tbuckley/cabot-search huggingface dataset:
Cost differential among systemic therapies for breast, bladder, lung, and colon cancer.
Authors: Hasan Nadeem, Thejus Thayyil Jayakrishnan, T. Clark Gamblin, Kiran Turaga
Journal: Journal of Clinical Oncology (2014)

e17541 Background: According to the National Cancer Institute (NCI), national cancer care expenditures were an estimated $124.6 billion in 2010, of which a significant portion was attributed to chemotherapy. The National Comprehensive Cancer Network (NCCN) has outlined recommendations for the treatment of various cancers that incorporates alternative chemotherapeutic strategies presumed as equivalently effectiveness. Methods: Details of the chemotherapy regimens and dosages outlined in NCCN guidelines (2013) were acquired for breast, bladder, colon, and lung cancer. Baseline costs (in US dollars) were calculated based on the payment allowance for Medicare part B drugs database (2013). Dosage amounts were calculated for an average American male patient and additional costs (treatment time, pumps) were added to the total regimen cost. The total costs were calculated for a treatment period of six months. Results: A total of 70 regimens (adjuvant and advanced/metastatic) were studied for the aforementioned cancer sites. The median cost for systemic treatment of advanced/metastatic cancer was $8,470.52 (n = number of regimens = 38, range: $451-$4,248,806). The median cost for adjuvant treatment was $4,900 (n=34, range: $249-$65,821). The largest cost differential between any two regimens of equivalent effectiveness was found within the treatment of colon cancer: Capecitabine and Folfiri+ziv-Aflibercept (D=$4,247,619.63). The addition of novel antineoplastics dramatically increased the price of treatment regimens as shown in the table below. Conclusions: Significant cost differential exist between chemotherapeutic regimens of equal effectiveness. The addition of novel antineoplastics substantially increased the total costs. Therefore, policies regarding therapy administration and medicine allotment need further scrutiny. Costs of systemic therapies for colorectal cancer. Paradigm Cost ($US) Percent increase (%) Advanced/metastatic Folfiri 10,286.3952 Base Folfiri + bevacizumab 47,369.3352 360 Folfiri + panitumumab 68,781.69 568 Folfiri + cetuximab 75,215.9952 631 Folfiri + ziv-aflibercept 4,248,806.395 41205 Adjuvant Capecitabine 33,229.28 - CapeOX4 7,199.008 - mFOLFOX6 13,867.8144 - FLOX2 3,470.436 -
Abstract 12495: Enhanced Thrombin Activity in Biglycan-deficient Mice Promotes Vascular Inflammation in Murine Atherosclerosis
Authors: Maria Grandoch, Ariane Melchior-Becker, Kathrin Feldmann, Julia Müller, Christina Klatt, Susanne Homann, Lena-Sophia Dick, Nadine Nagy, Liliana Schäfer, Philipp Skroblin, Xiaoke Yin, Manuel Mayr, Lisa Tannock, Jens W Fischer
Journal: Circulation (2015)

Introduction: Thrombin signalling initiates inflammatory events directly and through activation of platelets. Endogenous and pharmacologic inhibitors of thrombin are therefore of relevance during atheroprogression and for therapeutic intervention. The small leucine-rich proteoglycan biglycan (BGN) is thought to inhibit thrombin activity by activation of heparin cofactor II. Hypothesis: Genetic deletion of BGN affects thrombin activity, inflammation and atherosclerosis. Methods:Male mice deficient in apolipoprotein E and BGN (ApoE-/-/Bgn-/0) were compared with their ApoE-/- littermates. Results: In ApoE-/- mice BGN was detected in the plasma and subendothelial matrix of capillaries, arterioles and in atherosclerotic plaques. In line with a role of BGN in balancing thrombin activity, ApoE-/-/Bgn-/0 mice exhibited higher activity of circulating thrombin and greater platelet activation than did ApoE-/- mice. Furthermore, higher concentrations of circulating cytokines in ApoE-/-/Bgn-/0 mice suggested a proinflammatory phenotype. Accordingly, isolated peritoneal macrophages released elevated concentrations of proinflammatory cytokines in response to Toll-like receptor stimulation. Immunohistochemistry and FACS analysis of the aorta demonstrated increased macrophage content in atherosclerotic lesions. Furthermore, ApoE-/-/Bgn-/0 mice exhibited higher aortic plaque burden and larger atherosclerotic lesions at the aortic root. Treatment with the thrombin inhibitor argatroban reversed platelet activation and aortic macrophage accumulation in ApoE-/-/Bgn-/0 mice. Finally, ApoE-/-/Bgn-/0 mice exhibited progressive dilation of the aortic arch, a pathological finding corroborated by markedly reduced collagen fibril density. Conclusions: The present results indicate that BGN plays a previously unappreciated protective role during progression of atherosclerosis by inhibiting thrombin activity and platelet activation, and ultimately macrophage-mediated plaque inflammation.
Protein/creatinine ratio in random urine instead of 24-hour urine collections for the assessment of renal involvement in patients with amyloidosis.
Authors: Giampaolo Talamo, Junjia Zhu, Joseph J. Drabick, Manoj K. Pandey, Nathan G. Dolloff, Michael H. Creer, Jozef Malysz
Journal: Journal of Clinical Oncology (2014)

e19591 Background: Daily proteinuria should be measured in all patients with amyloidosis at the time of diagnosis, because the kidney is a major target organ for systemic amyloidosis of any type. This has traditionally been achieved with 24 hour urine collections. However, the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines state that the protein/creatinine (Pr/Cr) ratio in an untimed urine specimen should replace protein excretion in a 24 hour collection as the preferred method for measuring proteinuria. We evaluated the accuracy of the random urine Pr/Cr ratio in assessing proteinuria in patients with amyloidosis. Methods: We retrospectively analyzed data from 77 patients with amyloidosis in whom both random urine Pr/Cr ratio and 24-hour urine collections for total proteinuria were available for comparison. Results: Amyloidosis was of primary (AL) type, transthyretin (TTR), and other types in 53, 14, and 10 patients, respectively. Renal involvement was observed in 36 patients (47%). A strong correlation (Spearman’s ρ = 0.90, p <0.001) was found between the random urine Pr/Cr ratio and the 24 hour urine protein excretion. Receiver operating characteristics (ROC) curve analysis demonstrated that the optimal cutoff value for predicting the presence of renal involvement is about 765 mg (sensitivity 100%, specificity 94%, area under the curve [AUC] 97%) using the traditional 24 hour urine protein excretion, and 860 mg (sensitivity 93%, specificity = 96%, AUC 96%) using the urine Pr/Cr ratio in random urine samples. Conclusions: This is the first study to examine the role of the random urine Pr/Cr ratio in patients with amyloidosis. It suggests that the Pr/Cr ratio in random urine samples can potentially replace the 24 hour urine collection for the assessment of daily proteinuria in patients with amyloidosis.
HER2 amplification and IGF-IR coexpression in CETCs to explain the resistance to trastuzumab in HER2-positive breast cancers.
Authors: Dorothea Zimon, Monika Pizon, Ulrich A. Pachmann, Katharina Pachmann
Journal: Journal of Clinical Oncology (2014)

e11570 Background: The human epidermal growth factor receptor 2 (ErbB2, HER2) is amplified and/or overexpressed in 20-30% of invasive breast carcinomas and is associated with increased metastatic potential and decreased overall survival. Trastuzumab is a humanised monoclonal antibody directed against the extracellular domain of HER2 and has shown activity both as a single agent and in combination with chemotherapy in HER2-overexpressing breast cancers. Nevertheless, 70% of patients with HER2-positive breast cancers develop intrinsic or secondary resistance to trastuzumab. It has been shown that the trastuzumab-induced growth inhibition in HER2-overexpressing cells can be compensated for by increased IGF-IR signalling, resulting in resistance to trastuzumab. Detection of circulating epithelial tumor cells (CETCs) expressing HER2 can be regarded as an adverse prognostic marker; therefore we investigated the expression of IGF-IR on the CETCs in addition to HER2 amplification in breast cancer patients to identify patients who might benefit from a combined targeted therapy against HER2 and IGF-IR. Methods: CETCs were determined from blood of 30 breast cancer patients. The number of vital CETCs and the expression of IGF-IR were investigated using the maintrac approach. Fluorescence in situ hybridisation was used for analysis of HER2 amplification in CETCs. Results: CETCs could be detected in all breast cancer patients. Number of CETCs ranged from 4 to 163 in 100 µl of cell suspension. IGF-IR expression on the surface of CETCs was detected in all patients, whereas HER2 positive CETCs were observed in 93.3% of patients. A statistically high correlation was found between IGF-IR and HER2 in CETCs. No statistically significant correlations were observed between the number of CETCs and IGF-IR or HER2 in CETCs. Conclusions: Our results demonstrate for the first time a parallel expression of IGF-IR and HER2 in CETCs. Therefore, IGF-IR might be an important potential therapeutic target in breast cancers resistant to trastuzumab. Targeting IGF-IR may be a rational approach to improve response to trastuzumab in the sub-group of HER2 positive breast tumors that express IGF-IR.
Media Coverage of the Benefits and Harms of the 2017 Expanded Definition of High Blood Pressure
Authors: Raymond Noel Moynihan, Justin Clark, Loai Albarqouni
Journal: JAMA Internal Medicine (2018)

1. Choosing Wisely.Endocrine Society: avoid routine multiple daily self-glucose monitoring in adults with stable type 2 diabetes on agents that do not cause hypoglycemia.http://www.choosingwisely.org
MGMT immunohistochemistry (IHC) and exclusion of pancreatic NET (PanNET) patients from treatment with temozolomide-based therapy.
Authors: Diane Lauren Reidy, Olca Basturk, Anuja Kriplani, Ghassan K. Abou-Alfa, William R. Jarnagin, Peter J. Allen, Leonard Saltz, David S. Klimstra, Liying Zhang
Journal: Journal of Clinical Oncology (2014)

e15169 Background: Predictive markers are needed for improved selection of patients for Capecitabine/Temozolomide (C/T) therapy in metastatic PanNETs. Treatment efficacy has been reported to correlate with tumor O6-methylguanine-methyltransferase (MGMT) deficiency. Based on these data, retained MGMT expression by IHC has been proposed as an exclusionary marker. However, a marker would only be clinically useful if it is able to identify patients so unlikely to benefit that treatment would be inappropriate. We conducted a retrospective analysis to assess MGMT expression in PanNETs and to correlate this with the efficacy of C/T. Methods: Using an institutional electronic pharmacy database, we identified patients with PanNETs with tissue available treated with C/T from 1/2003-10/2013. Expression of MGMT protein was assessed by IHC on primary tumors or metastases. Immunolabeling in ≥5% of tumor nuclei was defined as "positive" staining (retained expression) of MGMT protein. When possible, pyrosequencing to detect the level of methylation in 5 CpG sites in exon 1 of the MGMT gene, was used to evaluate MGMT promoter hypermethylation in the tumor. Results: Thirteen patients (mean age, 57) were identified; 3 (23%) low grade, 8 (61%) intermediate grade, 2 (15%) high grade. 4/13 (31%) patients with evidence of tumor shrinkage had MGMT IHC positive tumors. Of these, 1 patient (promoter hypermethylation absent) had unresectable disease rendered resectable after a significant response to C/T and is now 2 years free of disease. Tissue was unavailable to test for promoter hypermethylation in the remaining 3 patients. Of the 9 patients where MGMT by IHC was absent, all 9 had evidence of tumor shrinkage (100%). Tumor burden (0%, <10%, 10-50%, >50%), number of prior systemic treatments, and tumor grade did not correlate with tumor shrinkage. Conclusions: In this study, absence of MGMT expression correlated with response, however 30% of MGMT positive tumors responded. More discriminant markers are required. The possibility that hypermethylation of MGMT gene is a predictor is being explored in ongoing studies.
AQP1 expression and survival in patients with colon cancer.
Authors: Byung Woog Kang, Jong Gwang Kim, Yee Soo Chae, Soo Jung Lee, Sang Kyun Sohn, Joon Ho Moon, Jongwon Seo, Ghil Suk Yoon
Journal: Journal of Clinical Oncology (2014)

e14586 Background: Aquaporin (AQP), a family of transmembrane water channel protein that are widely distributed in various tissues throughout the body, play a key role in water homeostasis by regulating cellular water transport. Recent studies have revealed certain AQP subtypes as targets for novel anti-tumor therapy because they likely play a role in carcinogenesis, tumor progression, and invasion. Accordingly, we analyzed the prognostic impact of aquaporin 1 (AQP1), aquaporin 3 (AQP3), and aquaporin 5 (AQP5) expression in a large number of patients with colon cancer. Methods: AQP1, AQP3, and AQP5 expression were investigated on the basis of the immunohistochemistry of tissue microarray specimens from 486 colon cancer patients who underwent curative surgery between 2006 and 2010. We scored the staining intensity (0 through 3) and percentage of positive cells (0 through 4), and the staining score was defined as sum of these scores used to categorize the AQP expression as negative (0 through 2), weak (3 through 5), or strong (6 or more). Results: For the 486 patients, the median age was 66 (30-90) years at the time of surgery. The pathologic stages after the surgical resection were as follows: stage I (n=98), stage II (n=213), and stage III (n=175). A total of 298 (61.3%) were identified as AQP1-positive (staining score >6). AQP3 and AQP5 overexpressed in 56 (11.5%) and 145 (29.8%) of the cohort, respectively. AQP1 overexpression was closely correlated with patient' overall survival (OS; P=0.003) and disease-free survival (DFS; P=0.08). Moreover, a multivariate analysis revealed that AQP1 overexpression was an independent prognostic marker of survival for the colon cancer patients. However, no significant association was observed between AQP3 and AQP5, and survival in a multivariate analysis. Conclusions: AQP1 expression in tumor tissue can be considered a prognostic marker in patients with colon cancer after curative surgery.
Comparative effectiveness of gemcitabine plus cisplatin (GC) versus methotrexate, vinblastine, doxorubicin, plus cisplatin (MVAC) as neoadjuvant therapy for muscle-invasive bladder cancer (MIBC).
Authors: Matt D. Galsky, Lauren Christine Harshman, Simon J. Crabb, Yu-Ning Wong, Evan Y. Yu, Simon Chowdhury, Thomas Powles, Sumanta Kumar Pal, Erin L. Moshier, Sylvain Ladoire, Syed A. Hussain, Neeraj Agarwal, Ulka N. Vaishampayan, Federica Recine, Dominik Berthold, Andrea Necchi, Christine Theodore, Matthew I. Milowsky, Joaquim Bellmunt, Jonathan E. Rosenberg
Journal: Journal of Clinical Oncology (2014)

4512 Background: GC has been adopted as a standard neoadjuvant regimen for MIBC, supported by practice guidelines, despite a lack of prospective (randomized) data in this setting. Given the historical difficulties completing perioperative chemotherapy trials in MIBC, an adequately powered clinical trial to definitively address whether GC is comparable to regimens supported by Level I evidence (MVAC, CMV) may not be completed and additional levels of evidence are needed to support or refute current practice. Methods: Data were collected via an electronic data capture platform from 25 international centers. Eligible pts had cT2-4aN0M0 urothelial cancer of the bladder and received neoadjuvant GC or MVAC prior to cystectomy. Logistic regression was used to compute propensity scores as the predicted probabilities of patients being assigned to MVAC vs. GC given their: age, calculated creatinine clearance (CrCl), number of cycles of chemotherapy, pure versus mixed histology, Eastern Cooperative Oncology Group performance status, year of diagnosis, cT-stage, and gender. These propensity scores were then included in a log binomial model used to estimate an adjusted relative risk comparing the probability of complete pathologic response (pCR) between patients who received MVAC vs. GC. Survival between the two groups was analyzed as an exploratory endpoint. Results: 244 patients met eligibility for the analysis (GC: 175, MVAC: 69). Patients were median age 64, predominantly male (77%), had a median CrCl of 72, and received a median of 3 cycles of neoadjuvant chemotherapy. The pCR rate, adjusted for propensity scores, is shown in the Table. Overall survival was not significantly different between the groups. Conclusions: Neoadjuvant GC and MVAC achieved comparable rates of pCR, in this large retrospective cohort, providing additional evidence to support current practice. pCR adjusted for propensity scores. pCR GC N=175 MVAC N=69 Relative risk [95% CI] P value Yes No 47 (27%) 128 (73%) 19 (28%) 50 (72%) 0.97 [0.60-1.56] P=0.9
Abstract P070: Glucose, Insulin, Insulin Resistance and Exposure to Ambient Air Pollution
Authors: Rahul Gondalia, Archana P Lamichhane, Katelyn M Holliday, Regina A Shih, Beth A Griffin, Gregory A Wellenius, Duanping Liao, Jeffrey D Yanosky, Jaime Madrigano, James D Stewart, Eric A Whitsel
Journal: Circulation (2017)

Background: Numerous studies suggest that long-term exposure to ambient particulate matter (PM) and nitrogen oxide (NOx) air pollution may be diabetogenic, but little is known about the effects of shorter-term exposures on markers of diabetes risk. Therefore, our objective was to determine whether short- and long-term ambient PM and NOx exposures are associated with glucose, insulin, and insulin resistance measures. Methods: We studied a stratified, random minority oversample of non-diabetic Women’s Health Initiative (WHI) clinical trials participants for whom estimates of fasting glucose, fasting insulin, insulin resistance, and geocoded address-specific daily mean concentrations of PM &lt; 10 μm (PM 10 ), PM &lt; 2.5 μm (PM 2.5 ), and NOx were available at screening and up to three follow-up visits between 1993-2004 (total n=4,019; mean age: 62.2 yr; 24% black; 12% Hispanic; 51% white). We measured insulin resistance using the homeostatic model assessment [HOMA], triglyceride to high-density lipoprotein cholesterol ratio, and the triglyceride-glucose index. We log-transformed the glucose, insulin, and insulin resistance measures, then used multi-level, mixed, longitudinal models weighted for sampling design / attrition and adjusted for sociodemographic, clinical, and meteorological covariates to estimate their associations with 2- and 365-day mean PM 10 and NOx and 365-day mean PM 2.5 concentrations. Results: Measures of glucose homeostasis decreased with short-term exposure to ambient PM 10 . For example, we found a -0.2% (95% confidence interval: -0.4%, 0.1%), -0.9% (-1.7%, -0.1%), and -1.1% (-2.0%, -0.3%) change in glucose, insulin, and HOMA per 10 μg/m 3 increase in the 2-day mean PM 10 concentration. In contrast, we found generally null results per 10 μg/m 3 increase in 365-day mean PM 10 concentration. Measures of glucose homeostasis similarly did not appear to be associated with short- and long-term increases in mean NOx or PM 2.5 concentrations. Conclusion: The findings suggest that responses to ambient exposure to PM 10 in women may be adaptive (i.e. capable of re-establishing normal glucose homeostasis and improving insulin sensitivity) over the short-term. Endoplasmic reticulum stress-response mechanisms involving decreases in protein misfolding may help explain this observed phenomena. Contrary to previous studies, results also suggest that sustained exposure to ambient PM and NOx has nominal influence on glucose homeostasis.
Efficacy and Safety of Single-Agent Quizartinib (Q), a Potent and Selective FLT3 Inhibitor (FLT3i), in Patients (pts) with FLT3-Internal Tandem Duplication (FLT3-ITD)-Mutated Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) Enrolled in the Global, Phase 3, Randomized Controlled Quantum-R Trial
Authors: Jorge E. Cortes, Samer K. Khaled, Giovanni Martinelli, Alexander E. Perl, Siddhartha Ganguly, Nigel H. Russell, Alwin Kramer, Herve Dombret, Donna Hogge, Brian A. Jonas, Anskar Y.-H. Leung, Priyanka Mehta, Pau Montesinos, Markus P. Radsak, Simona Sica, Meena Arunachalam, Melissa Holmes, Ken Kobayashi, Ruth Namuyinga, Nanxiang Ge, Antoine Yver, Yufen Zhang, Mark J. Levis
Journal: Blood (2018)
Determinants of omalizumab drug survival in a long‐term daily practice cohort of patients with chronic urticaria
Authors: L. S. Spekhorst, J. M. P. A. van den Reek, A. C. Knulst, H. Röckmann
Journal: Allergy (2018)

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hnRNP K: A Regulator of Global Transcription and Translation That Drives Lymphomagenesis
Authors: Prerna Malaney, Miguel Gallardo, Marisa J Hornbaker, Xiaorui Zhang, Todd Link, Vrutant Shah, Sanzhar Alybayev, Meng-Han Wu, Laura R Pageon, Huaxian Ma, Rodrigo Jacamo, Li Yu, Zijun Yidan Xu-Monette, Haley Steinman, Hun Ju Lee, Dos Sarbassov, Inmaculada Rapado, Michelle Barton, Joaquin Martinez-Lopez, Carlos E. Bueso-Ramos, Ken H. Young, Sean M Post
Journal: Blood (2018)
A novel “diapeutic” molecular imaging agent for combined oncologic diagnosis and therapy in a broad spectrum of human cancers: Preliminary clinical experience with CLR1404.
Authors: Perry J. Pickhardt, Lance T. Hall, Matthew Lee, Marc Longino, Anatoly Pinchuk, Maria Banash, Joe Grudzinski, Benny Titz, Christine Jaskowiak, John S. Kuo, Jamey Weichert
Journal: Journal of Clinical Oncology (2014)

11000 Background: Extensive preclinical investigation into CLR1404, an akylphosphocholine analog, has demonstrated highly selective uptake and prolonged retention within a variety of human cancer preclinical models. Radioiodine labeling using 124I and 131I may allow for combined oncologic imaging and treatment in humans, respectively, potentially bridging the gap between cancer imaging and therapy. We report preliminary imaging experience with this "diapeutic" agent in early phase human trials. Methods: Prospectiveimaging studies with 124I-CLR1404 PET/CT (n=14) and 131I-CLR1404 SPECT/CT (n=9) in 22 enrolled patients (mean age, 61 years; M:F 12:10) with proven metastatic cancer were analyzed and compared with 18FDG PET/CT and other imaging studies. Underlying primary cancer types included bronchogenic (n=7), colorectal (n=4), prostate (n=3), triple-negative breast (n=2), esophageal (n=2), head and neck (n=2), pancreatic (n=1), and melanoma (n=1). Results: There is preferential uptake of 124I- and 131I-CLR1404 within a variety of metastatic foci in all cancer subtypes. Persistent retention within sites of disease coupled with progressive washout of background activity favored more delayed imaging phases, days-weeks after injection. Distinct advantages in oncologic imaging over FDG PET include greater conspicuity of brain metastases (FDG false-negatives) and lack of uptake in areas of post-treatment false-positive FDG activity. CLR1404 uptake was also evident in nodal, skeletal, pulmonary, hepatic, and other sites of active metastatic disease. Conclusions: Selective tumor uptake with prolonged retention of CLR1404 was demonstrated within a broad spectrum of historically difficult-to-treat metastatic cancers. This novel molecular imaging agent appears to have distinct advantages over FDG for oncologic PET imaging. Combined diagnosis and therapy using same molecule (ie, a "diapeutic" approach with 124I and 131I labeling) could lead to truly personalized care by ensuring pre-treatment tumor-specific uptake, providing patient-specific dose planning, and enabling treatment-specific imaging surveillance.