tbuckley/cabot-search huggingface dataset:
Prognostic characteristics of 492 newly diagnosed breast cancer patients by serum vitamin D levels.
Authors: Luke Joseph Peppone, Mohamedtaki Abdulaziz Tejani, Karen Michelle Mustian, Michelle Christine Janelsins, Charles Stewart Kamen, Supriya Gupta Mohile, Anita Roselyn Peoples, Marie Anne Flannery, Kristin A. Skinner
Journal: Journal of Clinical Oncology (2015)

e12619 Background: Studies have linked lower 25-hydroxy vitamin D (25-OH Vit D) levels to increased risk of breast cancer incidence and mortality, but there is a lack of research on the link between vitamin D levels and prognostic factors. We examined the association between 25-OH vitamin D levels at surgery and prognostic factors for breast cancer patients. Methods: This cohort consists of 492 surgical breast cancer patients between 2009 and 2014. Prognostic variables included age, race, stage, ER/PR status, tumor size, Ki-67, and molecular phenotype. Logistic regression was used to calculate odds ratios (OR) by 25-OH Vit D categories (optimal: ≥ 32 ng/ml [Reference]; insufficient: 20-31 ng/ml; and deficient: < 20 ng/ml) for prognostic variables. Results: Sub-optimal 25-OH Vit D values were strongly associated with poor prognostic factors including hormone receptor negative disease, later stage, and Basal-like tumors (table). Non-Caucasians and premenopausal women were also significantly more likely to have deficient 25-OH Vit D levels. Analyses stratified by race and menopausal status showed increased OR for prognostic factors among non-Caucasian and premenopausal women, respectively. Conclusions: Breast cancer patients with sub-optimal vitamin D levels were more likely to have tumors with a more aggressive profile, lending support to decreased breast cancer survival among vitamin D deficient individuals. Further research should elucidate the biological relationship between vitamin D and prognostic markers. Odds ratios (OR) for categorical 25-OH Vit D by prognostic factors. 25-OH Vit D Optimal [Ref] Insufficient OR Deficient OR (≥ 32 ng/ml) (20-31 ng/ml) (≤ 19 ng/ml) Ptrend Caucasian (Ref) vs 1.00 1.17 5.00* <0.01 Non-Caucasian Post-menopausal (Ref) vs 1.00 2.39* 3.24* <0.01 Pre-menopausal ER+ (Ref) vs 1.00 1.90* 1.83^ 0.08 ER− PR+ (Ref) vs 1.00 1.80* 2.09* 0.01 PR− Stage: I (Ref) vs 1.00 1.17 1.64 0.04 II Stage: I (Ref) vs 1.00 1.04 2.24* 0.02 III Triple Negative: No (Ref) vs 1.00 1.85^ 2.52* 0.10 Yes Luminal A (Ref) vs 1.00 3.31* 5.13* <0.01 Basal-like Luminal A (Ref) vs 1.00 1.65* 1.58^ 0.02 Luminal B Tumor: < 20 mm (Ref) vs 1.00 1.13 1.43^ 0.12 ≥ 20 mm Ki-67: < 20% (Ref) vs 1.00 1.45 1.57 0.03 ≥ 20% *, p < 0.05; ^, p < 0.10
A Predictive Model for Tumor Lysis Syndrome in Acute Myelogenous Leukemia.
Authors: Anthony R. Mato, Brett E. Riccio, Li Qin, Daniel Heitjan, Alison Loren, Martin Carroll, David Porter, Donald Tsai, Edward Stadtmauer, Sasha Perl, Alan Gewirtz, Sunita Nasta, Stephen Schuster, Steven Goldstein, Selina M. Luger
Journal: Blood (2004)
Transcatheter Treatment of Severe Tricuspid Regurgitation With the Edge-to-Edge MitraClip Technique
Authors: Georg Nickenig, Marek Kowalski, Jörg Hausleiter, Daniel Braun, Joachim Schofer, Ermela Yzeiraj, Volker Rudolph, Kai Friedrichs, Francesco Maisano, Maurizio Taramasso, Neil Fam, Giovanni Bianchi, Francesco Bedogni, Paolo Denti, Ottavio Alfieri, Azeem Latib, Antonio Colombo, Christoph Hammerstingl, Robert Schueler
Journal: Circulation (2017)

Background: Current surgical and medical treatment options for severe tricuspid regurgitation (TR) are limited, and additional interventional approaches are required. In the present observational study, the safety and feasibility of transcatheter repair of chronic severe TR with the MitraClip system were evaluated. In addition, the effects on clinical symptoms were assessed. Methods: Patients with heart failure symptoms and severe TR on optimal medical treatment were treated with the MitraClip system. Safety, defined as periprocedural adverse events such as death, myocardial infarction, stroke, or cardiac tamponade, and feasibility, defined as successful implantation of 1 or more MitraClip devices and reduction of TR by at least 1 grade, were evaluated before discharge and after 30 days. In addition, functional outcome, defined as changes in New York Heart Assocation class and 6-minute walking distance, were assessed. Results: We included 64 consecutive patients (mean age 76.6±10 years) deemed unsuitable for surgery who underwent MitraClip treatment for chronic, severe TR for compassionate use. Functional TR was present in 88%; in addition, 22 patients were also treated with the MitraClip system for mitral regurgitation as a combined procedure. The degree of TR was severe or massive in 88% of patients before the procedure. The MitraClip device was successfully implanted in the tricuspid valve in 97% of the cases. After the procedure, TR was reduced by at least 1 grade in 91% of the patients, thereof 4% that were reduced from massive to severe. In 13% of patients, TR remained severe after the procedure. Significant reductions in effective regurgitant orifice area (0.9±0.3cm 2 versus 0.4±0.2cm 2 ; P &lt;0.001), vena contracta width (1.1±0.5 cm versus 0.6±0.3 cm; P =0.001), and regurgitant volume (57.2±12.8 mL/beat versus 30.8±6.9 mL/beat; P &lt;0.001) were observed. No intraprocedural deaths, cardiac tamponade, emergency surgery, stroke, myocardial infarction, or major vascular complications occurred. Three (5%) in-hospital deaths occurred. New York Heart Association class was significantly improved ( P &lt;0.001), and 6-minute walking distance increased significantly (165.9±102.5 m versus 193.5±115.9 m; P =0.007). Conclusions: Transcatheter treatment of TR with the MitraClip system seems to be safe and feasible in this cohort of preselected patients. Initial efficacy analysis showed encouraging reduction of TR, which may potentially result in improved clinical outcomes.
Analysis of gene expression in the re-replication pathway and selective blockade with checkpoint inhibitors as a potential therapeutic option in NSCLC.
Authors: Daniela Morales-Espinosa, Miguel Angel Molina-Vila, Ana Gimenez Capitan, Silvia Garcia-Roman, Jordi Bertran-Alamillo, Pedro Mendez, Jose Luis Ramirez-Serrano, Carles Codony, Santiago Viteri Ramirez, Niki Karachaliou, Rafael Rosell
Journal: Journal of Clinical Oncology (2015)

e13516 Background: Targeted lung cancer therapy has undoubtedly made a difference to the treatment of EGFR mutation and ALK translocation carriers. However, targeted therapies for other subgroups like squamous cell carcinoma are still scarce. Re-replication of the genome could initiate gene amplification and cause chromosomal translocation and loss, contributing to tumor progression. It has been shown that cell cycle checkpoints and DNA damage response are activated when re-replication is induced. Cell cycle checkpoints, mediated by CHK1 and 2, are essential to prevent re-replication and maintain genomic integrity. Specific CHK1 inhibitors such as LY2603618 have been shown to delay tumor growth when given in combination with pemetrexed in NSCLC xenograft models. Methods: We selected a panel of NSCLC adenocarcinoma and squamous cell carcinoma cell lines representing different genetic backgrounds with TP53, KRAS and EGFR mutations. In addition, six PC9-derived, TKI resistant cell lines were included (PC9-ER, PC9-GR1 to GR5). Expression of genes involved in the re-replication pathway (MDC1, ATR, ATM, CHEK2, Rap80, Cdc1, Cdc6, MYC, SLX4, CHEK1, BRCA1, BRCA2, p53, ORC4, ORC5, ORC6 and GMNN) was analyzed by RT-PCR. All cell lines were treated with CHK1 and a CHK1/2 inhibitors, and the IC50 was determined by the MTT assay. Results: We observed different expression levels of key genes involved in the re-replication pathway. Interestingly, a p53 mutated squamous cell line (SK MES1), which has high expression levels of CHK1 and CHK2 (22.31 and 18.66, respectively), showed the lowest IC50 in our study (IC50 = 0.024 μM) with a CHK1 selective inhibitor (LY2603618). Also, two EGFR-resistant cell lines, one harbouring the T790M mutation, were highly sensitive to CHK1 inhibition (IC50 of 0.19μM for PC-GR5; 0.40 μM for PC9-GR4). Conclusions: Nowadays, few specific therapeutic options exist for squamous cell carcinoma of the lung. Expression of genes involved in the re-replication pathway, and the sensitivity of some NSCLC cell lines to CHK-1 inhibitors identify this pathway as a possible therapeutic target worthy of further investigation.
HLA class II alleles predict recurrence and pattern of failure in early-stage melanoma patients
Authors: Y. S. Chun, Y. Wang, J. E. Gershenwald, M. I. Ross, M. M. Johnson, P. Liu, C. W. Schacherer, J. D. Reveille, J. E. Lee
Journal: Journal of Clinical Oncology (2007)

8503 Background: Prior reports have suggested a link between specific HLA class II alleles, including HLA-DRB1*1101, and melanoma recurrence. We therefore investigated the relationship between HLA class II alleles and clinical outcome in a large population of patients who presented with localized melanoma. Methods: HLA class II alleles were determined by typing of genomic DNA from patients who presented with localized melanoma (AJCC stage IA-IIC). Patients found to have occult regional disease by sentinel node biopsy were excluded. Log-rank and Cox analysis of outcome versus standard prognostic factors and common HLA class II alleles (=5% of the population) was performed. Results: 1,241 patients underwent HLA typing. The median primary tumor thickness was 1.1 mm, 16% were ulcerated, and the median follow-up was 56 months. Tumor thickness, ulceration, and Clark level were independent predictors of recurrence. The HLA class II allele HLA-DRB1*1101 (11% of the population) independently predicted a higher risk of recurrence [hazard ratio (HR) 2.04, P=0.004] while HLA-DRB1*0401 (20% of the population) predicted a lower risk of recurrence (HR 0.42, P=0.004). HLA- DRB1*1101 was a particularly strong predictor of recurrence in stage I patients (HR 2.73, P&lt;0.0001). Among patients who recurred, HLA- DRB1*1101 was an independent predictor of local-regional vs. distant recurrence (HR 2.7, P=0.007), and was more common in those whose first recurrence was isolated to the regional nodal basin, compared to those whose first recurrence was elsewhere or in multiple locations (24% HLA-DRB1*1101-positive vs. 14%, P&lt;0.009). Conclusions: These results confirm that HLA-DRB1*1101 is a genetic marker of increased risk of melanoma recurrence, while HLA-DRB1*0401 is a marker of decreased risk of recurrence. HLA-DRB1*1101 is a particularly strong marker among the group of patients predicted clinically to be at the lowest overall risk for recurrence, and independently predicts pattern of recurrence (regional nodal failure). This information is of value in the development of surveillance strategies for melanoma patients, as well as the selection, stratification and randomization of early-stage melanoma patients for clinical trials. No significant financial relationships to disclose.
Identification of APE1 as a novel prognostic factor and possible therapeutic target for advanced NSCLC patients receiving platinum-based doublet chemotherapy.
Authors: Mengxia Li, Zheng Li, Shiheng Zhang, Yi Cheng, Dong Wang
Journal: Journal of Clinical Oncology (2015)

e22061 Background: Although platinum-based doublet chemotherapy is the most common therapeutic regime for advanced non-small-cell lung cancer (NSCLC) patients, a substantial proportion of patients are resistant to platinum-based chemotherapy. ERCC1 is the most recognized predictive biomarker for response to platinum-based chemotherapy, but a recent study revealed that ERCC1 is not an ideal predictive marker. DNA repair capacity has been established as an important factor responsible for the cellular response to platinum treatment, and APE1, a critical DNA repair enzyme, has been linked to intrinsic resistance to platinum. Methods: The protein levels of ERCC1 and APE1 of 172 NSCLC patients were evaluated by immunohistochemistry (IHC) and their correlation with response rate to platinum-containing chemotherapy, progress-free survival (PFS) and overall survival (OS) was analyzed. The involvement of APE1 in cellular response to platinum treatment and possible synergistic effects with ERCC1 inhibition were confirmed by introducing an shRNA against APE1. Further mechanistic studies were also conducted to explore the possible crosstalk between DNA repair pathways in platinum treatment. Results: The clinicopathological data demonstrate that the response rate, PFS and OS were significantly better in NSCLC patients with low ERCC1 expression than those with high expression levels (p< 0.05). Patients with APE1-negative tumors had a better response to chemotherapy (p= 0.002) and a better median PFS (p= 0.016) but no significant change in OS (p= 0.263). Moreover, patients with both APE1- and ERCC1-negative tumors had a significantly higher response rate and a better median PFS and OS than those with double- positive tumors (p< 0.01). Double inhibition of APE1 and ERCC1 has a synergistic effect on platinum cytotoxicity in various NSCLC cell lines in vitro. The mechanistic study revealed that APE1 deficiency sensitizes cells to platinum by impairing DNA double strand break repair capacity through its redox activity. Conclusions: The current study identified APE1 as a novel prognostic factor for NSCLC patients who received platinum-based chemotherapy.
Correlation of gene expression signatures and clinical outcomes in patients with advanced gastric cancer treated with pembrolizumab (MK-3475).
Authors: Veena Shankaran, Kei Muro, Yung-Jue Bang, Ravit Geva, Daniel Virgil Thomas Catenacci, Shilpa Gupta, Joseph Paul Eder, Raanan Berger, Andrey Loboda, Andrew Albright, Razvan Cristescu, Erin Murphy, Terri McClanahan, Mark Ayers, Michael Nebozhyn, Jared K. Lunceford, Minori Koshiji, Karl Heath, Jonathan D. Cheng, Hyun-Choel Chung
Journal: Journal of Clinical Oncology (2015)

3026 Background: Pembrolizumab, an anti–PD-1 monoclonal antibody, has shown antitumor activity in advanced gastric cancers. Hypothesis testing of 4 prespecified multigene immune expression signatures enriched for T-cell mediated interferon signaling and antigen presentation genes was used to evaluate associations with clinical outcomes in patients with gastric cancer enrolled in KEYNOTE-012, a multicohort, phase 1 study of pembrolizumab in patients with PD-L1+tumors. Methods: 33 of 39 pembrolizumab-treated advanced gastric cancer patients had RNA expression profiling data of sufficient quality. RNA was extracted from formalin-fixed, paraffin-embedded samples and analyzed using the NanoStringnCounter system. Hypothesis testing was conducted on 4 prespecified signatures ("Interferon-gamma," "TCR-signaling," "Expanded-immune," and "Denovo") that were constructed based on analyses in patients with melanoma and prior to linking any NanoString data to clinical outcome data. Results: In the patients with NanoString data, ORR was 30%. For ORR, all 4 signatures showed a P value <0.10 (Table). For PFS, all signatures achieved P< 0.05. All signatures showed a general pattern such that pts with very low signature scores did not respond. ROC analyses suggest that cutoffs with high sensitivity and a resultant high negative predictive value (NPV) can readily be achieved. The cutoff associated with the Youden Index of the ROC curve for the Interferon-gamma signature yielded a positive predictive value (PPV) of 45% with a NPV at 92%. Conclusions: Immune response signatures were associated with clinical benefit from anti–PD-1 therapy with pembrolizumab in patients with advanced gastric cancer enrolled in KEYNOTE-012. Clinical trial information: NCT01848834. Signature Nominal One-Sided Pa ORR N = 33 PFS N = 33 IFNγ (6 gene) 0.077 0.032 TCR Signaling (13 gene) 0.034 0.024 Expanded Immune (18 gene) 0.062 0.049 Denovo (33 gene) 0.068 0.037 aFrom logistic or Cox regression for ORR and PFS, respectively.
Autoantibodies (AA) against the EGF/EGFR and VEGFA/VEGFR1 as prognosticator in epithelial ovarian cancer (EOC) patients.
Authors: Elena Ioana Braicu, Ralf Dechend, Duska Dragun, Andreas Busjahn, Rolf Wachter, Gabriela Riemekasten, Michaela Golic, Harald Heidecke, Marc Kuhberg, Dominik N Mueller, Jalid Sehouli
Journal: Journal of Clinical Oncology (2014)

5584 Background: Angiogenesis plays a major role in EOC. Anti-angiogenic therapy prolongs progression free survival in both primary and recurrent EOC, but no predictive biomarkers are currently known. Methods: In this study 132 healthy women and 201 primary EOC patients were enrolled. Most of the EOC patients had a FIGO IIIc (66%) and high grade serous ovarian cancer (96.4%). All EOC patients were treated with primary tumor debulking and platinum based chemotherapy. Mean follow up period was 62 months (range 19-149). Autoantibodies (AA) against epidermal growth factor (AA-EGF), epidermal growth factor receptor (AA-EGFR), vascular growth factor A (AA-VEGFA) and against vascular growth factor receptor 1 (AA-VEGFR1) were detected in preoperative serum samples using ELISA. Results: AA-EGF, AA-EGFR and AA-VEGFA, AA-VEGFR1 were detected in both control and EOC patients. AA concentrations were significantly lower in EOC (p<0.001). In the multivariate analysis AA-EGF, AA-EGFR, AA-VEGFA,AA-VEGFR1 were a significant predictor for mortality (p=0.001, 95%CI=0.12-0.154; p<0.001, 95%CI=0.0.047-0.83; p=0.001, 95%CI=0.118-0.173; p=0.001, 95%CI=0.125-0.167, respectively) and the combined endpoint (mortality or relapse) (p=0.001, 95% CI=-0.094-0.114; p=0.001, 95%CI=0.07-0.123; p=0.001, 95% CI=-0.093-0.028; p<0.01, 95%CI=-0.08-0.057). Conclusions: This is the first study that attests the existence of AA against EGF, EGFR and VEGFA, VEGFR1. AAs seem to have a protective role for the development of ovarian cancer. Furthermore higher AAs levels were associated with longer progression free and overall survival in EOC patients.
TBCRC 022: Phase II trial of neratinib for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer and brain metastases (BCBM).
Authors: Rachel A. Freedman, Rebecca Sue Gelman, Jeffrey Scott Wefel, Ian E. Krop, Michelle E. Melisko, Alarice Lowe, Nathalie Agar, Kimberly L. Blackwell, Roisin M. Connolly, Polly Ann Niravath, Catherine H. Van Poznak, Shannon Puhalla, Nicole Ryabin, Elizabeth S Lawler, Nuhad K. Ibrahim, Minetta C. Liu, Antonio C. Wolff, Eric P. Winer, Nancy U. Lin
Journal: Journal of Clinical Oncology (2014)

528 Background: Evidence-based treatments for metastatic, HER2+ breast cancer to the central nervous system (CNS) are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4 with promising activity in HER2+ disease. Preclinical evidence suggests it may cross the blood brain barrier. We evaluated neratinib in pts with HER2+ BCBM in a multicenter, phase II open label trial. We report the results of cohort 1 here. Methods: Pts with measurable BCMC (>/= 1 cm in longest dimension) who progressed after receipt of local CNS therapy were eligible. Pts received neratinib 240 mg orally once daily over 28 day cycles. Brain MRI and non-CNS imaging were obtained at baseline and every two cycles. Circulating tumor cell collections and neurocognitive evaluations were performed serially. The primary endpoint was composite CNS objective response rate (ORR). CNS ORR required all of the following: >/=50% reduction in volumetric sum of target CNS lesions, no progression of non-target lesions, no new lesions, no escalating steroids, no progressive neurologic signs/symptoms, and no non-CNS progression by RECIST 1.1. If patients progressed outside the CNS, the addition of trastuzumab was offered. We used a two-stage design to distinguish between ORR 6% vs 20% (responses in >/=1/18 pts to enter 2ndstage; responses in >/=5/40 pts to be promising). Results: 40 pts were enrolled between 2/12-6/13; median age was 51. Most pts (80%) had received 2+ lines of therapy for metastatic disease, 85% had prior lapatinib, and 75% had prior WBRT. As of 1/10/14, 0 patients remain on protocol therapy and 22 patients have died. Three women experienced a response (CNS ORR=7.5%; 95% CI 2-27%). The median number of cycles received was 2 (range 1-15+); 6 women (15%) received 6+ cycles of therapy. The most common grade 3+ event was diarrhea (25%); this event decreased after an amendment mandated 2 mg loperamide prophylaxis once daily during cycle 1 (33% grade 3+ diarrhea pre-prophylaxis vs. 21% post-prophylaxis). Conclusions: Neratinib is associated with a low CNS ORR in pts with BCBM but provided durable disease control in some pts. Updated results will be presented at the meeting. Clinical trial information: NCT01494662.
Accuracy of adverse event reporting on a phase III clinical trial for pediatric acute myeloid leukemia: A report from the Children’s Oncology Group.
Authors: Tamara P. Miller, Yimei Li, Marko Kavcic, Todd Allen Alonzo, Matt Hall, Yuan-Shung Huang, Robert B Gerbing, Brian Fisher, Selina M. Luger, David Rubin, Andrea B. Troxel, Lillian Sung, Alan S. Gamis, Richard Aplenc
Journal: Journal of Clinical Oncology (2015)

10028 Background: Adverse events (AE) on Children’s Oncology Group (COG) trials are reported by clinical research associates (CRA) on case report forms using the Common Terminology Criteria (CTC). CTC has increased in complexity from initially 49 AEs to 789 currently. This complexity challenges CRAs to accurately identify AEs. This study sought to evaluate the accuracy of AE reporting on a COG clinical trial and to determine if Pediatric Health Information System (PHIS) billing or microbiology data can improve AE reporting. Methods: Two pediatric oncologists performed chart review to identify 12 Grade III-V AEs (Table) for patients enrolled on AAML0531 at 11 hospitals across the United States and establish a gold standard. The sensitivity and PPV for COG AEs and AEs based on PHIS billing or microbiology data were calculated comparing to the gold standard. Results: Chart abstraction was performed on 179 patients (661 courses). PHIS billing data were available on all patients and PHIS microbiology data were available on 53 patients (202 courses) at 3 hospitals. The sensitivity of COG AE reports was lower than PHIS billing data, but COG reports had a higher PPV (Table). Sensitivity and PPV for viridians group streptococci (VGS) bacteremia using PHIS microbiology data were 92.3% (95% CI 79.1-98.4) and 97.3% (95% CI 85.8-99.9), respectively. Conclusions: The sensitivity of COG AE reports is modest with a relatively good PPV. PHIS billing data are generally more sensitive but have a lower PPV. While nearly 25% of VGS episodes were missed by COG AE report, the sensitivity and PPV of PHIS microbiology data for VGS was greater than 92%. These data suggest that current COG AE reporting is not sensitive and that accuracy may be improved by using external laboratory data. Sensitivity and PPV of 12 AEs. AE COG AE Report PHIS Billing Data Sensitivity % PPV % Sensitivity % PPV % Hypertension 23.1 66.7 65.4 39.5 Hypotension 56.1 76.7 12.2 55.6 Hypoxia 16.7 96.2 72.0 60.3 ARDS 38.5 50.0 30.8 44.4 Anorexia 32.5 95.7 74.5 98.5 Typhlitis 33.3 88.9 66.7 66.7 DIC 10.4 83.3 72.9 71.4 VGS 76.9 96.8 29.9 70.0 Fungal Infection 62.5 45.5 62.5 31.3 Pain 17.1 88.7 97.8 61.1 Seizure 0 0 100 6.5 Renal Failure 60.0 100 80.0 80.0