tbuckley/cabot-search huggingface dataset:
Erythropoietin Receptor-Mediated Molecular Crosstalk Promotes T Cell Immunoregulation and Transplant Survival
Authors: Carolina Purroy, Robert L. Fairchild, Toshiaki Tanaka, William M. Baldwin, Joaquin Manrique, Joren C. Madsen, Robert B. Colvin, Alessandro Alessandrini, Bruce R. Blazar, Miguel Fribourg, Chiara Donadei, Umberto Maggiore, Peter S. Heeger, Paolo Cravedi
Journal: Journal of the American Society of Nephrology (2017)

Although spontaneous kidney transplant acceptance/tolerance occurs in mice and occasionally in humans, mechanisms remain unclear. Herein we test the hypothesis that EPO, a hormone predominantly produced by the adult kidney, has immunomodulating properties that are required for spontaneous kidney graft acceptance. In vitro , in a manner dependent on the EPO receptor and CD131 on antigen-presenting cells, EPO induced the secretion of active TGF β by antigen-presenting cells, which in turn converted naïve CD4 + T cells into functional Foxp3 + regulatory T cells (Treg). In murine transplant models, pharmacologic downregulation of kidney-derived EPO prevented spontaneous Treg generation. In a controlled, prospective cohort clinical study, EPO administration at doses used to correct anemia augmented the frequency of peripheral CD4 + CD25 + CD127 lo T cells in humans with CKD. Furthermore, EPO directly inhibited conventional T cell proliferation in vitro via tyrosine phosphatase SHP-1–dependent uncoupling of IL-2R β signaling. Conversely, EPO-initiated signals facilitated Treg proliferation by augmenting IL-2R γ signaling and maintaining constitutively quenched IL-2R β signaling. In additional murine transplant models, recombinant EPO administration prolonged heart allograft survival, whereas pharmacologic downregulation of kidney-derived EPO reduced the expression of TGF β mRNA and abrogated kidney allograft acceptance. Together, our findings delineate the protolerogenic properties of EPO in inhibiting conventional T cells while simultaneously promoting Treg induction, and suggest that manipulating the EPO/EPO receptor signaling axis could be exploited to prevent and/or treat T cell-mediated pathologies, including transplant rejection.
Effect of the 12-gene colon cancer assay results on treatment recommendations in patients with stage II colon cancer.
Authors: Thomas H. Cartwright, Calvin Chao, Margarita Lopatin, Tanya G. Bentley, Michael S. Broder, Eunice Chang
Journal: Journal of Clinical Oncology (2012)

3626 Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has been clinically validated as an independent predictor of individual recurrence risk in stage II colon cancer patients following surgery. As a result, physicians have been ordering the Oncotype DX assay for stage II colon cancer patients since January 2010, yet no data exist on the assay’s impact on adjuvant treatment planning in clinical practice. We performed a survey to characterize the impact of the assay on adjuvant treatment recommendations in stage II colon cancer. Methods: U.S. medical oncologists (n=346) who ordered Oncotype DX for ≥3 patients with stage II colon cancer were contacted and asked to complete a web-based survey regarding the single most recent stage II colon cancer patient for whom the assay was ordered. The survey was developed through cognitive interviews with four medical oncologists, and the protocol was institutional review board approved. Results: We analyzed survey results from 116 eligible physicians. Physicians were more often in community (86%) than academic or other practices, and had a median of 14.5 years (range, 2-40) of practice experience. The median patient age was 62 years (range, 32–85). Most patients (81%) had T3 disease. Patients had ≤8, 9-11 and ≥12 nodes examined 3%, 13% and 84% of the time and 38% had comorbidities. Of the 76 patients tested for MMR/MSI, 13 (17%) were MMR-D or MSI-H and 46 (61%) were MMR-P or MSI-L; 17 (22%) unknown. Median RS was 20 (range, 1-77). Before obtaining the RS, chemotherapy was planned in 52 (45%) patients, observation in 40 (34%), and there was no recommendation in 24 (21%). For the 92 patients with pre-assay recommendations, recommended treatment changed after obtaining the RS for 27 patients (29%). Treatment intensity decreased for 18 (67%) and increased for 9 (33%) of 27 changed recommendations. A significant trend of decreasing treatment intensity with lower RS values was observed (p=.0035). Conclusions: These findings indicate that for stage II colon cancer patients, treatment recommendations were changed by RS results in 29% of patients. Use of the Oncotype DX assay may lead to reductions in treatment intensity, contributing to the assay’s cost effectiveness.
Review of special populations for the use of colony-stimulating factors
Authors: R. W. Dubois, L. Pinto, M. Bernal, E. Badamgarav, G. H. Lyman
Journal: Journal of Clinical Oncology (2004)

6154 Background: Identifying predisposing factors of febrile neutropenia (FN) may help to improve quality of cancer care by identifying appropriate CSF patients. Many studies have identified different risk factors that increase the likelihood of FN or related complications. A systematic literature review was conducted to evaluate the body of evidence. Methods: MEDLINE databases were searched for English-language articles published between 01/87–02/03 containing the search terms chemotherapy, neutropenia, risk factors, and epidemiologic factors, among others. Two reviewers conducted the review and interrater reliability was calculated. Results: MEDLINE search yielded 932 articles. Following title and abstract review, 133 were selected for full-text review. 24 studies assessing risk factors for FN and related complications in lymphoma and solid tumor patients met the inclusion criteria. Interrater reliability at each phase exceeded 0.70. Eight studies assessed FN predictors; 10 evaluated neutropenia predictors; and 4 studied FN-related hospitalizations. Age, performance status, bone marrow involvement, and myelosuppressive chemotherapy were the most frequently assessed predictors. Age (>70 years [24%] vs <70 years [7%], P<0.001) and receipt of myelosuppressive chemotherapy (OR ranged from 2.69 to 14.4 in studies reporting multivariate results) consistently significantly increased FN risk. Other factors such as performance status [3 of 8 studies; multivariate OR = 7.2 (95% CI: 2–22) for solid tumor patients and 18.8 (95% CI: 3.71–95) for lymphoma patients] and bone marrow involvement (1 out of 6 studies) were statistically significant in some studies but not others. Conclusions: This review suggests that older patients, patients undergoing myelosuppressive chemotherapy, and those with low performance status were at increased FN risk and may benefit from first-cycle CSF administration. Commonly recognized risk factors such as prior chemotherapy, tumor stage/type, prior FN history, and low hemoglobin levels were associated with FN in only some of the studies reviewed. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Inc. Amgen, Inc. Amgen, Inc.
Cooperation of bisphosphonates with tyrosine kinase inhibitors in advanced non-small cell lung cancer with EGFR activation mutation: A retrospective study.
Authors: Chu-ying Huang, Li Wang, Cheng-jun Feng, Ping Yu, Yongsheng Wang
Journal: Journal of Clinical Oncology (2014)

e19073 Background: Preclinical and clinical data suggest that bisphosphonates (BPs) may exhibit anti-tumor activity and prevent tumor progression of Non-small cell lung cancer (NSCLC). In this study, we aimed to evaluate whether the combination of BPs with inhibitors of EGFR tyrosine kinase (TKI) show an increased therapeutic effects in advanced NSCLC patients with EGFR activation mutation. Methods: Between 2008 and 2013, 114 advanced (staged IV) NSCLC patients with EGFR activation mutation from two cancer centers were treated with TKI as first-line therapy. The patients were separated into those treated with TKI alone (group A) or TKI plus BPs (group B) for comparison and analysis of treatment efficacy. Median progression free survival (mPFS) and median overall survival (mOS) distributions were estimated using the Kaplan-Meier method and survival curves were compared by log-rank test. Results: 114 patients (71 in group A, 43 in group B) received TKI/TKI plus BPs as first-line therapy, median PFS was significantly prolonged with TKI plus BPs treatment (mPFS: 12 vs 15 months, P=0.02). Median OS was prolonged 4 months with the combined therapy, but the differences were not significant (mOS: 21 Vs 25, P=0.119). Among 114 patients, 62 with bone metastases (19 in group A, 43 in group B) received TKI/TKI plus BPs as first-line therapy. Median PFS and OS significantly improved in the combination group compared with the TKIs group (mPFS: 7 vs 15 months, P=0.001; mOS: 10 vs 23 months, P=0.001). Conclusions: Concomitant use of BPs and EGFR-TKI may improve therapeutic efficacy and bring survival benefit to advanced NSCLC patients with EGFR activation mutation.
An evaluation of national treatment trends in pancreatic cancer.
Authors: Brian S. Seal, Fang Xia, Rebecca Germino, Petra Rietschel, Carl V Asche, Anna O. D'Souza, Kellie Morland, Michael Eaddy
Journal: Journal of Clinical Oncology (2014)

e15211 Background: Real-world data on national treatment patterns in pancreatic cancer (PC) are sparse. This study evaluated treatment patterns and survival among patients with PC. Methods: A retrospective study analyzed data spanning 10/2008–06/2012 from 3 large integrated claims databases. Adult patients with an ICD-9 diagnosis code for PC were included if they had a minimum eligibility of 12 months prior to and 3 months following their first PC diagnosis and had no diagnosis of cancer in the 12-month pre-period. Patients were categorized as having exocrine PC, endocrine PC, or metastatic exocrine PC. Treatment patterns and survival were evaluated after cancer diagnosis. Results: There were 2,901, 6,119, and 464 patients in each of the 3 databases meeting all inclusion criteria, respectively. The majority of patients had exocrine PC (97–98%), with 40–76% having metastatic disease. Patients were on average 60.3–64.5 (±11.3–14.0) years of age and 43%–52% were female. No treatment was received by 35–55% of patients, 36–55% of patients received chemotherapy ± radiation and/or surgery, and 9–10% received radiation and/or surgery without chemotherapy. Patients with metastatic disease were less likely to receive no treatment (21–24% vs 73–79%) and more likely to receive chemotherapy ± radiation and/or surgery (67–69% vs 13–16%) compared to those without metastatic disease. Second-line chemotherapy was received by 17–32% (35–41% metastatic vs 5–6% non-metastatic), while third-line chemotherapy or greater was received by 9–17% (18–22% metastatic vs 2–5% non-metastatic) of patients. Based upon survival data available in database 3, 14% of patients with exocrine, 0% of patients with endocrine, and 53% of patients with metastatic exocrine PC died during the study period. Patients with exocrine PC were significantly less likely to die when compared to patients with metastatic exocrine PC (HR = 0.199, P<0.0001). Conclusions: Patients with non-metastatic exocrine PC most commonly receive no treatment, whereas patients with metastatic PC receive chemotherapy + radiation and/or surgery. Metastatic disease significantly decreases survival among patients with PC.
EVALUATION OF THE CARDIOSMART POPULATION HEALTH MANAGEMENT INITIATIVE: CHANGES IN HEALTH RISKS AND PARTICIPANT SATISFACTION
Authors: Neil F. Gordon, Richard D. Salmon, Brenda S. Wright, George C. Faircloth, Terri L. Gordon, Michael Hargrett, Martin R. Berk, Barry A. Franklin, Martha Gulati
Journal: Journal of the American College of Cardiology (2017)
A randomized phase 2 study evaluating optimal sequencing of sipuleucel-T (sip-T) and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Preliminary clinical data.
Authors: Emmanuel S. Antonarakis, Adam Stuart Kibel, George W. Adams, Lawrence Ivan Karsh, Aymen Elfiky, Neal D. Shore, Nicholas J. Vogelzang, John M. Corman, Robert Claude Tyler, Candice McCoy, Todd DeVries, Nadeem A. Sheikh, Charles G. Drake
Journal: Journal of Clinical Oncology (2014)

5041 Background: Sip-T is an autologous cellular immunotherapy targeting prostatic acid phosphatase (PAP) that is approved by the FDA and EMA for the treatment of certain patients with asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer. The STAND trial (NCT01431391) evaluated optimal sequencing of sip-T and ADT in men with BRPC at high risk of developing metastases (PSA-DT ≤12 mos). Methods: Men (N=68) were randomized (1:1) to Arm 1: sip-T followed by ADT (2 wks after infusion 3) or Arm 2: ADT (3 mo lead-in) followed by sip-T. Men received 3 doses of sip-T and 12 mos of ADT (leuprolide). The primary endpoint was cellular immune response to target antigen (ELISPOT to PA2024). Secondary endpoints included humoral and cytokine responses, product parameters, clinical efficacy, and safety. Here we report preliminary clinical data and longer-term immune responses. Results: 65 men have been followed for ≥9 mos from last ADT injection: 10/32 (31.3%) in Arm 1 and 14/33 (42.4%) in Arm 2 achieved undetectable PSA (<0.02 ng/mL) and testosterone (T; <0.35 ng/mL) at 9 mos from last ADT injection; 4/65 men (6.2%) developed PSA progression (2 consecutive PSA measurements, 4 wks apart, ≥50% above nadir, >5ng/mL). In both arms, sip-T induced robust and prolonged immune responses to PA2024 and PAP (measured by T cell memory and ELISA antibody responses), although no significant differences have yet emerged between arms. There appear to be higher levels of serum cytokines in Arm 2 vs Arm 1, with a pattern suggesting a mixed TH1/TH2 cellular immune response; significant increases were seen in TH1 (IFNg, IL-12), TH2 (IL-4, IL-10, IL-13), and TH17 (IL-17) subsets (P<0.05). Conclusions: These data suggest that tumor-specific T cell responses and broad-based immune responses are augmented in both arms, and cytokine responses may be superior when sipuleucel-T is given after (rather than before) ADT initiation. In addition, augmented PA2024- and PAP-specific humoral responses have persisted for at least 12 mos, and are equally robust in both groups. Longer-term T cell responses and cytokine responses will be presented. Clinical trial information: NCT01431391.
A phase I study of the VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK 222584) and gemcitabine in patients with advanced pancreatic cancer
Authors: T. Kuo, A. Fitzgerald, H. Kaiser, B. I. Sikic, G. A. Fisher
Journal: Journal of Clinical Oncology (2006)

4122 Background: The VEGF pathway is the predominant mediator of angiogenesis in pancreatic cancer. Vatalanib (PTK787/ZK 222584) is a small molecule tyrosine kinase inhibitor of all known VEGF receptors. We initiated a phase I study of vatalanib and gemcitabine for advanced pancreatic cancer. Methods: Patients with newly diagnosed unresectable or metastatic pancreatic adenocarcinoma were enrolled. Previous adjuvant chemoradiotherapy with fluorouracil was allowed. Gemcitabine was given by fixed-dose rate infusion weekly x 3 in a 28-day cycle, and vatalanib was given orally daily. Dose-limiting toxicities (DLT) are defined as any grade 3/4 toxicity during the first cycle. The dose levels are as follows: Results: To date, 11 patients are evaluable for toxicity (5M/6F; median age 62 years, range 40–82 years; median KPS 90%). Thus far, 42 cycles have been given, with a median of four cycles per patient. Two patients have experienced DLT. The first patient (cohort 1) experienced grade 3 diarrhea and hypokalemia and grade 4 neutropenia occurring simultaneously and treated without sequelae. The second patient (cohort 3) developed grade 3 deep vein thrombosis. Beyond the first cycle, grade 3 toxicities included neutropenia (1), anemia (3), thrombocytopenia (1), hypertension (2), diarrhea (1), hypokalemia (1), thrombosis (1), and proteinuria (1). Three of eleven patients (27%) did not complete treatment to the first evaluation timepoint (2 cycles); two discontinued due to toxicity and one discontinued due to disease progression. Two of eleven patients (18%) had a partial response by RECIST. Six of eleven patients (55%) had stable disease as the best response ranging from 2–6 months. Conclusions: The combination of gemcitabine and vatalanib is generally well-tolerated with most grade 3/4 toxicities occurring late in the treatment course. Antitumor responses have been observed at initial dose levels and accrual to the final cohort with BID dosing of vatalanib continues. [Table: see text] No significant financial relationships to disclose.
Cell-free miR-10b and miR-21 as diagnostic biomarkers for malignant effusions
Authors: L. Xie, X. Chen, X. Qian, J. Wei, Y. Ding, C. Zhang, B. Liu
Journal: Journal of Clinical Oncology (2009)

11035 Background: Numerous studies have proved the roles of tissue microRNAs (miRNAs) as biomarkers in cancer diagnosis. Cell-free miRNAs from plasma or serum have been shown to be good biomarkers in the diagnosis of cancers. Here we tried to explore the potential application of cell-free miRNAs as diagnostic biomarkers to discriminate malignant effusions from benign. Methods: To obtain a molecular signature for malignant effusions, a stem-loop real-time PCR was adopted to measure the expression of 23 tumor-related miRNAs. After a pre-screening for discarding low amount miRNAs in 10 samples (5 benign/5 malignant) and a proper internal control was identified, the expression levels of 7 miRNAs were further compared among 74 malignant effusion samples (35 gastric cancer-related ascites and 39 lung cancer-related plural effusions) and 30 benign effusions. miRNAs specifically associated with malignant effusions were derived from a training group (20 malignant/10 benign) and tested in a validation group (54 malignant/20 benign). All samples were confirmed by both pathological and clinical diagnosis. Results: miR-215 was employed as the reference RNA for its abundance and consistence. The expression of miR-10b was significantly different between benign and malignant effusions (P&lt; 0.001). Furthermore, it was showed that miR-10b can distinguish malignant plural effusions with high accuracy (areas under the curve (AUC) of receiver operating characteristic (ROC) curve 0.98, 95% CI, 0.90 to 1.0, P&lt; 0.001), and miR-21 can be used to discriminate malignant ascites (AUC of ROC curve 0.71, 95% CI, 0.56 to 0.83, P= 0.018). Conclusions: In the present study, we demonstrated that cell-free miRNA can serve as a novel diagnostic biomarker in distinguishing malignant from benign effusions. No significant financial relationships to disclose.
Midline Extraperitoneal Approach to Retroperitoneal Lymph Node Dissection in Testicular Cancer: Minimizing Surgical Morbidity
Authors: Sumeet Syan-Bhanvadia, Soroush T. Bazargani, Thomas G. Clifford, Jie Cai, Gus Miranda, Siamak Daneshmand
Journal: European Urology (2017)
Importance of Achieving Sustained Stringent Complete Response (sCR) Following Autologous Stem Cell Transplantation in Multiple Myeloma
Authors: Prashant Kapoor, Morie A Gertz, Angela Dispenzieri, Martha Q Lacy, David Dingli, Suzanne R Hayman, Francis K Buadi, Stephen Russell, Yi Lin, Thomas E. Witzig, John A Lust, Steven R Zeldenrust, Philip R. Greipp, Robert A. Kyle, Vincent Rajkumar, Shaji K. Kumar
Journal: Blood (2012)
Evaluation of the commonly used chemotherapeutics in the clinic by mouse clinical trial (MCT).
Authors: Henry Li, Jie Yang, Dawei Chen, Mengmeng Yang, Sheng Guo, Xuesong Huang, Jiahua Jiang, Zhun Wang, Jianyun Deng, Jean-Pierre Wery
Journal: Journal of Clinical Oncology (2014)

e15009 Background: For many cancers, chemotherapy is a major or even the only treatment option, but unfortunately without ultimate proof of clinical benefits in many cases, e.g. improved PFS/OS. In particular, lack of predictive biomarkers and stratification guidance has further hindered gaining of the true benefit for the patients. PDX has recently become popular for research that can directly be translated into clinic practice. Mouse clinical trial using PDX (MCT) exemplifies one of these most important new applications. We have recently established a large library of ~900 PDXs and used them for conducting trials to evaluate pharmaceuticals. In the present study, we have conducted several MCT to test common chemotherapy for several disease indications, aiming at assessing their overall efficacy and identifying predictive signatures. Methods: Cohorts of PDXs of single disease were tested in two arms, control vehicle and single-treatment group(s) using conventionally preclinical dose levels. The objective tumor response rate (ORR) and the “survival” (time to reach tumor volume of 600mm3) were analyzed. Hazard ratios and median survival times were calculated and tested for statistical significance. Many of these models have been genomic-profiled for discovery of predictive biomarkers for drug efficacy. Results: The trials revealed that some agents are efficacious in certain indications but not in others, in contrast to other agents with different efficacy patterns, as measured by ORR and “survival” endpoints. For instance, 5FU demonstrated certain levels of efficacy in the cohort of CRC-PDXs, but completely lack of efficacy in either cohort of gastric or esophageal PDXs. In contrast, Gemcitabin showing convincing efficacy in the cohort of pancreatic PDXs, but apparently lack of efficacy in that of HCC-PDXs. Initial biomarker analysis indicates activities of certain cancer related signaling pathways may determine drug response. Conclusions: Our results indicated that different agents have varying efficacy patterns among cancer types. Apparently, the most important issue is whether the observed efficacy patterns have any clinical relevance thus predictive value to guide clinical application of these agents.
Evaluation of Evidence of Statistical Support and Corroboration of Subgroup Claims in Randomized Clinical Trials
Authors: Joshua D. Wallach, Patrick G. Sullivan, John F. Trepanowski, Kristin L. Sainani, Ewout W. Steyerberg, John P. A. Ioannidis
Journal: JAMA Internal Medicine (2017)

Many published randomized clinical trials (RCTs) make claims for subgroup differences.
UNDERSTANDING THE ROLE OF STRAIN IMAGING IN THE EARLY DETECTION OF CHAGAS CARDIOMYOPATHY
Authors: Daniel M. Alyeshmerni, Patrick Green, Gustavo Duran, Margaret Prust, Freddy Tinajeros, Manuela Verastegui, Holger Mayta, Jorge Flores, Carballo Paula, Lola Camila, Caryn Bern, Thomas Crawford, Robert Gilman, Theodore Kolias
Journal: Journal of the American College of Cardiology (2017)