelines recommend CT scans in asymptomatic pts no more often than every 6 months for 2 years post treatment. A decision-analytic Markov model was developed to evaluate follow up (f/u) strategies for pts in CR1 after rituximab-containing treatment. Methods: Three strategies were compared in 55 year old pt cohorts: standard f/u without routine imaging, routine f/u with biannual CT scans for 2 years, or routine f/u with biannual PET/CT for 2 years. Our transition state model used 6 month length cycles with transition probabilities and clinical utilities derived from published studies. Costs were based on the Medicare fee schedule and future cost/benefits were discounted at a rate of 3% annually. The baseline model was biased to favor imaging strategies by associating asymptomatic imaging-detected relapses with improved clinical outcome. Quality-adjusted utility, lifetime costs, and incremental cost-effectiveness ratios (ICERs) were calculated for each f/u strategy. Conclusions were tested by multi-way sensitivity analyses that varied the rate of asymptomatic relapse detection, likelihood of favorable International Prognostic Index (IPI) with asymptomatic relapse, and the impact of IPI on salvage therapy outcome. Results: Surveillance strategies utilizing 2 years of routine CT or PET/CT scans were associated with minimal survival benefit versus f/u without routine imaging (mean OS, routine: 261.6 mos, CT: 261.8 mos, PET/CT: 262.1 mos). The benefit of imaging-based f/u remained small after quality-of-life adjustments (CT: 0.017 QALY, PET/CT: 0.023 QALY). Costs associated with imaging based surveillance strategies are considerable and ICERs were $202,300/QALY and $312,600/QALY for CT and PET/CT strategies respectively. ICERs for imaging strategies remained >$100,000/QALY or were dominated by routine f/u in multi-way sensitivity analyses over clinically relevant ranges. Conclusions: Our analysis suggests surveillance imaging of asymptomatic pts in CR1 following treatment for DLBCL offers little clinical benefit at substantial economic cost.
Area-Based Socioeconomic Status and Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Outcomes: A CIBMTR Analysis
Authors: Kira O Bona, Ruta Brazauskas, Naya He, Leslie E. Lehmann, Joanne Wolfe, Jignesh Dalal, Shahrukh K. Hashmi, Theresa E. Hahn, Nandita Khera, William A. Wood, Christine Duncan, Wael Saber
Journal: Blood (2018)
Transcriptomic analysis of lenalidomide and ENMD-2076 combination drug treatment in a human plasmacytoma xenograft mouse model.
Authors: Shahid Sattar Ahmed, Michelle Lee Grimard, Shuhong Zhang, Xingkui Xue, Jeffrey Altenburg, Jeanette McClintick, Sherif Farag
Journal: Journal of Clinical Oncology (2014)

e19565 Background: ENMD-2076 is a novel oral multi target kinase inhibitor with specific activity against aurora kinases. We have previously demonstrated an additive/synergistic effect of ENMD-2076 and Lenalidomide(LLMD) against myeloma cell lines in a murine model. The purpose of this study was to investigate differential gene expression following combination drug treatment with ENMD-2076 and LLMD in comparison to single drug regimen. Methods: Gene expression analysis by microarray was performed on human plasmacytoma cells obtained from xenografted H929 cells following treatment with ENMD-2076 in combination with LLMD compared to single drug regimen. Ingenuity Pathway Analysis (IPA) was performed to identify the pathways affected by these genes. Results: While treatment with ENMD-2076 alone did not produce significant changes in gene expression, 868 genes were differentially expressed following treatment with LLMD, and 2004 genes were differentially expressed when ENMD-2076 and LLMD were used in combination (FDR ≤1%). The IPA revealed that genes being differentially expressed were integral to various signaling pathways, such as PI3K/AKT, mTOR, ATM, ERK/MAPK, GADD45, cdc42, p53, JAK/STAT, and VEGF. Treatment with the combination regimen affected a significantly higher ratio of molecules in these pathways than with LLMD alone. Conclusions: ENMD-2076 with LLMD synergistically alter expression of several key genes in canonical pathways regulating cell cycle, proliferation, apoptosis and cell signaling.
The association of treatment breaks with survival in metastatic cancer.
Authors: Kuan Rui (Sean) Tan, Laurence Lafond, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2014)

6609 Background: As outcomes for specific metastatic cancers continue to improve, the concept of treatment to disease progression must be tempered by the potential for cumulative toxicities of ongoing therapy. Early research suggests that treatment holidays or “breaks” may provide improved quality of life without significantly compromising outcomes, but data are inconsistent. Using a population-based cohort of metastatic colorectal cancer (mCRC) patients to test this hypothesis, our aim was to determine the impact of treatment breaks on overall survival (OS). Methods: Patients diagnosed with mCRC from 2008 to 2010 and who initiated palliative systemic therapy at any 1 of 5 regional cancer centers in British Columbia were reviewed. Treatment breaks were defined as any intervals of >/= 4 weeks without receipt of any systemic therapy. The number and average length of breaks were characterized for first (1L) and second (2L) line therapy. Using Cox regression that controlled for confounders that included number of lines of therapy and total duration of therapy, we examined for the effect of treatment breaks on OS. Results: In total, 946 patients were identified: median age 64 (IQR 55-72) years, 521 (55%) were men, and 624 (66%) had colon cancer. The median number of treatments received in 1L and 2L therapy were 9 (IQR 4-13) and 7 (IQR 4-12) cycles, respectively. Treatment breaks were prevalent with 223 (24%), 76 (8%) and 55 (6%) patients in the cohort experiencing 1, 2 and >/=3 breaks, respectively. The median length of breaks varied depending on the line of therapy: 49 (IQR 36-99) days for 1L and 56 (IQR 38-100) days for 2L. There were no differences in baseline patient and tumor characteristics between subjects who underwent breaks and those who did not (all p>0.05). On multivariate analyses that adjusted for prognostic factors, patients who received more and longer treatment gaps did not experience worse OS (Table) Conclusions: This study suggests that treatment breaks from systemic therapy in carefully selected patients with mCRC do not compromise outcomes. Total number of breaks HR for death p-value Median duration of breaks (days) HR for death p-value None 1.0 <0.001 0 1.0 <0.001 1 0.72 1 to 30 0.79 2 0.62 31 to 60 0.58 3+ 0.46 61 to 90 0.30
Adoption and impact of concurrent chemotherapy with radiation in the treatment of patients with vaginal cancer: A National Cancer Data Base (NCDB) study.
Authors: Malolan Sri Rajagopalan, Jeff Feng-Hsu Lin, Karen Man Xu, Paniti Sukumvanich, Thomas C. Krivak, Joseph L. Kelley, Sushil Beriwal
Journal: Journal of Clinical Oncology (2014)

5525 Background: Vaginal cancer is uncommon entity for which concurrent chemoradiation (CCRT) is increasingly used based on extrapolation from cervical cancer. However, studies supporting CCRT use are limited to single-institution reports. We sought to explore the adoption rate of CCRT and determine its impact on survival in vaginal cancer patients. Methods: We identified patients in the NCDB diagnosed with vaginal cancer from 1998-2011 who received definitive radiation therapy with or without chemotherapy. Univariate and multivariable exploratory analyses of factors associated with CCRT use were performed. Log-rank test and Cox proportional hazards modeling identified the overall and independent contribution of CCRT use on overall survival (OS) in the context of known/putative prognostic factors. Results: A total of 13,689 patients were identified of whom 8,086 (59.1%) received radiation therapy. Of these, 3,932 (48.6%) received CCRT, the use of which increased from 20.8% in 1998 to 59.1% in 2011. Of the 23 patient, disease, treating facility, and treatment factors explored, 13 were found to have significant associations in chi-square testing and were entered into a binary logistic regression model. Younger age, larger tumor size, later year of diagnosis, treatment at a higher volume facility, squamous histology, and higher stage (in order of increasing association) are independently associated with increased use of CCRT. Median OS of patients who received CCRT is significantly longer than those who did not (56.2 vs. 41.2 months, p<0.0005). On multivariable analysis, younger age, treatment at a facility with higher-volume, squamous histology, lower Charlson-Deyo comorbidity score, treatment with CCRT, treatment with brachytherapy and lower stage (in order of increasing association) are independently prognostic of improved survival. Conclusions: Use of concurrent chemotherapy with radiation therapy in the treatment of vaginal cancer has become increasingly adopted over the past decade and is associated with a significant improvement in OS in this large national cohort. CCRT should be integrated into treatment guidelines for vaginal cancer.
Three-dimensional (3D) telomeric architecture of esophageal squamous cell carcinoma.
Authors: Somkiat Sunpaweravong, Patrapim Sunpaweravong, Sabine Mai
Journal: Journal of Clinical Oncology (2014)

e15048 Background: Telomeres are the ends of chromosomes and their function is to preserve chromosomal integrity and prevent terminal end-to-end fusions. Telomere loss or dysfunction results in breakage–bridge–fusion cycles, aneuploidy, and chromosomal rearrangements and can lead to genomic instability and promote carcinogenesis. To study the hypothesis that changes in certain telomeres contribute to the development of esophageal squamous cell carcinoma (ESCC), and to determine whether there are differences between young and old patients, we compared the 3D nuclear telomeric architecture of ESCC tumors and normal epithelia. Methods: The patients were divided by age into two equal groups, under 45 years and over 80 years.Tumors and normal epithelia at least 10 cm distant from the border of the tumor were biopsied in ESCC patients. Hematoxylin and eosin (H&E) staining was done in each sample to confirm and identify the cancer and normal epithelial cells. The study was based on quantitative 3D fluorescent in situ hybridization (Q-FISH), 3D imaging and 3D analysis of paraffin-embedded slides. The 3D data were measured evaluating 100 nuclei per slide. The main parameters compared were as follows; the number of signals (number of telomeres), signal intensity (the telomere length), number of telomere aggregates, a/cratios (indicating the phase of the cell cycle), and nuclear volume. Results: Tumor and normal epithelium samples from 16 patients were compared. The normal epithelia had more telomere signals and higher intensities than the tumors, with p-values of p<0.0001 and p=0.0078 respectively. There were no statistically significant differences between the number of telomere aggregates, the a/cratios (the cell cycle phase), or the nuclear volumes between the tumors and the normal epithelia. Secondary analyses examined the effect of age on telomere architecture and found no statistically significant differences in all parameters between young and old patients in either tumor or epithelium parameters. Conclusions: The 3D nuclear telomeric signature was able to detect differences in telomere architecture between ESCC and normal epithelium tissue. However, there were no differences between young and old patients.
Plasma levels and tumor tissue RNA of MMP2 and MMP9 exhibit similar distribution in newly diagnosed and recurrent glioblastoma (GB).
Authors: Emeline Tabouret, Francoise Boudouresque, Emilie Denicolai, Maryline Barrie, Celine Boucard, Philippe Metellus, Didier Autran, Alexia Terciolo, Dominique Figarella-Branger, L'houcine Ouafik, Olivier L. Chinot
Journal: Journal of Clinical Oncology (2014)

2074 Background: We have previously showed that a high MMP2, and to a lesser extend a low MMP9 plasma levels were associated to a high response rate, a prolonged PFS and OS in recurrent GB treated with bevacizumab (BEV), but not with cytotoxic agents, (Tabouret and col. Neuro-Oncol 2013). In order to further explore the optimal timing of bevacizumab administration, we analyzed potential differences of MMP2/MMP9 plasma levels and tumor RNA in patients with newly diagnosed and recurrent GB. Methods: Plasma was collected before radiotherapy in newly diagnosed GB patients (pts) (Pop ND) and in a distinct population of pts at the time of recurrence (Pop RD). MMP2 and MMP9 plasma levels were assessed using ELISA. In a third population with paired initial and recurrent GB tumors (Pop NDT and RDT respectively), MMP2 and MMP9 RNA were analyzed using quantitative RT PCR. Correlations were analyzed using the Mann Whitney U test, the Spearman corelation and the T-test. Results: MMP plasma levels were tested in 44 ND and 76 RD pts. Mean levels of ND and RD MMP2 levels were 196.4 pg/ml (± 9.6) and 218.2 pg/ml (± 9.6). Mean levels of ND and RD MMP9 levels were 365.4 pg/ml (± 50.7) and 302.0 pg/ml (± 34.9). No significant difference was observed between ND and RD plasma levels of MMP9 and MMP2. In ND pts, no correlation was found between MMP2 and MMP9 plasma levels, neither between these plasma markers and KPS or age. In NR pts, MMP2 and MMP9 plasma levels were inversely correlated (p<0.001). Paired MMP9 and MMP2 RNA were available in NDT and RDT for 29 pts. No difference was observed between NDT and RDT expressions of MMP9 and MMP2. At initial diagnosis, MMP9 and MMP2 were 95.7-fold and 15.9-fold over-expressed compared with normal brain. At recurrence, MMP9 and MMP2 were 80.6-fold and 25.9-fold over-expressed. MMP2 and MMP9 RNA were correlated in NDT (p=0.001) but not in RDT. Conclusions: In this retrospective study, the prebiomarkers of BEV activity, MMP2 and MMP9, did not show significant change between GB initial presentation and recurrence both for plasma levels and tumor RNA. These results may suggest that BEV could be similarly active for pts with newly diagnosed and recurrent GB. Adequate prospective studies are warranted.
Abstract MP046: Visceral Adipose Tissue but Not Subcutaneous Adipose Tissue Associates With Cholesterol Efflux Capacity in Psoriasis
Authors: Joshua P Rivers, Amit K Dey, Abhishek Chaturvedi, Jonathan H Chung, Mohammad Tarek Kabbany, Mark A Ahlman, Justin A Rodante, Aditya A Joshi, Charlotte L Harrington, Martin P Playford, Jianhua Yao, Tiffany M Powell-Wiley, Nehal N Mehta
Journal: Circulation (2017)

Background: Psoriasis (PSO), a chronic inflammatory disease associated with increased cardiovascular (CV) risk, provides an ideal model to study inflammatory atherogenesis in vivo. PSO is associated with impaired cholesterol efflux capacity (CEC) and increased cardiometabolic dysfunction including adipose tissue dysregulation. Recently, visceral adiposity (VAT) was shown to be associated with increased CV events. However, neither VAT nor subcutaneous adiposity (SAT) have been shown to be associated with CEC. Hypothesis: Increased VAT by CT is associated with a decrease in CEC independent of CV risk factors. Methods: Consecutively recruited PSO patients (N=76) underwent CT scans to measure abdominal adiposity. VAT and SAT volume was quantified from the level vertebral level T10 to pubic symphysis. CEC was quantified using a cell-based ex vivo assay measuring the ability of apoB-depleted plasma to mobilize cholesterol from lipid-laden macrophages. The relationship of VAT and SAT with CEC was analyzed using multivariable regression models (STATA 12). Results: The cohort had a low CV risk by FRS [median (IQR): 4.0 (2.0-7.0)], mild to moderate PSO [median (IQR): 5.2 (3.0-8.5)], overweight to obese with a mean BMI of 30, 40% were on statin treatment, and 40% were on systemic/biologic therapy for PSO. In unadjusted models VAT was inversely associated with CEC (beta = -0.41, p &lt;0.001) while SAT was not significantly associated (beta = -0.12, p = 0.32). In fully adjusted models VAT retained inverse association with CEC (beta = -0.35, p = 0.04) while SAT remained insignificant (beta coefficient = 0.15, p-value = 0.43) (Table 1). Conclusions: VAT inversely associated with CEC while SAT showed no significant relationship suggesting that VAT may directly drive inflammatory HDL dysfunction while SAT may not. However, larger studies are needed to confirm these findings.