tbuckley/cabot-search huggingface dataset:
Presence and function of CD14+CD16-HLADRlow monocytes in the peripheral blood of patients with Β-cell non-Hodgkin lymphoma (NHL).
Authors: Bing Xiu, Yi Lin, Deanna Grote, Steven Ziesmer, Zhi Zhang Yang, Michael P Gustafson, Mary Maas, Zhe Zhang, Allan B Dietz, Aibin Liang, Luis F. Porrata, Anne Novak, Stephen Maxted Ansell
Journal: Journal of Clinical Oncology (2014)

e19539 Background: The antitumor immune response in patients with B-cell NHL plays an important role in determining clinical outcome. We have previously shown that an increased absolute monocyte count in the peripheral blood of lymphoma patients is associated with a poor prognosis. Furthermore, we have identified a population of CD14+HLADRlow monocytes in NHL patients that are immunosuppressive. The goal of this study was to further define the phenotype of suppressive monocytes in lymphoma patients and to identify the conditions that promote their expansion. Methods: Peripheral blood specimens were obtained from patients with newly diagnosed, untreated B-cell NHL (n=20) and 20 matched controls; and the phenotype of the monocyte fraction was analyzed by 10-color flow cytometry. Monocytes from an additional 15 healthy controls were polarized to express a phenotype similar to that seen in lymphoma patients. Serum from 361 lymphoma patients and 337 matched controls were used to confirm differences in cytokine production. Results: The number of monocytes in the peripheral blood of NHL patients was increased compared to controls (p=0.024), due in part to an increase in CD14+CD16- HLADRlow monocytes that also expressed CD32 and CD163, and were positive for IL-10. Increased levels of IL-10 were found in the serum of lymphoma patients (median: 27.5ng/ml; 14.5-53.4) when compared to controls (median: 16.4ng/ml; 8.8-26, p=0.001). Monocytes from healthy donors were then polarized with GMCSF+/-LPS and IFNg or MCSF+/-IL-4 to attempt to mimic the phenotype seen in lymphoma patients. Monocytes treated with MCSF+/-IL-4 developed a similar phenotype to monocytes from lymphoma patients and were CD14+CD16-IL10+, however they remained HLADR+. When MCSF- or GMCSF-treated monocytes were co-cultured with T-cells, MCSF-treated monocytes suppressed T-cell cytokine secretion and induced FoxP3 expression. Conclusions: CD14+CD16-HLADRlow monocytes in NHL patients express immunosuppressive ligands, secrete IL-10 and suppress T-cell function. They may represent a therapeutic target in lymphoma patients.
The usefulness of UGT1A1 polymorphism testing before starting irinotecan-based chemotherapy.
Authors: Taishi Harada, Haruhiro Saito, Makiko Sugiura, Shuji Murakami, Tetsuro Kondo, Fumihiro Oshita, Kouzo Yamada
Journal: Journal of Clinical Oncology (2013)

11055 Background: A few studies have revealed an association between UGT1A1 genotype and irinotecan-induced neutropenia. However, the usefulness of UGT1A1 polymorphism testing before starting irinotecan-based chemotherapy is controversial, even now. We assessed the clinical usefulness of UGT1A1 polymorphism testing before chemotherapy. Methods: 136 lung cancer patients were treated with nedaplatin and irinotecan combination chemotherapy as initial chemotherapy. Except for the patients with low enzyme activity of UGT1A1, 70 patients were treated after UGT1A1 polymorphism testing. (test group) 66 patients were treated without UGT1A1 polymorphism testing. (non-test group) We retrospectively analyzed adverse events and compared the test group with non-test group. Results: We could not confirm any reduction in hematologic or non-hematologic toxicity statistically in the test group. In 9 patients with non-hematologic toxicity of grade 4 and 5, 6 patients had febrile neutropenia (FN). All patients with FN were older than 70 years old. Adverse events in elderly patients were significantly more frequent than in the non-elderly. Conclusions: In patients treated with nedaplatin and irinotecan combination chemotherapy, UGT1A1 polymorphism testing before starting chemotherapy did not reduce adverse events. With UGT1A1 polymorphism testing only, it was difficult to predict the onset of severe adverse events. Therefore, it is more important to manage adverse events carefully, especially in elderly patients.
Thrombus leukocytes exhibit more endothelial cell-specific angiogenic markers than peripheral blood leukocytes do in acute coronary syndrome patients, suggesting a possibility of trans-differentiation: a comprehensive database mining study
Authors: Hangfei Fu, Nish Vadalia, Eric R. Xue, Candice Johnson, Luqiao Wang, William Y. Yang, Claudette Sanchez, Jun Nelson, Qian Chen, Eric T. Choi, Jian-Xing Ma, Jun Yu, Hong Wang, Xiaofeng Yang
Journal: Journal of Hematology & Oncology (2017)

Current angiogenic therapies for cancers and cardiovascular diseases have not yet achieved expected benefits, which reflects the need for improved understanding of angiogenesis. In this study, we focused on solving the problem of whether tissues have different angiogenic potentials (APs) in physiological conditions and how angiogenesis is regulated in various disease conditions.In healthy and diseased human and mouse tissues, we profiled the expression of 163 angiogenic genes, including transcription regulators (TRs), growth factors and receptors (GF/Rs), cytokines and chemokines (C/Cs), and proteases and inhibitors (P/Is). TRs were categorized as inflammatory, homeostatic, and endothelial cell-specific TRs, and C/Cs were categorized as pro-angiogenic, anti-angiogenic, and bi-functional C/Cs.We made the following findings: (1) the human heart, muscle, eye, pancreas, and lymph node are among the tissues with the highest APs; (2) tissues with high APs have more active angiogenic pathways and angiogenic C/C responses; (3) inflammatory TRs dominate regulation of all angiogenic C/Cs; homeostatic TRs regulate all to a lower extent, while endothelial cell-specific TRs mainly regulate pro-angiogenic and bi-functional C/Cs; (4) tissue AP is positively correlated with the expression of oxygen sensors PHD2 and HIF1B, VEGF pathway gene VEGFB, and stem cell gene SOX2; (5) cancers of the digestive system tend to have increased angiogenesis dominated by endothelial cell-specific pro-angiogenic pathways, while lung cancer and prostate cancer have significantly decreased angiogenesis; and (6) endothelial cell-specific pro-angiogenic pathways are significantly increased in thrombus-derived leukocytes in patients with acute coronary artery disease.Our results demonstrate that thrombus-derived leukocytes express more endothelial cell-specific angiogenic markers to directly promote angiogenesis after myocardial infarction and that certain solid tumors may be more sensitive to anti-angiogenic therapies than others.
Serum activinA and TGF-β as biomarkers of breast cancer bone metastasis behavior.
Authors: Christina L. Addison, Nathaniel Bouganim, Huijun Zhao, Lisa Vandermeer, Sasha Mazzarello, Ranjeeta Mallick, Koralee Berghout, Glenwood D. Goss, Mark Clemons
Journal: Journal of Clinical Oncology (2012)

10620 Background: Bisphosphonates (BP) are prescribed to pts with metastatic bone disease every 3-4 weeks regardless of individual risk for skeletal related events (SREs). In an era of personalized medicine this “one size fits all” approach is not appropriate and novel markers of SRE risk are required. TRIUMPH is an ongoing clinical trial evaluating 12 weekly IV BP therapy for 1 year in women with low risk bone metastases from breast cancer (BC) as defined by the bone resorption marker C-telopeptide (CTx,) levels &lt;600 ng/L. This sub-study evaluated the utility of novel biomarkers in better predicting the risk of developing SREs. Methods: Serum obtained from pts at baseline and 6 weeks post-entry were analyzed for tumor growth factor-β (TGF-β) and activinA levels by ELISA (sensitivity ~15-30 pg/ml). Levels were correlated with pt parameters including time to development of bone metastasis, and number of previous SREs using linear regression analysis. Changes in levels of biomarkers from baseline to 6 weeks were used to calculate odds ratios using logistic regression analysis. Results: Baseline activinA correlated with baseline CTx and bone specific alkaline phosphatase (p=0.004 and p&lt;0.0001 respectively). Baseline activinA also correlated with weight (p=0.02), BMI (p=0.007) and trended towards total number of prior SREs (p=0.07). Baseline TGF-β correlated with pt age (p=0.02), weight (0.006), BMI (p=0.0005) and duration of metastatic bone disease (p=0.004), but did not correlate with any other biomarker. Change in activinA (baseline to week 6) was the only biomarker that trended to predict coming off study early (p=0.053) as per protocol (i.e. CTx&gt;600 ng/ml, SREs or pt/physician choice). Conclusions: Baseline levels of activinA trended to predict incidence of SREs in patients with bone metastases, and changes in levels from baseline to 6 weeks trended to predict coming off study early. These findings warrant future studies in BC pts assessing activinA as a predictor of risk associated with breast cancer bone metastases. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario, and with funding from the Ontario Chapter of the Canadian Breast Cancer Foundation.
Patterns and effectiveness of surveillance after curative intent surgery in stage I-IIIA non-small cell lung cancer.
Authors: Christine Agnes Ciunci, Emily C. Paulson, Nandita Mitra, Christine Marie Veenstra, Jianing Yang, Corey J. Langer, Andrew J Epstein, Anil Vachani
Journal: Journal of Clinical Oncology (2015)

7546 Background: The optimal strategy for imaging surveillance of non-small cell lung cancer (NSCLC) patients after curative intent surgery is unknown. Current guidelines recommend computed tomography (CT) every 6-12 months for 2 years and then annually. There are no large population-based studies identifying how patients are managed, or comparing the effectiveness of chest radiography (CXR) and CT surveillance. Methods: We performed a retrospective cohort study using Surveillance, Epidemiology and End Results (SEER)-Medicare data to determine the primary surveillance modality following surgical resection in stage I-IIIA NSCLC between 1998 and 2009. Primary surveillance modality was defined as the imaging study used between 90-365 days after surgery. Comparative effectiveness of CT vs. CXR surveillance was explored in terms of overall survival (OS) using a stratified Cox model based on stage and adjusted for age, gender, race, CMI, Charlson comorbidity index, and adjuvant chemotherapy. Results: 5,968 (54%)patients were followed by CT, and 5,083 (46%) by CXR. Patients with earlier stage, older age, and lower census median income (CMI) were less likely to undergo CT surveillance (p<0.001). CT surveillance increased over the study period from 23% in 1998 to 68% in 2009 (p<0.001). In the analysis of surveillance modality and OS, a significant interaction was identified between imaging and diagnosis year (p<0.001). The effect of CT surveillance on OS steadily improved over time, and was significantly better than CXR in the most recent time periods of study (Table). Conclusions: OS was improved in patients with CT surveillance in the most recent time periods of analysis supporting surveillance guidelines. Further studies to determine how CT surveillance leads to improved outcomes, to evaluate the appropriate interval of CT imaging, and to elucidate why patients are not followed according to guidelines are warranted. Multivariable Cox Regression for Overall Survival with CT surveillance as reference group. Diagnosis year Adjusted HR 95% Confidence Interval 1998-2000 1.09 0.96-1.25 2001-2003 0.97 0.88-1.08 2004-2006 0.82* 0.74-0.91 2007-2009 0.69* 0.61-0.78 *p<0.001
Serial FDG-PET imaging of metastatic prostate cancers reveals intrapatient intermetastases polyclonality through same patient heterogeneous responses to systemic therapy.
Authors: Fannie Morin, Jean-Mathieu Beauregard, Michelle Bergeron, Molière Nguilé-Makao, Louis Lacombe, Vincent Fradet, Yves Fradet, Frederic Pouliot
Journal: Journal of Clinical Oncology (2017)

e590 Background: Although intrapatient prostate cancer (PCa) metastasis polyclonality has been recently characterized by genomic and transcriptomic studies, systemic treatment response heterogeneity has yet to be reported or imaged. It remains unknown if polyclonal differentiation leads to heterogeneous treatment responses between metastases in a single patient undergoing therapy. Methods: Between 2010 and 2015, fifteen patients with metastatic PCa were imaged by FDG-PET/CT before and during systemic therapy, and metabolic response was recorded for individual metastatic lesions. Intermetastasis heterogeneity was defined by opposite metabolic responses of at least two metastases from the same compartment (bone or soft tissue) between the two scans. We examined intrapatient intermetastasis heterogeneity of response to systemic therapy based on the assessment of metabolic response in a total of 165 individual lesions (change in SUVmax, complete response, or new lesion). Change in total lesion glycolysis (TLG) was assessed for each patient. Biochemical response and progression-free survival (PFS) were also recorded. Results: Intrapatient intermetastasis response heterogeneity was found in 40% of cases. In univariate statistical analysis, response heterogeneity was associated with a decrease in PFS (p-value= 0.001), but not with age, CRPC status, Gleason score, PSA-DT, TLG, maximum SUVmax, or sum of SUVmax. In two cases, new metastasis and complete metastasis responses were observed in the same patients. Conclusions: Our results suggest that systemic therapies can induce heterogeneous responses among individual metastases in patients with PCa, supporting the polyclonal evolution of PCa in advanced disease. Molecular imaging may thus be useful to identify clinical resistance earlier after therapy initiation and could also enable targeted biopsy of resistant clones for molecular analysis.
DNA repair components modulating the function of breast cancer susceptibility gene 1 (<i>BRCA1</i>) in advanced non-small cell lung cancer (NSCLC) patients (p) treated with platinum-based chemotherapy.
Authors: Laura Bonanno, Carlota Costa, Margarita Majem, Jose Javier Sanchez, Ana Gimenez Capitan, Alain Vergnenegre, Bartomeu Massuti, Clara Mayo, Miguel Angel Molina-Vila, Adolfo G. Favaretto, Cinta Pallares, Susana Benlloch, Massimo Rugge, Miquel Taron, Rafael Rosell
Journal: Journal of Clinical Oncology (2012)

e18130 Background: The standard first-line treatment for advanced NSCLC p with wild-type epidermal growth factor receptor (EGFR) is platinum-based chemotherapy, but median overall survival (OS) is about 12 months, with great heterogeneity in terms of efficacy and tolerability. Low BRCA1 mRNA expression has been correlated with sensitivity to cisplatin, but BRCA1 function is modulated by other DNA repair components. For example, AEG1 can induce BRCA1 expression, and CASPASE 3 cleaves the mediator of DNA damage checkpoint 1 (MDC1) preventing the activation of the DDR pathway Methods: Paraffin-embedded samples were collected from 115 advanced NSCLC p treated with first-line platinum-based chemotherapy (not including taxanes and vinca alkaloids). Samples were screened for EGFR, KRAS and p53 mutations, and gene expression levels of BRCA1, RAP80, AEG1, MDC1, CASPASE 3, 53BP1, MMSET, PIAS4, UBC9, UBC13, NPM1 and HERC2 were quantified by real-time PCR. Results: Gene expression levels were significantly higher in squamous tumors, and the correlation among genes confirmed the biological model. Median OS was 11 months and median progression free survival (PFS) was 7.1 months. In p with low levels of both BRCA1 and RAP80, PFS was 12 months and OS was not reached, while in p with high level of both genes, PFS was 5.1 months and OS was 6.2 months and in p with other combinations, PFS was 7.4 months and OS was 10.9 months (P=0.02). Increased levels of AEG1 increased the risk of death (HR: 1.3; P=0.01) and of progression (HR: 1.2; P=0.04). When CASPASE 3 levels were divided into tertiles, intermediate levels were associated with improved PFS (P=0.005) and OS (P=0.05). The multivariate analysis confirmed the role of BRCA1 (P=0.02) and CASPASE 3 (P=0.008). Conclusions: The study showed the predictive value of combined BRCA1 and RAP80 mRNA levels. In addition, AEG1 and CASPASE 3 have emerged as potential predictive markers.
Triplet chemotherapy (TC) with FOLFIRINOX regimen in metastatic colorectal cancer (mCRC): Experience of the Val d’Aurelle Center.
Authors: Emmanuelle Samalin, Virginie Loriot, Simon Thézenas, Eric Assenat, Fabienne Portales, Sebastien Carrere, Philippe Rouanet, Jean-Pierre Bleuse, Francois Quenet, Marc Ychou
Journal: Journal of Clinical Oncology (2012)

3633 Background: TC is a treatment option for mCRC to improve the tumor response rate in selected patients (pts) and the conversion rate of initially non-resectable liver metastases. The aim of this study was to evaluate the impact and feasibility of FOLFIRINOX regimen in mCRC pts. Methods: All mCRC pts with non-resectable disease who have received FOLFIRINOX alone or combined with targeted therapies (bevacizumab or cetuximab) from October 2000 to December 2010 were selected for this analysis. Clinical data were collected in a mCRC specific data base and analyzed by the end of 2011. Results: Ninety two pts (52% of men), median age 59 yrs (range: 27-76) were treated with FOLFIRINOX (D1 oxaliplatin 85 mg/m² IV 2H then irinotecan 180 mg/m² IV 90 min and elvorin 200 mg/m², then 5FU 200 mg/m² and 2400 mg/m² by 46H infusion, D1=D15) alone (64%) or combined with cetuximab(30%) or bevacizumab (6%), as 1 st -line in 82 pts (89%). Prophyllactic G-CSF was given in 58% of them. Primary tumor was located in colon (58%) or rectum (42%), and 64 (69%) of pts presented with synchronous metastases: liver 100%, lung 40%, peritoneum 17% and nodes 17%. Median number of cures was 8 (range: 1-12). There was 1 toxic death. Grade 3-4 toxicities were: diarrhea 22%, neuropathy 21%, cutaneous 12%, neutropenia 28%, febrile neutropenia 0%, thrombopenia 6%. Objective Response rate according to RECIST criteria was 72% [CI95% 61-81] including 10 pts with complete response (11%). The primary tumor was resected in 70 pts (76%) and 14% had KRAS mutated tumor. Among the pts with liver metastases, 63 (68%) pts were evaluated for secondary resectability by a multidisciplinary committee and 40 pts (43%) had resection achieved (70% R0). Median overall survival was 49 months [CI95%28-62]. Conclusions: These results confirm the feasibility of FOLFIRINOX regimen with or without targeted therapies and its efficacy in terms of response rate and overall survival as 1rst-line treatment in selected mCRC pts.
Are mastectomy rates really increasing? Experiences from a single institution and a population-based database.
Authors: Min Yi, Elizabeth Ann Mittendorf, Rosa F. Hwang, Gildy Babiera, Henry Mark Kuerer, Jaime Crow, Georgia Lange, Ruchita R. Shah, Kelly Hunt
Journal: Journal of Clinical Oncology (2012)

1028 Background: Recent studies have reported increased mastectomy rates for the treatment of early stage breast cancer during the last decade. The aims of this study were to examine trends in mastectomy rates at a single institution and in a population-based database and to compare differences between the two cohorts. Methods: Patients with stage 0-II breast cancer diagnosed from 2000 to 2008 were identified from our cancer center institutional database (CC cohort, n=8,915) and the Surveillance, Epidemiology and End Results database (SEER cohort, n=359,572). Patients without primary surgery or unknown surgery type were excluded. Mastectomy rates by the year of diagnosis were evaluated and multivariable logistic regression models were built to identify clinicopathologic factors that predicted mastectomy as the treatment choice. Results: The proportion of patients treated with mastectomy decreased from 44.5% to 37.8% between 2000 and 2005 in the CC cohort (P=0.003) and from 42.8% to 36.6% in the SEER cohort (P&lt;0.0001). Subsequently, the mastectomy rate increased to 48.6% in the CC cohort (P&lt;0.0001) and to 40.1% in the SEER cohort by 2008 (P&lt;0.0001). Multivariable analysis found that patients with younger age (&lt;50), stage 0 or II cancer vs. stage I, high grade tumor, low median household income, and lobular histology were more likely to choose mastectomy in both the SEER and CC cohorts. In the CC cohort, patients with preoperative breast MRI were also more likely to undergo mastectomy. The percentages of patients receiving preoperative MRI and choosing prophylactic contralateral mastectomy increased each year in the CC cohort. The rate of preoperative breast MRI increased from 4.7% in 2005 to 9.6% in 2008 (P&lt;0.0001). Patients choosing prophylactic contralateral mastectomy increased from 8.4% in 2005 to 11.8% in 2008 (P=0.06). Conclusions: Our study shows that there was a decrease in mastectomy rates from 2000 to 2005 and a subsequent increase in mastectomy rates from 2005-2008 in both the CC and SEER cohorts. Increased use of preoperative breast MRI and the decision to undergo contralateral prophylactic mastectomy likely contributed to the increased mastectomy rates in the CC cohort.
The Development of Cardiac Arrhythmia Ablation
Authors: Melvin A. Scheinman, John D. Rutherford
Journal: Circulation (2017)

Dr Melvin A. Scheinman is Professor of Medicine and holds the Walter H. Shorenstein Endowed Chair in Cardiology at the University of California, San Francisco. He has received awards including the Paul Dudley White Award for Excellence in Teaching by the American Heart Association and the Distinguished Science Award of the American College of Cardiology. He grew up in Brooklyn, New York, and took his undergraduate degree at Johns Hopkins University, where he graduated first in his class. Postgraduate medical education included the Albert Einstein College of Medicine, residency training at the University of North Carolina (Chapel Hill), and cardiology training at the University of California, San Francisco Medical Center.