tbuckley/cabot-search huggingface dataset:
Incidence of colorectal cancer among young adults in the state of Colorado.
Authors: Christopher Hanyoung Lieu, David Sheneman, Jack L Finch, Sarah Lindsey Davis, Stephen Leong, Colin D. Weekes, William T. Purcell, Karyn A. Goodman, Wells A. Messersmith, S. Gail Eckhardt
Journal: Journal of Clinical Oncology (2016)

3585 Background: Colorectal cancer (CRC) incidence has decreased overall, both nationally and across Colorado, since 1990. Since National Comprehensive Cancer Network (NCCN) guidelines recommend screening beginning at age 50 for individuals with average risk, little is known about the CRC incidence in individuals under age 50. However, from 1992 to 2011 there has been a continuous increase in the rate of CRC in patients under 50, which has not been evaluated by geographic region. We examined CRC incidence, focusing on age, in order to better understand CRC in the under-50 population in Colorado. Methods: We analyzed 39,575 CRC cases from the Colorado Central Cancer Registry, examining effects of age, gender, stage at diagnosis, disease location, first treatment received, and length of disease. We calculated the annual percentage change over the 23-year study period (1990 – 2013) to analyze changes in age-adjusted incident rates. Results: The age-adjusted incidence of CRC was lower in individuals under 50, ranging from 4.3 to 6.8 per 100,000 person-years compared to individuals over 50, where incidence ranged from 104.7 to 178.2 per 100,000. However, increasing age-adjusted incidence rates averaging 0.8% per year (p < 0.05) were observed in the under-50 population, while age-adjusted rates fell on average 2.5% per year (p < 0.05) in the over-50 population. Age-adjusted incidence rose in males under 50 by 1.0% per year (p < 0.05) and increased 0.8% per year in females. The increase in incidence appeared to be driven mostly by an increase in stage IV CRC in the under-50 population with an increase of 2.4% per year from 2003 through 2013 (p < 0.05) compared to an increase in early-stage CRC of 0.8% per year. Conclusions: The absolute incidence of CRC continues to fall in the state of Colorado in individuals over age 50. However, incidence is rising in individuals under age 50, particularly among males, and the increase in incidence appears to be driven by an increase in late-stage diagnosis. Additional research into CRC in individuals under age 50 is necessary to better characterize this rise in incidence and possible causative mechanisms.
International harmonization of diagnostic criteria for <i>HER2</i>-amplified metastatic colorectal cancer and application of targeted next-generation sequencing panel as a diagnostic method.
Authors: Satoshi Fujii, Anthony Martin Magliocco, Emanuele Valtorta, Jihun Kim, Wataru Okamoto, Jeong Eun Kim, Kentaro Sawada, Yoshiaki Nakamura, Valter Torri, Scott Kopetz, Woong Yang Park, Katsuya Tsuchihara, Tae Won Kim, Kanwal Pratap Singh Raghav, Salvatore Siena, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2018)

3594 Background: HER2 amplification (HER2+) in metastatic colorectal cancer (mCRC) is associated with resistance to anti-EGFR antibodies and response to HER2 targeted therapies. This study assessed the diagnostic criteria on HER2+ mCRC among four groups (GI-SCREEN-Japan, SWOG-USA, HERACLES-Italy, and Korea) and harmonized the criteria for patient enrollment in clinical trials that target these patients (pts). Methods: Samples from 475 and 16 pts with mCRC were used in exploratory and validation cohorts, respectively. We assessed HER2 status by immunohistochemistry (IHC) and HER2/CEP17 ratio and gene copy number (GCN) by fluorescence in situ hybridization (FISH) and copy number variations (CNV) by targeted next-generation sequencing (NGS) panel. OCA by ThemoFisher and AMC v3 by illumina were used in exploratory and validation cohorts, respectively for the cross-validation of NGS panels. Results: The consensus diagnostic criteria for HER2+ mCRC was reached; IHC 3+ or IHC 2+ and HER2/CEP17 ratio by FISH ≥ 2.0, and tumor content > 10% for surgically resected specimens (separate quantity criteria were established for biopsy specimens). The median GCN and CNV for pts who met consensus criteria for HER2+ was 10.9 and 27.7 compared to 2.5 (P< 0.0001) and 3.5 (P< 0.0001), respectively in pts who were HER2-. These findings were validated in validation cohort (GCN: 16.2 v 2.4, P= 0.0002; CNV: 42.5 v 2.0, P= 0.0003). GCN also showed strong correlation with CNV in both cohorts (r: exploratory: 0.90, validation: 0.97; P< 0.0001). CNV in cross validation of OCA and AMC v3 also showed strong correlation (r: 0.97, P< 0.0001). The CNV for pts fulfilling the consensus criteria was more than 4.0 in the two cohorts. The accuracy of the IHC/FISH criteria was validated for mCRC pts, providing cross-validation of NGS panels. Conclusions: We were able to verify the HER2 classification consistency between CNV by NGS and IHC/FISH by harmonizing diagnostic criteria for HER2+. This strategy can help establish diagnostic criteria for HER2+ cancer by allowing for different methodologies to be used for pts screening for trial eligibility.
NLR Family Pyrin Domain‐Containing 3 Inflammasome Activation in Hepatic Stellate Cells Induces Liver Fibrosis in Mice
Authors: Maria Eugenia Inzaugarat, Casey D. Johnson, Theresa Maria Holtmann, Matthew D. McGeough, Christian Trautwein, Bettina G. Papouchado, Robert Schwabe, Hal M. Hoffman, Alexander Wree, Ariel E. Feldstein
Journal: Hepatology (2018)

The NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays an important role in liver fibrosis (LF) development. However, the mechanisms involved in NLRP3-induced fibrosis are unclear. Our aim was to test the hypothesis that the NLRP3 inflammasome in hepatic stellate cells (HSCs) can directly regulate their activation and contribute to LF. Primary HSCs isolated from wild-type (WT), Nlrp3-/- , or Nlrp3L351PneoR knock-in crossed to inducible (estrogen receptor Cre-CreT) mice were incubated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP), or 4OH-tamoxifen, respectively. HSC-specific Nlrp3L351P knock-in mice were generated by crossing transgenic mice expressing lecithin retinol acyltransferase (Lrat)-driven Cre and maintained on standard rodent chow for 6 months. Mice were then sacrificed; liver tissue and serum were harvested. Nlrp3 inflammasome activation along with HSC phenotype and fibrosis were assessed by RT-PCR, western blotting, fluorescence-activated cell sorting (FACS), enzyme-linked immunosorbent assay, immunofluorescence (IF), and immunohistochemistry (IHC). Stimulated WT HSCs displayed increased levels of NLRP3 inflammasome-induced reactive oxygen species (ROS) production and cathepsin B activity, accompanied by an up-regulation of mRNA and protein levels of fibrotic makers, an effect abrogated in Nlrp3-/- HSCs. Nlrp3L351P CreT HSCs also showed elevated mRNA and protein expression of fibrotic markers 24 hours after inflammasome activation induced with 4-hydroxytamoxifen (4OHT). Protein and mRNA expression levels of fibrotic markers were also found to be increased in isolated HSCs and whole liver tissue from Nlrp3L351P Lrat Cre mice compared to WT. Liver sections from 24-week-old NlrpL351P Lrat Cre mice showed fibrotic changes with increased alpha smooth muscle actin (αSMA) and desmin-positive cells and collagen deposition, independent of inflammatory infiltrates; these changes were also observed after LPS challenge in 8-week-old NlrpL351P Lrat Cre mice. Conclusion: Our results highlight a direct role for the NLRP3 inflammasome in the activation of HSCs directly triggering LF.
Overexpression of Notch-1 induced tamoxifen resistance through down regulation of ESR1 in positive estrogen receptor breast cancer.
Authors: Nasser Ghaly Yousif, Majid Al-Matwari
Journal: Journal of Clinical Oncology (2012)

e11046 Background: Tamoxifen is one of the most widely used drugs in the treatment of estrogen-receptor positive breast cancer, and acquired resistance to tamoxifen during treatment are largely unknown and recent research showed that lower levels of ESR1 associated with tamoxifen resistance in ER-positive breast tumors, from other hand highly expression of Notch-1 and/or Jagged-1 has negative prognostic significance in breast cancer, in this study we show the cross-talk between Notch and the lower levels of ESR1 estrogen receptor positive breast cancer. Methods: A retrospective study with clinico-pathological analysis of 195 patients had ER-positive breast cancer used tamoxifen as an adjuvant systemic therapy, gene expression profiling of paraffin-embedded tumors for ESR1, Real-time PCR and Western blot analysis were performed to detect Notch-1/Jagged-1. Results: From 195 patients 32% had tamoxifen resistance which related with lower levels of ESR1 expression (P=0.019) and there was, a highly significant association of over expression Notch1 protein with the lower levels of ESR1 (P=0.006). Conclusions: The results from this study demonstrate for the first time that Notch-1 regulate levels of ESR1 in ER-positive breast cancer, and partly responsible for tamoxifen resistance, the Notch signaling pathway may be a potential therapeutic target beside current breast cancer therapy and need further investigation to know the mechanism of this pathway.
Efficacy and safety of endostar in the treatment of advanced lung squamous cell carcinoma.
Authors: Weiheng Hu, Jian Fang, Jun Nie, Ling Dai, Jie Zhang, Xiaoling Chen, Xiangjuan Ma, Guangming Tian, Di Wu, Jindi Han, Sen Han, Yang Wang, Jieran Long
Journal: Journal of Clinical Oncology (2017)

e20574 Background: From the early 2000s, many advances in non-small cell lung cancer (NSCLC) have been made with the emergence of targeted therapies. However, because of safety concerns and a lower prevalence of relevant therapeutic targets, patients with squamous NSCLC have been excluded from many of these breakthroughs. Endostar is a novel inhibitor of tumor angiogenesis that acts specifically on neovascular endothelial cells. This study is to explore the clinical efficacy and safety of endostar in advanced squamous NSCLC patients. Methods: We performed a retrospective analysis of 259 newly diagnosed advanced squamous NSCLC patients who had received platinum-based doublet chemotherapy (PBDC) between September 2009 and March 2016. Of these patients, 116 received Endostar combined with PBDC, and 143 received PBDC only. Clinical tumor responses, progression-free survival (PFS), overall survival (OS), and toxicity profiles were recorded and analyzed. Results: After a median follow-up of 13.5 months, a improvement in PFS was observed in the Endostar group, the median PFS was7.7 months compared with 5.4 months in the control group (HR, 0.745; P= 0.034). The median OS was 19.0 months in the Endostar group versus 14.3 months in the control group, but the difference was not significant (HR, 0.780; P= 0.094). Multivariate analysis demonstrated that in patients with advanced squamous NSCLC, anti-angiogenesis therapy with Endostar, radiotherapy of primary tumor and Ⅲb stage were significant and independent predictors of improved PFS ( P&lt; 0.05). For both arms, hematologic and gastrointestinal toxicities were the most common adverse events. Patients treated with Endostar had slightly higher rates of cardiac disorder and thromboembolic event, as compared with the control patients, but there were no statistically significant differences in toxicities overall between the 2 treatment groups. Conclusions: The current study indicates that Endostar as an anti-angiogenesis therapy combined with PBDC is able to provide further survival benefits with satisfactory toxicity in previously untreated squamous NSCLC patients, which merits further evaluation in randomized trials.
Medical Schools in the United States, 2005-2006
Authors: Barbara Barzansky, Sylvia I Etzel
Journal: JAMA (2006)

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Activity of PF-03084014 in adults with desmoid tumors/aggressive fibromatosis.
Authors: Geraldine Helen O'Sullivan Coyne, Shivaani Kummar, Khanh Tu Do, Peter L. Choyke, Baris Turkbey, Eric Polley, Yvonne Horneffer, Lamin Juwara, Rasa J Vilimas, Robert S. Meehan, Lee J. Helman, James H. Doroshow, Alice P. Chen
Journal: Journal of Clinical Oncology (2016)

11028 Background: Desmoids are rare, locally invasive, slow growing soft tissue tumors that are either sporadic or associated with familial genetic syndromes such as familial adenomatous polyposis. Desmoids are characterized by stabilization and abnormal nuclear localization of β-catenin. Mutations in the CTNNB1 gene are found in 85-90% of desmoids. Gamma-secretase cleaves intracellular Notch, resulting in Notch signaling. PF-030844014 (PF) is an oral, reversible γ-secretase inhibitor that was well tolerated in a phase I trial. We report here the updated results of PF in a phase II trial of patients with progressive, symptomatic desmoid tumors. Methods: PF was administered orally at 150mg BID; 21 day cycles. Archival samples were sequenced for germline/somatic mutations in APC and CTNNB1 genes. Primary objective: response rate (RR); single stage study; 90% power to rule out unacceptably low RR of 10% in favor of 35% RR. Response defined by RECIST 1.1 using CT. Optional dynamic contrast-enhanced MRI (DCE-MRI) was obtained at baseline and with every restaging. Results: 17 patients (pts) entered between November 2014-May 2015. Currently, 10/17 pts (59%) remain on study. 7 pts discontinued treatment by choice or co-morbid conditions, including allergy, desire to conceive, and travel issues (median #cycles 14, range 4-23). All pts were previously treated and had disease progression prior to enrollment; no pt has progressed on study to date. Median follow-up: 17 months (range 3-26 months). 12 pts remained on study ≥ 1year, with 2 pts continuing treatment for > 2years. Grade 3 toxicities were limited to hypophosphatemia (8 pts, 47%). Dose reduction to 100mg BID daily occurred in 2 pts due to persistent grade 2 nausea and diarrhea, respectively, which resolved completely following dose reduction. 12 pts (70%) experienced stable disease; 4 pts achieved a confirmed PR, and 1 pt’s PR awaits confirmation, meeting the primary endpoint of the study. Late responses were noted; time to response ranged from 9 to 18 months. Preliminary DCE-MRI analysis demonstrated reductions of tumor volume. 15/17 pts had a somatic/germline mutation. Conclusions: PF is clinically active in pts with progressive demoids with 5/17 pts achieving an objective response. Clinical trial information: NCT01981551.
A randomized, phase 2 trial of denintuzumab mafodotin and RICE vs RICE alone in the treatment of patients (pts) with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) who are candidates for autologous stem cell transplant (ASCT).
Authors: Robert W. Chen, Eric D. Jacobsen, Ana Kostic, Tina Liu, Craig H. Moskowitz
Journal: Journal of Clinical Oncology (2016)

TPS7584 Background: The only curative option for DLBCL pts who relapse after initial treatment is salvage chemotherapy to obtain the best possible response prior to ASCT. With current salvage regimens, only 50% of pts proceed to ASCT (Gisselbrecht 2010). The primary unmet need is to achieve a higher rate of response, in particular complete remission (CR), as pts transplanted in a PET-negative CR have better long-term outcomes. Denintuzumab mafodotin is an antibody-drug conjugate targeting CD19, a B-cell specific marker expressed uniformly on almost all B-cell malignancies. A phase 1 study of denintuzumab mafodotin monotherapy in r/r DLBCL after failure of 2nd-line salvage and beyond showed a 38% objective response rate (ORR) and 23% CR rate, with low rates of myelosuppression and neuropathy; antitumor activity was higher in relapsed pts (60% ORR, 40% CR rate) with a median duration of response of 47 wks (95% CI: 16, –) (Moskowitz, presented at ASH 2015). Preclinical data suggests synergistic activity of denintuzumab mafodotin with RICE. With encouraging clinical/preclinical data and no overlapping toxicities, combining denintuzumab mafodotin with the 2nd-line salvage regimen of RICE could lead to improved outcomes. Methods: This randomized, open-label, phase 2 study (NCT02592876) evaluates the activity and safety of denintuzumab mafodotin with RICE (19A+RICE) vs RICE in pts with r/r DLBCL or Grade 3b follicular lymphoma. Pts must have only received frontline CD20-directed immunotherapy with anthracycline-based multi-agent chemotherapy, have measurable FDG-avid disease, and be candidates for ASCT. Up to approximately 150 pts will be randomized 1:1 to receive 19A+RICE or RICE q3 wks for 3 cycles. The primary objective is to compare the CR rates at end of treatment (EOT) between study arms. Secondary objectives include comparisons of safety, progression-free survival (PFS), overall survival (OS), and the proportion of pts receiving ASCT after EOT. Response is assessed by CT and PET scans using the Lugano classification criteria (Cheson 2014). Study enrollment began in late 2015. Clinical trial information: NCT02592876.
TCT-540 Incidence, Predictors, and Impact of Post-Discharge Gastrointestinal Bleeding After Coronary Drug-Eluting Stents Implantation: The ADAPT-DES Study
Authors: Gennaro Giustino, Roxana Mehran, Ajay Jayant Kirtane, Bjorn Redfors, Zixuan Zhang, Thomas McAndrew, Bernhard Witzenbichler, Franz-Josef Neumann, Michael Rinaldi, Timothy Henry, David Cox, Peter L. Duffy, Tom Stuckey, Ori Ben-Yehuda, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
Low T3 syndrome with hyperthyrotropinemia and early detection of liver metastasis.
Authors: Irina V. Kaplieva, Elena Mikhaylovna Frantsiyants, Lidia K. Trepitaki, Yulia A. Pogorelova, Valeria Bandovkina, Lyudmila Dmitriyevna Tkalya, Elena F. Islamova, M. A. Cherkes, Oleg I. Kit
Journal: Journal of Clinical Oncology (2017)

e23010 Background: Numerous clinical studies have shown an association between changing thyroid gland (TG) function and the development of tumors. The purpose of the study was to analyze the dynamics of thyroid hormones in the pituitary gland, TG and blood serum (BS) during liver metastasis in order to create thyroid profile of metastasis and to detect thyroid markers of metastasis in BS. Methods: The experiment included 44 white male rats weighing 180-250 g. Sarcoma 45 was transplanted intrasplenically. Levels of thyroid stimulating hormone (TSH) were studied in the pituitary gland, TG, BS; the amount of free (fT4) and total (T4) thyroxine and free (fT3) and total (T3) triiodothyronine in TG and BS were determined by radioimmunoassay (Immunotech, Czech Republic; Arian analyzer, Russia). Results: Exertion of the pituitary gland and overproduction of TSH were observed since the early days of the tumor development, later accompanied by TG hypofunction. Quantitative changes of thyroid hormones in organs did not coincide with their dynamics in BS. The first diagnostic signs of experimental liver metastasis, in the absence of formed metastases in the body, were hyperthyrotropinemia and a tendency to fT3 decrease in BS. Already formed liver metastases were characterized by a marked low T3 syndrome which transformed into a more severe lowT3/lowT4 syndrome during the secondary metastasis. Conclusions: The development of liver metastases is accompanied by the exertion and imbalance of the thyroid system function. Analysis of dynamics of the thyroid axis hormones in BS allows predicting the appearance of liver metastasis and identification of “the point of no return” in the development of the pathology that leads to secondary metastasis and irreversible progression of the disease.
Safety of axitinib plus avelumab in patients with recurrent glioblastoma.
Authors: Laila Ben Salama, Johnny Duerinck, Stephanie Du Four, Gil Awada, Lydia Fischbuch, Jennifer De Cremer, Anne Rogiers, Bart Neyns
Journal: Journal of Clinical Oncology (2018)

e14082 Background: Both PD-L1 and VEGFR are legitimate therapeutic targets in recurrent glioblastoma (rGB). Axitinib, a potent, selective small molecule VEGFR 1-3 inhibitor with single-agent activity in rGB, may synergize with the PD-L1 blocking IgG1 mAb avelumab for the treatment of rGB. Methods: A phase II clinical trial investigating avelumab plus axitinib in patients (pts) with rGB is ongoing (NCT03291314). Pts with rGB are stratified according to their baseline use of corticosteroids (CS). Pts without baseline CS use initiated treatment with axitinib (AXI, 5 mg po BID) plus avelumab (AVELU, 10 mg/kg IV Q2w) (Cohort A). Pts with baseline CS use initiated AXI monotherapy (AXI mono); AVELU could be added after 6w if the CS dose could be tapered to ≤ 10 mg prednisolone (Cohort B). Results: From Jun 2017 to Jan 2018, 32 pts (med age 50y [range 29-70]; 62% male; 56% WHO PS 1 or 0) initiated study treatment (16 in Cohort A and 16 in -B) . All pts had failed prior radiotherapy and temozolomide. In Cohort B, 7 pts (44%) initiated treatment with AXI+AVELU after 6w of AXI mono. Treatment with AXI+AVELU was ongoing in 10 pts (across both cohorts). Safety data are available for a total of 280 AXI+AVELU treatment weeks (median 8w [range 4-30]/pt). Treatment-related AEs (TRAE) of any grade occurred in 100% of pts. All-cause grade 3 AE occurred in 10 (43%) pts; 7 [30%] pts experienced a grade 3 TRAE. There were no gr 4 or 5 AE. PD was the only reason for stopping AXI+AVELU treatment. Conclusions: The safety profile of avelumab plus axitinib appears manageable in pts with rGB. This clinical trial is currently being continued for the evaluation of efficacy. Clinical trial information: NCT03291314. CTCAEv4 Grade 1 or 2 3 n % n % Worse lab value Lymphopenia 16 69.6 0 0 Thrombocytopenia 8 34.8 0 0 Increased Hb 7 30.4 0 0 Increased TSH 5 21.7 0 0 Leukocytosis 5 21.7 0 0 Hb decreased 4 17.4 0 0 ALT increased 4 17.4 0 0 AST increased 3 13.0 0 0 TSH decreased 3 13.0 0 0 Adverse event Hypertension 12 52.2 4 17.4 Dysphonia 13 56.5 0 0 Fatigue 10 43.5 1 4.3 Diarrhea 7 30.4 1 4.3 Oral dysesthesia/mucositis 7 30.4 0 0 Anorexia 4 17.4 1 4.3 Fever 4 17.4 0 0 Nausea 3 13.0 0 0 Confusion 2 8.6 1 4.3