tbuckley/cabot-search huggingface dataset:
mRNA expression profiles in circulating tumor cells (CTCs) of patients with metastatic breast cancer (MBC) treated with aromatase inhibitors (AI).
Authors: Esther Anneke Reijm, Anieta M. Sieuwerts, Joan Bolt-de Vries, Bianca Mostert, Wendy Onstenk, Dieter Peeters, Luc Yves Dirix, Caroline Seynaeve, A. Jager, Felix E. de Jongh, Paul Hamberg, Anne M. van Galen, Jaco Kraan, Maurice P. H. M. Jansen, Jan-Willem Gratama, John A. Foekens, John W. M. Martens, Els M. J. J. Berns, Stefan Sleijfer
Journal: Journal of Clinical Oncology (2013)

11045 Background: Enumeration of CTCs can be used to assess prognosis in MBC and to evaluate treatment response. Besides enumeration, molecular CTC characterization is a promising tool to develop a more personalized treatment approach. Here, we evaluated the association between mRNA expression of currently known CTC-specific genes and response to first-line AI in MBC patients with estrogen receptor (ER)+ primary tumors. Methods: CTCs were isolated and enumerated from blood of 25 MBC patients before first-line therapy with an AI. Fourteen patients received a non-steroidal AI (8 letrozole, 6 anastrozole) and 11 patients were treated with exemestane. mRNA expression levels of 96 genes were measured by quantitative RT-PCR as previously described (Sieuwerts et al. Clin Cancer Res. 17:3600-3618, 2011). Expression levels of these genes were studied for their association with time to progression (TTP) after start first-line AI. Results: Median TTP was 338 (range 14–1,239) days. Median baseline CTC count for the 25 patients was 14 (range 0–753). In this relatively small cohort, the clinically relevant cut-off level of ≥5 CTCs in association with TTP did not reach statistical significance (Hazard Ratio [HR] 4.76, 95% Confidence Interval [CI]: 0.59–38.22, P=0.14). For type of AI, when comparing steroidal with non-steroidal AI, the measures in Cox univariate regression analysis were HR 2.54 (95% CI: 0.67–9.64), P=0.17. A 10-gene CTC profile was constructed based on the Wald statistics of the contribution of the individual genes in univariate Cox regression analysis of TTP. To identify patients with good and poor outcome, the Wald corrected sum of the 10 genes was used to dichotomize the continuous 10-gene predictor (HR 12.87 [95% CI: 1.60–103.56], P=0.016). In multivariate analysis, corrected for the clinically relevant variables type of AI and CTC count, only the 10-gene CTC profile was an independent factor associated with TTP (HR 12.46 [95% CI: 1.29-120.08], P=0.029). Conclusions: A 10-gene CTC predictor was constructed which distinguishes good and poor outcome to first-line AI in MBC patients. This profile is currently being validated in an independent group of patients.
Humanized Anti-PR1/HLA-A2 T Cell Receptor-like Monoclonal Antibody, h8F4, Has Multiple Effector Mechanisms
Authors: Anna Sergeeva, Hong He, Kathryn Cox, Lisa St John, Mei Sang, Celine Kerros, Qiaochuan Li, Amanda Herrmann, Karen Clise-Dwyer, Qing Ma, Gregory Lizee, Gheath Alatrash, Jeffrey J. Molldrem
Journal: Blood (2016)
Effect of improving guideline-based prophylactic growth factor (pGCSF) use with chemotherapy (CT) on the risk of febrile neutropenia (FN) in non-small cell lung cancer (NSCLC) patients (pts): A Cleveland Clinic Taussig Cancer Institute (TCI) Quality Improvement (QI) Project.
Authors: Lindsey Martin Goodman, Machelle Moeller, Carole Kathleen Dalby, Abdel Azzouqa, Amy E. Guthrie, Marc A. Earl, Vamsidhar Velcheti, Marc A. Shapiro, Nathan A. Pennell, James Stevenson
Journal: Journal of Clinical Oncology (2015)

6565 Background: Per accepted guidelines, pGCSF is not recommended for pts receiving CT regimens with low risk ( < 10%) for FN. Factors contributing to inappropriate pGCSF use include lack of provider familiarity with national guidelines as well as the presence of standing pGCSF orders in EMR CT templates. Inappropriate use of pGCSF increases pt morbidity and healthcare costs. Methods: A multidisciplinary team performed a QI project through the ASCO Quality Training Program. All NSCLC pts at TCI who initiated a new CT regimen from April 2013 to October 2014 were reviewed. First-cycle pGCSF use was deemed appropriate if prescribed for CT associated with high risk of FN ( > 20%) or intermediate risk (10-20%) if other risk factors for FN were present. Use with low-risk CT was considered inappropriate. We implemented three QI strategies: education of NSCLC providers, development of TCI Consensus Guidelines for the use of pGCSF in NSCLC, and EMR modification: labeling of CT regimens by FN risk and removal of standing pGCSF orders from low-risk CT. Follow up data were collected from January to October 2014. FN rates before and after the QI interventions were documented. Results: 300 NSCLC pts received a new CT regimen during the specified time period. Prior to the interventions, 34/118 pts (29%) treated with low-risk CT received pGCSF (average 2.6 doses/pt). In all other instances pGCSF use was in accordance with guidelines. Following QI interventions, 8/126 (6%) treated with low-risk CT received pGCSF. No patient treated with low-risk CT required inpatient admission for FN during post-intervention follow up. Cost analyses indicate a potential reduction of $1.9 million in charges over 1 year with guideline-based pGCSF usage with low-risk CT. Conclusions: Excessive pGCSF use can be improved with focused provider education and EMR modification. The lack of FN admissions in the post-intervention period validates current guidelines. Appropriate pGCSF administration in NSCLC leads to significant cost savings without increasing neutropenic complications.
Erratum: PoInTree: A polar and interactive phylogenetic tree (Genomics, Protoemics and Bioinformatics 3 (58-60))
Authors: Marco Carreras, Eleonora Gianti, Luca Sartori, Simon Edward Plyte, Antonella Isacchi, Roberta Bosotti
Journal: Genomics Proteomics & Bioinformatics (2005)
Effect of number of prior lines versus prior regimens in pts receiving trifluridine/tipiracil (TAS-102).
Authors: Eric Van Cutsem, Atsushi Ohtsu, Catherine Leger, Nadia Amellal, Camille Poirot, Ronan Fougeray, Robert J. Mayer
Journal: Journal of Clinical Oncology (2017)

720 Background: RECOURSE showed that treatment with trifluridine/tipiracil in patients (pts) with refractory metastatic colorectal cancer was associated with significantly improved overall survival (OS) versus placebo. Pts were classified in this analysis according to number of prior regimens of anticancer therapy, i.e. regardless of treatment duration or occurrence of progressive disease (PD). Classification by prior lines of treatment may provide a better appreciation of prognosis than prior regimens. Methods: We performed a post hoc analysis of the RECOURSE population to explore the effect of number of prior lines of treatment vs prior regimens on OS in metastatic disease. We analysed individual pt data (n = 800) and reclassified pts on the basis of prior lines of treatment (&lt; 3, 3, and &gt; 3). In our analysis, a line of treatment ended with clinical or radiological PD. Adjuvant treatments counted as a line if the pt had had PD within 6 months after the end of treatment. If there was a delay &gt; 6 months between 2 regimens, they could still count as 1 line. Treatments stopped due to toxicity were not considered as a line (since they were not stopped due to PD). Results: When the RECOURSE population was divided by prior lines, there were 170/83 trifluridine-tipiracil/placebo pts receiving &lt; 3 lines of treatment, 174/72 receiving 3 lines, and 190/111 receiving &gt; 3 lines. By contrast, there were 95/45 pts receiving &lt; 3 regimens, 119/54 receiving 3 regimens, and 320/167 receiving &gt; 3 regimens. Conclusions: Clinically, it appears that patients with 1 or 2 prior lines of anticancer therapy (with PD between lines) are different from patients with 1 or 2 prior regimens (which may have been within the same line of treatment). Analyzing the RECOURSE results according to prior lines of treatment provides a more homogeneous classification than prior regimens (smaller CIs) with lower HRs for OS. Clinical trial information: NCT01607957. [Table: see text]
Quality of life (QOL), mood, and prognostic awareness during hospitalization for hematopoietic stem cell transplantation (HSCT).
Authors: Areej El-Jawahri, Lara Traeger, Kailyn Kuzmuk, Justin Eusebio, Emily R. Gallagher, Harry VanDusen, Joseph A. Greer, William F. Pirl, Karen K. Ballen, Thomas R. Spitzer, Steven L McAfee, Vicki A. Jackson, Yi-Bin Albert Chen, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2014)

9642 Background: During HSCT, patients endure significant side effects in the hopes of curing their disease. While many studies have focused on the long-term outcomes of HSCT recipients, the acute impact of hospitalization for HSCT on patients' QOL and mood is unknown. Furthermore, data on patients' perception of their prognosis are lacking. Methods: We conducted a prospective longitudinal study of patients hospitalized at Massachusetts General Hospital for HSCT. At baseline and weeks 1, 2, and 3 of hospitalization, we assessed QOL (Functional Assessment of Cancer Therapy- Bone Marrow Transplantation [FACT-BMT]; higher scores indicate better QOL), fatigue (FACT-Fatigue; high scores indicate less fatigue), and mood (Hospital Anxiety and Depression Scale score > 7 on anxiety or depression subscale considered clinically significant). Using a 10-item questionnaire, we measured patients' information preferences, and perception of their prognosis. Results: We enrolled 60 consecutive patients undergoing autologous (n=30), or myeloablative allogeneic (n=30) HSCT. Patients' QOL declined and fatigued increased throughout hospitalization [Table 1]. The proportion of patients with depression symptoms increased from baseline to week 3 (18.3% to 33.3%, p=0.002) whereas the proportion of patients with anxiety did not change significantly from baseline (22.6%, p=0.7). Although 90.0% of patients stated that it is 'extremely' or 'very' important to know about their prognosis, 86.2% reported inaccurate and overly optimistic perception of their prognosis compared to their physicians (p < 0.0001). Conclusions: Patients undergoing HSCT report an overly optimistic perception of their prognosis and experience significant decline in QOL with increasing rates of depression throughout their hospitalization. Interventions to improve QOL, psychological outcomes, and prognostic awareness of patients hospitalized for HSCT are warranted. Outcome Type HSCT Week-1 Week-2 Week-3 P-Value QOL Auto Allo 105.8 110.0 94.9 97.5 96.3 96.9 < 0.0001 < 0.0001 Fatigue Auto Allo 34.4 38.5 27.0 34.3 27.3 30.9 < 0.0001 = 0.002 Depression Auto Allo 23% 13% 40% 30% 43% 23% = 0.002 = 0.03
Improved Risk Stratification in Pediatric Septic Shock Using Both Protein and mRNA Biomarkers. PERSEVERE-XP
Authors: Hector R. Wong, Natalie Z. Cvijanovich, Nick Anas, Geoffrey L. Allen, Neal J. Thomas, Michael T. Bigham, Scott L. Weiss, Julie C. Fitzgerald, Paul A. Checchia, Keith Meyer, Michael Quasney, Mark Hall, Rainer Gedeit, Robert J. Freishtat, Jeffrey Nowak, Shekhar S. Raj, Shira Gertz, Jocelyn R. Grunwell, Christopher J. Lindsell
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: We previously derived and validated the Pediatric Sepsis Biomarker Risk Model (PERSEVERE) to estimate baseline mortality risk in children with septic shock. The PERSEVERE biomarkers are serum proteins selected from among the proteins directly related to 80 mortality risk assessment genes. The initial approach to selecting the PERSEVERE biomarkers left 68 genes unconsidered.Objectives: To determine if the 68 previously unconsidered genes can improve upon the performance of PERSEVERE and to provide biological information regarding the pathophysiology of septic shock.Methods: We reduced the number of variables by determining the biological linkage of the 68 previously unconsidered genes. The genes identified through variable reduction were combined with the PERSEVERE-based mortality probability to derive a risk stratification model for 28-day mortality using classification and regression tree methodology (n = 307). The derived tree, PERSEVERE-XP, was then tested in a separate cohort (n = 77).Measurements and Main Results: Variable reduction revealed a network consisting of 18 mortality risk assessment genes related to tumor protein 53 (TP53). In the derivation cohort, PERSEVERE-XP had an area under the receiver operating characteristic curve (AUC) of 0.90 (95% confidence interval, 0.85–0.95) for differentiating between survivors and nonsurvivors. In the test cohort, the AUC was 0.96 (95% confidence interval, 0.91–1.0). The AUC of PERSEVERE-XP was superior to that of PERSEVERE.Conclusions: PERSEVERE-XP combines protein and mRNA biomarkers to provide mortality risk stratification with possible clinical utility. PERSEVERE-XP significantly improves on PERSEVERE and suggests a role for TP53-related cellular division, repair, and metabolism in the pathophysiology of septic shock.
Body mass index (BMI), tumor subtype, and relapse-free survival (RFS) in CALGB 9741 (Alliance).
Authors: Jennifer A. Ligibel, Constance Cirrincione, Minetta C. Liu, Marc L. Citron, James N. Ingle, William John Gradishar, Silvana Martino, William M. Sikov, Richard Alan Michaelson, Clifford Hudis, Eric P. Winer, William Thomas Barry
Journal: Journal of Clinical Oncology (2013)

1032 Background: Obesity is a predictor of poor outcomes in women with early-stage breast cancer (BC). Some reports suggest that obesity is associated with aggressive tumor histology. We examined the relationship between BMI at diagnosis and PAM50 subtype, and explored the interaction between BMI and subtype on prognosis in early BC. Methods: CALGB 9741 evaluated dose-density and sequence in node-positive BC. All patients received doxorubicin, cyclophosphamide and paclitaxel dosed by actual body weight without cap or dose adjustment. The primary endpoint was RFS. Height and weight at diagnosis were abstracted from patient records; the PAM50 assay was performed using the Nanostring platform. Association between PAM50 and BMI was assessed by a chi-squared test. The prognostic value of BMI conditional on PAM50 was tested as a continuous variable using Cox models for RFS adjusted for number of involved nodes, tumor size, menopausal status, drug sequence, and dose density. Results: Baseline height and weight were available for 1909 of 2005 enrolled patients; 1272 also had subtype determination by PAM50. Distribution of subtypes differed significantly by BMI (p=0.03), with all weight groups having similar proportions of Basal and HER-2 Enriched subtypes and with obese patients having lower rates of Luminal A (30 vs 35%) and higher rates of Luminal B (39 vs 26%) tumors as compared to normal-weight individuals. In multivariate analyses, BMI and subtype were independent predictors of RFS (p=0.011 and p&lt;0.001, respectively). Exploratory analyses did not show a significant interaction between subtype and the relationship between increased BMI and RFS (p=0.15), although largest differences were seen among Luminal cancers (Table). Conclusions: Biologic subtypes were distributed differently in obese and non-obese individuals. The association between BMI and RFS did not differ significantly by subtype in this study. More work is needed to further explore the interaction of BMI and subtype, especially in a larger cohort of Luminal tumors. [Table: see text]
Effect of restoration of microRNA-18a on improvement of imatinib therapy on secondary imatinib-resistance metastatic melanoma.
Authors: Jun Guo, Yan Kong, Long Liang, Yiqian Li, Xiao Wei Xu, Lu Si, Zhihong Chi, Chuan Liang Cui, Xi Nan Sheng, Jie Dai
Journal: Journal of Clinical Oncology (2014)

9040 Background: Imatinib generated remarkable clinical response in melanomas harboring c-kit mutation. However, melanoma resistance to imatinib develops rather quickly in most of the patients. It has been shown that gene mutations, translocations, deletions, amplifications, and epigenetic changes are involved in the process of secondary imatinib-resistance in GI stromal tumor. But imatinib resistance in melanoma has not been well evaluated. Methods: The level of miRNAs expression was initially discovered through miRNA profiling using pretreatment and post treatment imatinib resistant melanoma tissues, and then confirmed by quantitative PCR. Scratch wound and in vitro invasion assays were performed to evaluate cell migration and invasion. Luciferase reporter assays, immunoblots, and immunohistochemistry analyses were conducted to examine the association between miR-18a and their targets in imatinib-resistant cell and specimens. Results: miR-18a was dramatically down-regulated in secondary imatinib-resistant melanoma tissues. Reintroduction of miR-18a led to imatinib-resistant cells become sensitive to imatinib treatment. Cell cycle and apoptosis analysis indicated that miR-18a overexpression in combination with imatinib treatment resulted in a decrease of cell numbers of S-phase and an increase of apoptotic cells, respectively. Wound healing assay and in vitro invasion assay indicated enforced expression of miR-18a, as well as imatinib treatment dampened the capacity of melanoma cell migration and metastasis. CCND2 and Notch2 were validated as bona fide effectors of miR-18a in melanoma cells. Furthermore, rescued assay was performed to probe the interaction among miR-18a, CCND2/Notch2, and phenotypic alterations, which demonstrated that the sensitivity of imatinib therapy on imatinib-resistant cell line was improved through miR-18a mediated regulation of CCND2/Notch2. Conclusions: Targeting of miR-18a is sufficient to enhance the therapeutic effect of imatinib on melanoma treatment, suggesting that restoration of miR-18a may be a promising strategy for the prevention of melanoma patients from developing secondary resistance.
Biomarker studies in a phase I trial of DKN-01 in advanced esophageal cancer.
Authors: John H. Strickler, Michael Kagey, Cynthia A. Sirard, Gabriel Dan Duda, Jorge Almenara, Celeste N. Powers, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2017)

161 Background: DKK1 is a modulator of Wnt signaling that is frequently overexpressed in tumors and such expression has been associated with worse survival. Preclinical studies have shown that DKK1 can promote tumor growth by increasing angiogenesis and contributing to an immunosuppressive tumor microenvironment. DKN-01 is a humanized IgG4 monoclonal antibody against DKK1 that has shown encouraging efficacy signals in patients (pts) with advanced esophageal (EC) or esophagogastric junction (EGJ) cancer when administered in combination with paclitaxel. Correlative studies are evaluating DKK1 expression and genetics in archived tumor specimens and baseline and on-treatment plasma levels of angiogenesis and inflammation biomarkers as predictors of response. Methods: Formalin fixed paraffin embedded (FFPE) archived tumor tissue was evaluated for DKK1 expression by immunohistochemistry (IHC) and scored for fraction of positive cells, intensity, and localization of DKK1. Genetics were collected if known and/or performed using an Archer VariantPlex Solid Tumor Panel covering 67 genes. Plasma samples, pre- and on DKN-01 treatment were evaluated by multiplexed array for angiogenesis (bFGF, PIGF/PGF, sFLT1/sVEGFR1, sTIE-2/TEK, VEGF, VEGF-C, and VEGF-D) and inflammation (IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70 and IL-13) markers (Meso-Scale Discovery) and by ELISA for HGF and SDF-1α (R&amp;D Systems). Results: ~90% of tissue samples showed DKK1+ expression in tumor cells (range 1 to 100%); intensity (weak 1+ to strong 3+); and localization (cytoplasmic and/or nuclear). Early data has not identified a correlation between DKK1 staining and response. One pt with an ongoing durable response had an activating mutation in β-catenin. Analysis of plasma biomarkers is ongoing. Conclusions: Analysis of DKK1 staining, tumor genetics, and prospective angiogenic/inflammatory biomarkers are ongoing to identify a predictive biomarker for DKN-01. The majority of EC/EGJ tumor biopsies were IHC DKK1+. Broader genomic screens are underway to further characterize DKN-01 sensitivity; mechanistically plausible activating mutations in β-catenin may be a biomarker for DKN-01. Clinical trial information: NCT02013154.
Surgical management of pancreatic cancer at a regional health system.
Authors: Aaron Chevinsky, Federico Augusto Sanchez, James Leighton Weese, Wesley Papenfuss, Ajay Sahajpal, William Deshur
Journal: Journal of Clinical Oncology (2017)

486 Background: 53,070 new PC in the US (2016) are expected with 41,780 deaths. PC care is evolving, multidisciplinary care, neoadjuvant chemotherapy (NCT) and Radiation (RT) and new adjuvant chemotherapy (ACT) regimens (GTX, GAX, FOLFIRINOX) now improve survival. Methods: Reviewed all surgeries for presumed PC to determine how many pts had NCT, ACT and/or RT, determine how many had RO (margin negative) resection, and proportion of &gt;10 lymph nodes (LNs) removed and subsequent pt outcome. Results: PC was dx in 371 pts in 2014-15 (2014-192, 2015-179). During this period 82 pts were explored for proven or suspected PC. 50 (61%) had PC, and 35(70%) had resection with curative intent (30% unresectable or metastatic). Other DX included cancers of the ampulla (5), bile duct (4), or other cancers (7) and benign disease (16). The majority were performed at 1 hospital (84%). 82% of resections were RO, and 74% had &gt;10 LNs removed. 86% of pts referred for surgery received CT, of which 51% received NAC and 52% received RT (37% pre-operatively). 42% of resected PC pts are alive and 24% are without evidence of disease (NED) up to 31 months post-operatively. 50% of pts with an R0 resection are alive (32% NED) as are 46% of those who had &gt;10 LNs removed (31% NED). 45% of those with both an R0 resection and &gt;10 LNs removed are alive (25% NED) 50% of pts with negative LNs (38% NED) compared to 47% of pts who had positive LNs (27% NED). Conclusions: NAC+/- RT is becoming the standard for most pts with operable or borderline resectable PC, allowing early metastatic disease to be recognized, and a higher probability of RO resection. Predictability of resection can be difficult even with sophisticated preoperative imaging. Interdisciplinary cooperation and treatment planning between medical, surgical and radiation oncology is key to improving survival and allowing for a seamless transition between treatment modalities. Negative surgical margins and negative lns provide the best survival. Only through the integration of pre and post-op therapies can we hope to see continued survival improvements.