tbuckley/cabot-search huggingface dataset:
Epidemiology of gastrointestinal neuroendocrine tumors (GINET) in the US: Analysis of 2 large insurance claims databases.
Authors: Beilei Cai, Michael S. Broder, Eunice Chang, Maureen Neary, Caroline Burk, Kris Grzegorzewski
Journal: Journal of Clinical Oncology (2016)

e13072 Background: The majority of NETs occur in the gastrointestinal (GI) and bronchopulmonary system. The overall incidence of GI NET in the US appears to have increased from the 1970s to 2004 with the latest estimate of 52.5 cases per million person-years in year 2004. Whether incidence has continued to increase in the last decade is not known. Methods: A retrospective, cross-sectional study was conducted using data 2010-2014 from 2 major US health insurance claims databases: Truven Health Analytics MarketScan and IMS PharMetrics. Patients were included if, during a calendar year, they were 18-64 years old, and had ≥ 1 inpatient or ≥ 2 outpatient claims with NET of the small intestine, appendix, large intestine, or other areas of the GI tract, identified by International Classification of Diseases 9 (ICD-9) codes: 209.0x, 209.1x, 209.23, 209.25-209.27, 209.4x-209.5x, 209.63, 209.65-209.67. Prevalence was calculated as the number of patients with GI NET divided by the number of enrollees per year. Incidence rates were calculated as the number of patients with a first observed NET diagnosis who were disease-free for 2 years prior to the diagnosis, divided by the number of enrollees. Analyses were conducted separately by year and database. Results: For years 2010-2014, there were 2,112-2,840 and 1,874-2,174 GI NET cases per year in MarketScan and PharMetrics databases respectively. Prevalence increased from 101.0 to 160.6 PMPY between 2010 and 2014 in MarketScan and from 88.4 to 144.8 per million per year (PMPY) in PharMetrics; it increased with age and was highest (207.8-374.8 PMPY depending on the year and data source) in 55-64 year olds; and it was similar in females (89.8-163.6 PMPY) and males (87.0-157.2 PMPY). Incidence increased in both datasets from 2011 to 2014: from 66.5 to 81.5 per million person-years in MarketScan and from 55.9 to 68.9 per million person-years in PharMetrics. Conclusions: In both MarketScan and PharMetrics databases, the incidence and prevalence rates of GI NET have increased considerably over the last decade. Increased awareness of GI NET in clinical oncology setting is needed to accommodate this increasing trend.
Tumor angiogenesis revisited: Regulators and clinical implications
Authors: Roberto Ronca, Mohammed Benkheil, Stefania Mitola, Sofie Struyf, Sandra Liekens
Journal: Medicinal Research Reviews (2017)

Abstract Since Judah Folkman hypothesized in 1971 that angiogenesis is required for solid tumor growth, numerous studies have been conducted to unravel the angiogenesis process, analyze its role in primary tumor growth, metastasis and angiogenic diseases, and to develop inhibitors of proangiogenic factors. These studies have led in 2004 to the approval of the first antiangiogenic agent (bevacizumab, a humanized antibody targeting vascular endothelial growth factor) for the treatment of patients with metastatic colorectal cancer. This approval launched great expectations for the use of antiangiogenic therapy for malignant diseases. However, these expectations have not been met and, as knowledge of blood vessel formation accumulates, many of the original paradigms no longer hold. Therefore, the regulators and clinical implications of angiogenesis need to be revisited. In this review, we discuss recently identified angiogenesis mediators and pathways, new concepts that have emerged over the past 10 years, tumor resistance and toxicity associated with the use of currently available antiangiogenic treatment and potentially new targets and/or approaches for malignant and nonmalignant neovascular diseases.
Preclinical activity of new investigational drug ONC201 in triple-negative and non-triple negative and BRCA1-deficient breast cancer cells.
Authors: Marie D Baumeister, Jessica Wagner, Varun V. Prabhu, Christina Leah B. Kline, Joshua E. Allen, David T. Dicker, Wafik S. El-Deiry
Journal: Journal of Clinical Oncology (2016)

e12564 Background: Breast cancer is a major cause of cancer-related death in United States women. ONC201 is an anti-cancer small molecule that utilizes a unique mechanism that involves activation of the integrated stress response and upregulation of TRAIL and its receptor DR5. The compelling efficacy of ONC201 and its ability to deplete cancer stem cells has been reported in a range of challenging preclinical models. The first-in-human clinical trial for ONC201 in advanced solid tumors has been completed and the agent is being tested in multiple phase I/II clinical trials. Methods: Cell viability assays were conducted to determine GI50 values for ONC201 in TNBC (n = 9) and non-TNBC (n = 5) cells. Propidium iodide staining and analysis of SubG1 DNA content was performed to assess cell death. Cell surface staining for death receptor expression was performed by flow cytometry. The Aldefluor assay was performed to identify the CSC subpopulation. Results: GI50 values for ONC201 are in the low micro-molar range across breast cancer subtypes, including 4 of 6 BRCA1-deficient TNBC cells. These concentrations are physiologically achievable based on human pharmacokinetic results. Sensitivity to ONC201 was observed regardless of sensitivity to TRAIL. ONC201 induced cell death in TNBC and non-TNBC cells. Furthermore, investigation of CSCs revealed that ONC201 depleted Aldefluor+ putative breast CSCs in vitro whereas paclitaxel did not. ONC201 treatment increased cell surface levels of pro-apoptotic TRAIL death receptors DR4 and DR5 in TNBC cells. ONC201 decreased expression of IAP family proteins XIAP, c-IAP1, and c-IAP2 in TNBC and non-TNBC cells. Conclusions: ONC201 is efficacious across a broad range of both TNBC and non-TNBC cells that include BRCA1-deficiency and paclitaxel resistance. ONC201 eliminates breast cancer cell lines regardless of TRAIL sensitivity, which may be explained by death receptor upregulation and suppression of anti-apoptotic IAP proteins. These findings provide a preclinical rationale for the use of ONC201 as a targeted therapy that could be broadly applied to chemo-refractory breast cancer.
Geographical distribution of industry driven clinical trials performed for leukemia over the last ten years.
Authors: Laura Vidal Boixader, Rob Jacobus Berg, Gabor Kos, Angel Uriol, Jim Wahl, Keren Rachel Moss
Journal: Journal of Clinical Oncology (2016)

2537 Background: The incidence of leukemia (L) is increasing worldwide, with an estimated 350,000 people diagnosed each year. One major motivation for looking abroad for drug clinical development is the lowered cost of running a clinical trial in developing countries, about one-half to one-third that in a developed country. We aim to describe variations on the geographical distribution of industry driven clinical trials performed for L over the last 10 years (2005-2015). Methods: INC clinical trial database was reviewed for L, all types and compared to industry sponsored clinical trials listed on Trialtrove, 2015, Citeline database. The geographic location of the trial was classified based on the following countries: North America (NA), Western Europe (WE), Eastern Europe (EE), Latin America (LA), Middle East and North Africa (MENA) and Asia Pacific (AP). A single site within a region was considered positive for regional trial involvement. Geographic distribution of INC L trials was compared to geographic distribution across all INC oncology clinical trials. Results: INC Research database included 61 trials: 72% included research sites in NA, 48% in WE, 25% in EE and 28% in AP. When compared with CiteLine´s database, including 1391 trials, similar percentages were observed except for a higher distribution in EE for INC (25% vs 10%) maybe reflecting the preferred choice of WE countries by pharmaceutical companies. When compared with INC geographical distribution for non-specific solid tumors, similar percentages to the L geographical distribution from CiteLines´s database were observed suggesting that industry is still going for same countries regardless cancer indication. A considerable gap between developing regions and developed countries is maintained through the last ten years with no significant signs of reduction. Conclusions: There are still important challenges associated with performing studies in cancer in less developed countries. For L, despite the impact of educational programs and networking on the management of this disease in developing countries, more effective measures need to be undertaken in order to offer a real chance for these patients to participate in clinical trials.
SAT0718-HPR Influence of patient global assessment on the disease activity assessment in patients with rheumatoid arthritis: a meteor cross-sectional study
Authors: RJO Ferreira, M Ndosi, C Duarte, P Carvalho, A Chopra, K Salomon-Escoto, D Vega, D van der Heijde, P Machado, JAP da Silva
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Disease activity indices (DAI) are used to guide immunosuppressive therapy in rheumatoid arthritis (RA). The inclusion of patient global assessment (PGA) in these indices has been questioned as it conveys mainly disease impact rather than disease activity. <h3>Objectives</h3> To determine the influence of PGA on patient disease states and to determine PGA correlations with inflammatory parameters, disease impact, demographic, clinical and contextual factors. <h3>Methods</h3> The METEOR international database was used, namely data from patients9 first available visit with no missing values on PGA, tender and swollen joint counts (TJC28, SJC28) and C-reactive protein (CRP). Remission rates were compared according to the DAS28CRP3v vs 4v and ACR/EULAR Boolean remission vs near-remission (failing 1 of the 4 criteria) definition. We assessed the correlation of PGA with (predominantly) inflammatory (TJC28, SJC28, CRP) and disease impact (pain and HAQ) factors. We used hierarchical modelling to explain PGA by 4 blocks (B) of independent variables (B1: gender, age, disease duration; B2: biologic DMARD, Gross National Income; B3: pain, HAQ; and B4: TJC28, SJC28, CRP). <h3>Results</h3> Among the 18280 patients analysed, 1930 (10.6%) were in DAS28CRP4v remission, and 2197 (12.0%) in DAS28CRP3v remission. According to the Boolean definition, 1207 (6.6%) patients were in remission. PGA was the main obstacle to Boolean remission: 2090 (79.0%) of the 2645 near-remission patients (Table 1). A considerable proportion of patients with low inflammation perceived high PGA (Figure 1). PGA correlated better with Pain (r<sub>p</sub>=.79) and HAQ (r<sub>p</sub>=.55) than with TJC28 (r<sub>p</sub>=.45), SJC28 (r<sub>p</sub>=.36) or CRP (r<sub>p</sub>=.25). In the entire dataset, 60.2% of PGA variance was explained by Pain and HAQ, 1.8% by B1 and B2 of covariates and only 1.3% by B4 (TJC28, SJC28, CRP) (Table 2). In near-remission patients, B4 did not contribute significantly to changes in the model. <h3>Conclusions</h3> Two thirds of patients that achieve TJC28, SJC28, and CRP≤1 still perceive high PGA despite disease “inflammatory” control. The weight of PGA in DAI could lead to immunosuppressive overtreatment. In these patients, disease impact management, including non-pharmacological treatments delivered by Health Care Professionals, are more likely to be effective. <h3>Disclosure of Interest</h3> R. Ferreira Grant/research support from: MERIT foundation, M. Ndosi: None declared, C. Duarte: None declared, P. Carvalho: None declared, A. Chopra: None declared, K. Salomon-Escoto: None declared, D. Vega: None declared, D. van der Heijde: None declared, P. Machado: None declared, J. da Silva: None declared
Rubella and Zika Vaccine Research—A Cautionary Tale About Caution
Authors: Anne Drapkin Lyerly, Samantha G. Robin, Elana Jaffe
Journal: JAMA Pediatrics (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Breast cancer incidence according to age, race, and hormone receptor subtype: A SEER database analysis.
Authors: Theresa Lynn Schwartz, Lorinette Wirth, Laurence Diggs, Leslie J. Hinyard
Journal: Journal of Clinical Oncology (2017)

e13059 Background: While incidence rates of breast cancer have been shown to vary based on age and race, hormone receptor (HR) subtype is an important prognostic indicator and it is unclear to what extent HR subtype varies across age and race. Identifying breast cancer at an early stage, especially in the more aggressive subtypes, correlates with improved overall outcomes. In this study we sought to examine the distribution age, race, within HR subtype in women diagnosed with incident breast cancer. Methods: Data from the SEER registry, years 2010-2013, was queried to produce race stratified age distributions of incident cases of invasive female breast cancer according to HR subtype: Her2+/HR+ (n = 21288), Her2+/HR- (n = 9325), Her2-/HR+ (n = 153130), Her2-/HR- (n = 24455). Race was categorized as White, Black, and Other. Mantel-Haenszel Chi-Square (χ 2 MH ) test was used to determine whether racial variations across the age categories (20-44 years, 45-64 years, and 65+ years) were the same across hormone receptor subtypes. Results: Across all HR subtypes and race categories, incident breast cancer burden was highest among women aged 45-64 years (p &lt; 0.001). Age distribution differed significantly across HR subtypes (p &lt; 0.001). Variations across age distributions and race differed by HR subtypes (p &lt; 0.001). When the incident burden for younger Black women (aged ≤ 44 years) to Black women aged 45-64 years was compared to the same age categories for White women, it was found that variations across the racial and age groups were different across HR subtypes (p &lt; 0.001). These results would suggest a significant three-way interaction between age, race, and HR subtype. Conclusions: There are significant differences in breast cancer incidence according to age, race, and HR subtype. Further investigation into a mortality effect is necessary to determine breast cancer screening strategies when these variables are taken into consideration.
Mutational Heterogeneity in <i>APC</i> and <i>KRAS</i> Arises at the Crypt Level and Leads to Polyclonality in Early Colorectal Tumorigenesis
Authors: Mireia Gausachs, Ester Borras, Kyle Chang, Sara Gonzalez, Daniel Azuara, Axel Delgado Amador, Adriana Lopez-Doriga, F. Anthony San Lucas, Xavier Sanjuan, Maria J. Paules, Melissa W. Taggart, Gareth E. Davies, Erik A. Ehli, Jerry Fowler, Victor Moreno, Marta Pineda, Y. Nancy You, Patrick M. Lynch, Conxi Lazaro, Nicholas E. Navin, Paul A. Scheet, Ernest T. Hawk, Gabriel Capella, Eduardo Vilar
Journal: Clinical Cancer Research (2017)

Abstract Purpose: The majority of genomic alterations causing intratumoral heterogeneity (ITH) in colorectal cancer are thought to arise during early stages of carcinogenesis as a burst but only after truncal mutations in APC have expanded a single founder clone. We have investigated if the initial source of ITH is consequent to multiple independent lineages derived from different crypts harboring distinct truncal APC and driver KRAS mutations, thus challenging the prevailing monoclonal monocryptal model. Experimental Design: High-depth next-generation sequencing and SNP arrays were performed in whole-lesion extracts of 37 familial adenomatous polyposis colorectal adenomas. Also, ultrasensitive genotyping of hotspot mutations of APC and KRAS was performed using nanofluidic PCRs in matched bulk biopsies (n = 59) and crypts (n = 591) from 18 adenomas and seven carcinomas and adjacent normal tissues. Results: Multiple co-occurring truncal APC and driver KRAS alterations were uncovered in whole-lesion extracts from adenomas and subsequently confirmed to belong to multiple clones. Ultrasensitive genotyping of bulk biopsies and crypts revealed novel undetected APC mutations that were prominent among carcinomas, whereas abundant wild-type APC crypts were detected in adenomas. KRAS mutational heterogeneity within crypts was evident in both adenomas and carcinomas with a higher degree of concordance between biopsy and crypt genotyping in carcinomas. Nonrandom heterogeneity among crypts was also observed. Conclusions: The striking degree of nonrandom intercrypt heterogeneity in truncal and driver gene mutations observed in adenomas and carcinomas is consistent with a polycryptal model derived from multiple independent initiation linages as the source of early ITH in colorectal carcinogenesis. Clin Cancer Res; 23(19); 5936–47. ©2017 AACR.
Value of mitotic index in residual tumors following neoadjuvant therapy for breast cancer: Single institution experience.
Authors: Shinoj Pattali, Nicholas Harding, Alexis Visotcky, Zainab Basir, John A. Charlson, Yee Chung Cheng, Anjishnu Banerjee, Christopher R. Chitambar
Journal: Journal of Clinical Oncology (2016)

548 Background: Pathologic complete remission (pCR) after neoadjuvant therapy (NAC) for breast cancer may predict favorable long-term outcome. Since markers of cell proliferation are linked to prognosis in breast cancer, we examined the prognostic value of the mitotic index (MI) in residual tumors after NAC. Methods: An institutional review board-approved retrospective study of all patients who received NAC for breast cancer at MCW between July 2004 - July 2014 was performed. Results: Of the 169 patients who received NAC, 167 patients received chemotherapy and 2 patients received hormonal therapy. Of the 167 patients, 84 patients were premenopausal and 83 patients were postmenopausal. The median age was 50 years (range 25-86). Pathology showed invasive ductal carcinoma in 141 patients, invasive lobular carcinoma in 18 patients and other histology in 7 patients. Mean tumor size prior to therapy was 4.5 cm (range 1-13 cm). Tumor grade was 1, 2, and 3 in 16, 80, and 64 patients, respectively. Clinical lymph node involvement was present in 122 patients and absent in 41 patients. No data was available for 6 patients. Eighty-seven patients (52.1%) had hormone receptor (HR)-positive, HER2-negative disease; 42 patients (25.2%) had triple-negative disease; 23 patients (13.8%) had HR-negative, HER2 positive disease; and 15 patients (8.9%) had triple-positive disease. All patients were treated according to NCCN guidelines. pCR was achieved in 38 patients and residual disease was present in 131 patients. On follow up at 5 years, 39 patients relapsed; 130 patients were alive, 21 died of metastatic disease, 6 died of other causes, and no follow-up data were available for 12 patients. Patients with residual disease and a tumor MI of > 1 had a significantly (p = 0.0059) higher rate of relapse or death than patients with a MI of zero. As expected, patients who attained a pCR also had a significantly lower rate of relapse or death. Only 49 patients in Cox regression model for relapse or death, mitotic figure post treatment value was significant while adjusting for estrogen receptor group. Conclusions: Post treatment MI is a predictive factor of relapse after NAC in breast cancer, independent of the type of regimen used.
Phase I first-in-man trial of a novel bromodomain and extra-terminal domain (BET) inhibitor (BI 894999) in patients (Pts) with advanced solid tumors.
Authors: Philippe Georges Aftimos, Oliver Bechter, Ahmad Awada, Christiane Jungels, Herlinde Dumez, Nathalie Huyvaert, Jo Costermans, Chooi Lee, Marie-Anne Meeus, Ute Burkard, Hanny Musa, Yihua Zhao, Patrick Schoffski
Journal: Journal of Clinical Oncology (2017)

2504 Background: The BET family (BRD2, BRD3, BRD4) regulates transcription, epigenetic memory and cell growth, emerging as a novel therapeutic strategy. BI 894999 is a highly potent and selective orally available BET inhibitor. Methods: BI 894999 was given once a day, continuously (1 cycle = 3 weeks; Arm A). An intermittent schedule was explored: once a day, D1-14 Q21 days (1 cycle = 3 weeks; Arm B). Bayesian Logistic Regression Model was used to guide dose escalation. HEXIM1, HIST2H2BF and CCR2 gene expressions were used as pharmacodynamic (PD) markers. Results: 28 pts were treated: 21 in Arm A, 7 in Arm B. Median number of cycles was 2 (range: 1-12). Pts were treated at 6 dose levels in Arm A (0.2-5 mg) and 2 dose levels in Arm B (1.5 and 2 mg). The maximum tolerated dose (MTD) was exceeded at 2 mg in Arm A. In Arm B, dose escalation was halted due to the observation of ECG changes in 3 pts and raised serum troponin in 8 pts, pending cardiology review. MTD in Arm A was defined as 1.5 mg. The most frequent (≥10%) treatment-related adverse events were: fatigue (50%), thrombocytopenia (29%), decreased appetite (21%), diarrhea (18%), increased troponin T (18%), dysgeusia (14%), nausea (14%), stomatitis (14%), increased CK (11%), neutropenia (11%) and vomiting (11%). DLTs included: thrombocytopenia grade (G) 4 (n=3), increased troponin G3 (n=1), hypophosphatemia G3 (n=1), multiple G2 events in 1 pt preventing adequate dose intensity in cycle 1. Of 27 evaluable pts, 3 had partial response (PR; one was confirmed) and 1 had stable disease (SD) lasting &gt;4 cycles. C max and AUC increased with dose in a greater than linear fashion particularly at higher dose levels. Mean terminal T 1/2 was ~1 day with high interpatient variability. PD analyses showed target engagement in all 3 genes at doses ≥1 mg in both schedules. Conclusions: BI 894999 showed target engagement at doses ≥ 1 mg and demonstrated clinical activity (3 PRs and 1 SD lasting &gt;4 cycles). Thrombocytopenia prevented continuous dosing and 1.5 mg was defined the MTD for Arm A, whilst dose escalation was halted in Arm B due to cardiac findings. Mitigating hematological toxicity of BI 894999 via synergistic drug combinations should be explored. Clinical trial information: NCT02516553.
Comparison of Real-Time PCR and Droplet Digital PCR for the Determination of JAK2V617F Mutation in Ph'-Negative Myeloproliferative Neoplasms
Authors: Giulia Fontanelli, Claudia Baratè, Elena Ciabatti, Francesca Guerrini, Riccardo Morganti, Roberta Arici, Sara Barsotti, Iacopo Petrini, Marzia Del Re, Mario Petrini, Sara Galimberti
Journal: Blood (2014)