tbuckley/cabot-search huggingface dataset:
Cancer-type dependent expression of CK2 transcripts.
Authors: Melissa Ming Jie Chua, Migi Lee, Isabel M. Dominguez
Journal: Journal of Clinical Oncology (2018)

e24333 Background: A multitude of proteins are aberrantly expressed in cancer cells, including the oncogenic serine-threonine kinase CK2. It is composed of two genes (CK2α and CK2α’). CK2 can function as a monomeric kinase, or within a tetrameric complex composed of two CK2 kinase subunits (CK2α and/or CK2α’) and two regulatory subunits (CK2β);within this complex, CK2β alters CK2 kinase substrate specificity. An intronless CK2α pseudogene (CK2αP) in humans is also relevant in cancer. CK2 transcript mis-expression in the top six cancers in the USA have been reported to correlate with patient survival. Here, we investigate all other cancers to determine whether they also display significant CK2 transcript dysregulation and if these correlate with patient survival. Methods: Oncomine database was used to analyze transcript level of CK2 genes where clinical specimens of cancer vs. normal patient datasets were compared. The prognostic value of the CK2 genes in gastric cancer was analyzed using Kaplan-Meier Plotter, a database that integrates gene expression and clinical outcomes . Prognostic value of the four CK2 genes in other cancers was analyzed using data downloaded from the web sites of the UCSC Xena and Cell Index. These data repositories contain overall survival and recurrence free survival information from TCGA clinical and phenotypic data. Results: CK2 transcripts are up- or downregulated depending on cancer type. While many cancer types showed the expected upregulation of all CK2 transcripts, others had mixed up- and downregulation of the CK2 genes. Intriguingly, all three CK2 genes and CK2αP were downregulated in testicular cancer, a cancer not widely studied with regards to CK2. Importantly, CK2 expression may play a role as a prognostic marker. We found direct correlations between CK2 transcript deregulation and overall patient survival. In most cancers, higher levels of CK2 gene expression led to lower survival. However, higher levels of CK2α in glioblastoma and higher levels of CK2αP renal clear cell carcinoma led to increased survival. Conclusions: CK2 transcript expression is dysregulated in cancer, depending on cancer type and is correlated with patient survival. Thus CK2 may play a role as a cancer prognostic marker and potentially as a target for therapy.
The INFORM personalized medicine study for high-risk pediatric cancer patients.
Authors: Barbara Christine Worst, Elke Pfaff, Cornelis M. Van Tilburg, Gnana Prakash Balasubramanian, Petra Fiesel, Kristian W. Pajtler, Angelika Freitag, Ruth Witt, Andreas E. Kulozik, Andreas von Deimling, Angelika Eggert, Uta Dirksen, Peter Lichter, David Capper, Stefan M. Pfister, David T. W. Jones, Olaf Witt
Journal: Journal of Clinical Oncology (2017)

10509 Background: Relapses from high-risk tumors pose a major clinical challenge in pediatric oncology. The German INFORM registry (INdividualized therapy FOr Relapsed Malignancies in children) addresses this problem using integrated next-generation sequencing to rapidly identify patient-specific therapeutic targets. Methods: Whole-exome, low-coverage whole-genome and RNA sequencing is complemented with microarray-based DNA methylation profiling. Identified alterations are discussed and prioritized according to biological significance and potential druggability in a weekly molecular tumor board. Results: To date, 214 tumor samples of high-risk pediatric cancer patients have been profiled from 47 German centers, with 39% being sarcomas, 30% brain tumors, 13% neuroblastoma and 18% hematological or other malignancies. Turnaround time from tissue arrival to molecular results was 21 calendar days on average. In 14/214 patients (7%) we identified an underlying germline predisposition syndrome. In several cases there were discrepancies between the original histological diagnosis and our molecular findings, especially in brain tumors. We detected one or more potentially druggable alterations in 147/214 (69%) cases. Tyrosine kinases, the PI3K/mTOR pathway, MAPK pathway, and cell-cycle as well as transcriptional regulators were commonly affected. Based on these findings, targeted therapeutics were incorporated into the therapy regime in one-third of patients, with anecdotal reports of marked responses, including a patient with a pleomorphic sarcoma, where we detected a previously undescribed RAF-fusion, showing a partial remission upon RAF-inhibition. Conclusions: In summary, real-time comprehensive profiling of pediatric tumors provides valuable diagnostic information and identifies potential therapeutic targets. In parallel, the implementation of a systematic program for reverse-translational evaluation is ongoing. Recently, this nationwide effort has expanded to include patients from other countries. We will also recruit patients to the complementary eSMART and INFORM2 biomarker-driven, phase I/II combination trial series, to provide unprecedented access to targeted therapies in Europe.
Multicenter randomized phase 2 trial of paclitaxel, ifosfamide, and cisplatin (TIP) versus bleomycin, etoposide, and cisplatin (BEP) for first-line treatment of patients (pts) with intermediate- or poor-risk germ cell tumors (GCT).
Authors: Darren R. Feldman, James Hu, Sandy Srinivas, Walter Michael Stadler, Brian Addis Costello, Leonard Joseph Appleman, Matthew I. Milowsky, Sujata Patil, Maria Bromberg, Patrick Nolan, Tanya B. Dorff, Victor E. Reuter, Hikmat Al-Ahmadie, Samuel Funt, Dean F. Bajorin, George J. Bosl, David I. Quinn, Robert J. Motzer
Journal: Journal of Clinical Oncology (2018)

4508 Background: A prior single arm phase 2 trial of TIP in intermediate- and poor-risk GCT found superior rates of response, progression-free survival (PFS), and overall survival (OS) compared to historical controls with BEP (JCO 34:21, 2016) leading to this randomized phase 2 study of TIP vs. BEP conducted across 7 centers. Methods: From 7/2013 to 7/2017, pts age ≥18 with untreated, IGCCCG intermediate- (LDH modified to ≥3x upper limit of normal) or poor-risk GCT were randomized to 4 cycles of TIP (paclitaxel 120mg/m2 days 1-2; ifosfamide 1200mg/m2 days 1-5; and cisplatin 20mg/m2 days 1-5) or standard BEP. Prophylactic G-CSF was given to both arms whereas levofloxacin was optional but encouraged for TIP pts. The primary endpoint was the 6-month favorable response rate (CR + PR-negative markers). With alpha of 0.1, a sample size of 88 pts had 80% power to detect a one-sided increase in 6-month favorable response rate from 65% with BEP to 85% with TIP. PFS, OS, and biologic correlates including next generation sequencing (NGS) were secondary endpoints. Results: Of 91 eligible pts (n = 45 TIP, n = 46 BEP), 81 had nonseminoma,10 had seminoma; 37 had intermediate-risk and 54 poor-risk. Primary site was testis in 69, mediastinum in 19, and retroperitoneum in 3. 86 pts (TIP: n = 42; BEP; n = 44) were evaluable for 6-month favorable response with no difference between the two arms overall (76% for TIP vs. 73% for BEP) or among intermediate- (100% vs. 88%) or poor-risk (57% vs. 63%) pts. With median follow-up of 1.71 years, estimated 1-year PFS was 72% for both arms (Table). Toxicity and biologic correlate data including NGS will be presented at the meeting. Conclusions: First-line TIP did not improve but had a similar 6-month favorable response rate as BEP among pts with intermediate- or poor-risk GCT. TIP could represent an alternative to BEP for pts with a contraindication to bleomycin. Clinical trial information: NCT01873326.Characteristics and outcomes for evaluable Pts. TIP (n = 42) BEP (n = 44) IGCCCG Risk, n Intermediate 19 17 Poor 23 27 Response, % CR 45 45 PR-negative markers 31 27 Favorable Response 76 73 IR 24 27 1-year PFS, % (95% CI) 72 (56, 83) 72 (56, 82)
TCT-75 Physiological and Clinical Consequences of Relief of Right Ventricular Volume Overload After Transcathether Repair of the Tricuspid Valve - Insights from cardiac magnetic resonance.
Authors: Philipp Lurz, Karl-Philipp Rommel, Christian Besler, Stephan Blazek, Thilo Noack, Christian Luecke, Joerg Seeburger, Mohamed Abdel-Wahab, Joerg Ender, Michael Borger, Holger Thiele
Journal: Journal of the American College of Cardiology (2018)
A Noninvasive Blood-based Combinatorial Proteomic Biomarker Assay to Detect Breast Cancer in Women over age 50 with BI-RADS 3, 4, or 5 Assessment
Authors: Meredith C. Henderson, Michael Silver, Quynh Tran, Elias E. Letsios, Rao Mulpuri, David E. Reese, Ana P. Lourenco, Joshua LaBaer, Karen S. Anderson, Josie Alpers, Carrie Costantini, Nitin Rohatgi, Haythem Ali, Karen Baker, Donald W. Northfelt, Karthik Ghosh, Stephen R. Grobmyer, Winnie Polen, Judith K. Wolf
Journal: Clinical Cancer Research (2018)

With improvements in breast cancer imaging, there has been a corresponding increase in false-positives and avoidable biopsies. There is a need to better differentiate when a breast biopsy is warranted and determine appropriate follow-up. This study describes the design and clinical performance of a combinatorial proteomic biomarker assay (CPBA), Videssa Breast, in women over age 50 years. A BI-RADS 3, 4, or 5 assessment was required for clinical trial enrollment. Serum was collected prior to breast biopsy and subjects were followed for 6-12 months and clinically relevant outcomes were recorded. Samples were split into training (70%) and validation (30%) cohorts with an approximate 1:4 case:control ratio in both arms. A CPBA that combines biomarker data with patient clinical data was developed using a training cohort (469 women, cancer incidence: 18.5%), resulting in 94% sensitivity and 97% negative predictive value (NPV). Independent validation of the final algorithm in 194 subjects (breast cancer incidence: 19.6%) demonstrated a sensitivity of 95% and a NPV of 97%. When combined with previously published data for women under age 50, Videssa Breast achieves a comprehensive 93% sensitivity and 98% NPV in a population of women ages 25-75. Had Videssa Breast results been incorporated into the clinical workflow, approximately 45% of biopsies might have been avoided. Videssa Breast combines serum biomarkers with clinical patient characteristics to provide clinicians with additional information for patients with indeterminate breast imaging results, potentially reducing false-positive breast biopsies.
TCT-595 Ultra-Low Contrast Percutaneous Coronary Intervention to Minimize the Risk for Contrast-Induced Acute Kidney Injury in Patients with Severe Chronic Kidney Disease
Authors: Lorenzo Azzalini, Alessandra Laricchia, Damiano Regazzoli, Barbara Bellini, Daisuke Hachinohe, Satoru Mitomo, Ozan Demir, Enrico Poletti, Davide Maccagni, Antonio Colombo
Journal: Journal of the American College of Cardiology (2018)
End-of-Life Care Intensity in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation: A Population-Level Analysis
Authors: Emily E. Johnston, Lori Muffly, Elysia Alvarez, Olga Saynina, Lee M. Sanders, Smita Bhatia, Lisa J. Chamberlain
Journal: Journal of Clinical Oncology (2018)

Intensity of end-of-life care receives much attention in oncology because of concerns that high-intensity care is inconsistent with patient goals, leads to worse caregiver outcomes, and is expensive. Little is known about such care in those undergoing allogeneic hematopoietic cell transplantation (HCT), a population at high risk for morbidity and mortality.We conducted a population-based analysis of patients who died between 2000 and 2013, within 1 year of undergoing an inpatient allogeneic HCT using California administrative data. Previously validated markers of intensity were examined and included: hospital death, intensive care unit (ICU) admission, and procedures such as intubation and cardiopulmonary resuscitation at end of life. Multivariable logistic regression models determined clinical and sociodemographic factors associated with: hospital death, a medically intense intervention (ICU admission, cardiopulmonary resuscitation, hemodialysis, intubation), and ≥ two intensity markers.Of the 2,135 patients in the study population, 377 were pediatric patients (age ≤ 21 years), 461 were young adults (age 22 to 39 years), and 1,297 were adults (age ≥ 40 years). The most common intensity markers were: hospital death (83%), ICU admission (49%), and intubation (45%). Medical intensity varied according to age, underlying diagnosis, and presence of comorbidities at time of HCT. Patients with higher-intensity end-of-life care included patients age 15 to 21 years and 30 to 59 years, patients with acute lymphoblastic leukemia, and those with comorbidities at time of HCT.Patients dying within 1 year of inpatient allogeneic HCT are receiving medically intense end-of-life care with variations related to age, underlying diagnosis, and presence of comorbidities at time of HCT. Future studies need to determine if these patterns are consistent with patient and family goals.
Results of real-time cell-of-origin subtype identification by gene expression profiling in patients with ABC-type diffuse large B-cell lymphoma in the phase III trial of lenalidomide plus R-CHOP vs placebo plus R-CHOP (ROBUST).
Authors: Grzegorz S. Nowakowski, Annalisa Chiappella, Thomas E. Witzig, David W. Scott, Michele Spina, Randy D. Gascoyne, Lei Zhang, Jacqueline Russo, Janet Kang, Jingshan Zhang, Yingyong Xu, Umberto Vitolo
Journal: Journal of Clinical Oncology (2018)

7548 Background: Gene expression profiling (GEP) is the gold standard in identification of activated B-cell-like (ABC) DLBCL, a subtype associated with inferior outcomes. The combination of lenalidomide + R-CHOP (R2-CHOP) provided efficacy based on cell-of-origin (COO) in phase II DLBCL studies. ROBUST is a global, randomized, double blind, phase III study comparing R2-CHOP vs placebo + R-CHOP in patients with previously untreated ABC-type CD20+ DLBCL (NCT02285062). Methods: ROBUST methods were previously described (Nowakowski, Fut Oncol 2016). Formalin-fixed paraffin-embedded excisional/surgical or core needle biopsy samples were analyzed by central pathology using the NanoString Lymphoma Subtyping Test (LST), based on the Lymph2Cx GEP assay (Scott, Blood 2014). Turnaround time was defined as number of days between central pathology sample receipt and results being provided to the study site. Results: From January 21, 2015 to August 3, 2017, 2093 patients were screened and 570 were enrolled in ROBUST. Three central pathology labs in China, USA and the UK received 2110 samples. Of 1798 successfully tested samples, COO was 788 (44%) ABC and 1010 (56%) non-ABC; 312 (15%) samples were non-processable for technical reasons (incorrect/insufficient slides or blocks, or low tissue RNA concentration and/or purity). According to geographic region of origin, the ABC-type DLBCL rate among successfully tested samples was 60% (241/404) from China/Japan/SK/Taiwan; 40% (441/1105) from Russia/Europe/Middle East; and 37% (106/289) from North America/Australia/New Zealand. Mean turnaround time was 2.4 days. Conclusions: Real-time COO assessment was feasible from multiple regions globally with a short turnaround time in the phase III ROBUST study, which minimizes the delay in receiving treatment. The percent of ABC-type DLBCL was similar to other reported studies of subtype analysis in the literature. Our findings impact the design and size estimation of future studies in newly diagnosed DLBCL utilizing COO as a biomarker, which provides a significant advance in precision medicine in DLBCL. Clinical trial information: NCT02285062.
Complex carbohydrates as a predictive marker in metastatic colorectal cancer (mCRC) cancer patients treated with a vascular endothelial growth factor (VEGF) inhibitor and chemotherapy.
Authors: Petra Martin, David William Fennelly, Pauline Rudd, Diarmuid O'Donoghue, Kieran Sheahan, Blathnaid Nolan, Jacintha O'Sullivan, Henning Stockmann
Journal: Journal of Clinical Oncology (2017)

e15134 Background: Aberrant expression of complex carbohydrates, known as glycans, is emerging as a key driver in oncopathology. Elevated levels of sialic acid sugars affect tumor growth, escape from apoptosis, metastasis formation, and resistance to therapy. Changes in sialylation can be associated with malignant transformation and with progression and poor prognosis of carcinomas, which can be explained by the recognition of malignant cells by selectins, causing interactions of tumor cells with platelets, leukocytes and endothelium facilitating metastasis. Secreted or proteolytically released carcinoma mucins bearing unusual forms of sialylation can be detected in the bloodstream and are used as diagnostic and prognostic aids. Bevacizumab directly binds VEGF (a glycoprotein) to inhibit angiogenesis. The aim of this study was to analyze the pool of asparagine-linked complex carbohydrates (i.e. the N-glycome), of whole serum to identify sugars that are associated with survival in mCRC patients treated with a VEGF and chemotherapy. Methods: We used our recently developed high-throughput automated platform to precisely measure the levels of complex serum carbohydrates in patients (n = 68) with metastatic colorectal cancer samples of patients who went on to receive bevacizumab and chemotherapy. Survival analysis was performed using the R package ‘survival’. Results: We observed several sialic-acid bearing glycans that correlated with overall survival and progression free survival. A complex tetra-antennary, highly sialylated glycan, known as A4G4S4, correlated with reduced overall survival probability (p = 0.0007, hazard ratio = 1.86). High levels of a sialylated tri-antennary glycan, called A3G3S3 demonstrated significantly reduced progression-free survival (p = 0.002). Conclusions: We believe that sialylated glycans could be excellent predictive markers of response to therapy and warrant further evaluation in clinical trials. Tri and tetra-antennary sialyated glycoproteins were associated with poorer survival in our patient cohort, suggesting that glycans could be key drivers of pathobiology.
Impact of early landmark responses with ponatinib on 4-yr outcomes in CP-CML patients (pts) in PACE, a pivotal phase II trial.
Authors: Martin Mueller, Michele Baccarani, Michael W.N. Deininger, Francois Guilhot, Andreas Hochhaus, Timothy P. Hughes, Neil P. Shah, Moshe Talpaz, Stephanie Lustgarten, Sergio Santillana, Victor M Rivera, Timothy Piers Clackson, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2017)

7050 Background: Ponatinib is approved for pts with refractory CML or Ph+ ALL for whom no other TKI therapy is indicated, or for patients with T315I. Previously (Mueller ASCO ‘16), we reported the positive association of early landmark responses with ponatinib on survival at 3 yrs in heavily pretreated pts with CP-CML in PACE (NCT01207440). Here, we provide an update with survival outcomes at 4 yrs. Methods: The association of molecular (assessed in a central lab) and cytogenetic responses (CyR) at 3, 6 and 12 mo with 4-yr post-landmark PFS and OS was evaluated in CP-CML pts (n = 267). P values: calculated using log-rank test. Data cutoff: 3 Oct ‘16. Results: At baseline, median time from diagnosis: 7 (range, 0.5–27) yrs; median age: 60 (18–94) yrs; median %Ph+: 100% (3–100), ≤10% Ph+: 19 pts (7%); 61% of pts had ≥3 prior TKIs. Among evaluable pts at 3, 6 and 12 mo, MCyR/CCyR was achieved in 48%/39%, 62%/52% and 71%/56% and MMR in 14%, 29% and 39% of pts, respectively. Greater reductions in BCR-ABL1 levels (Table) and CyR at most landmark time points were associated with improved 4-yr post-landmark PFS and OS. Deeper responses at all landmark time points were associated with achievement of MR 4.5 over time. Conclusions: As with the 3-yr landmark analysis, CyR and deep reductions in BCR-ABL1 transcripts at early time points correlated with improved 4-yr post-landmark survival in this refractory population. These data continue to demonstrate the prognostic value of early cytogenetic and molecular responses with ponatinib in heavily pretreated pts with CP-CML. Clinical trial information: NCT01207440. [Table: see text]
TCT-245 A Significant Reduction in the Frequency of Substantial-Dose Interventional Coronary Procedures from 2007 to 2017
Authors: S. Balter, Sarah Myoung, Darshan Doshi, Dimitrios Karmpaliotis, Ajay Jayant Kirtane, Manish Parikh, Yonina Grossberg, Ming Liao, Jeffrey W. Moses
Journal: Journal of the American College of Cardiology (2018)
Genetic counseling (GC) and germline (GL) testing rates after adoption of an integrated clinical cancer genetics (CCG) approach to genomics tumor board (GTB).
Authors: Stefan Klek, Brandie Heald, Alex Milinovich, Ying Ni, Jame Abraham, Petros Grivas, Haider Mahdi, Alok A. Khorana, Brian James Bolwell, Davendra Sohal, Pauline Funchain
Journal: Journal of Clinical Oncology (2018)

1511 Background: The clinical impact of addressing potentially GL alterations (PGA) from somatic next-generation sequencing (NGS) is not well characterized. We hypothesize that the addition of screening for PGA by genetics professionals at GTB increases GL findings in those who underwent NGS. Methods: In a prospectively accrued cohort with tumor NGS via FoundationOne (F1), we quantified (1) patients with ≥1 GC visit, (2) whether GC occurred pre- or post-F1 testing, (3) GC referrals due to F1 reports, (4) which had GL testing, and (5) results of GL testing. We analyzed these variables across 4 sub-cohorts: patients whose F1 reports were presented at GTB (C1) before and (C2) after the addition of screening for PGA by genetics professionals at GTB. C2 was further subdivided: (C2A) after the addition of GL screening at GTB and (C2B) after the addition of GL screening at GTB plus a formal CCG workflow to coordinate post-GTB GC. P-values were determined using a 2-sample, one-tailed z-test. Results: 907 F1 reports were reviewed at GTB from 2013 to 2017 (nC1 = 281, nC2 = 626, nC2A = 493, and nC2B = 133). Overall, the number of GC visits showed an increasing trend from C1 to C2A (14.6 to 19.9%, P = .066) with significance from C1 to C2B (14.6 to 33.1%, P = .0012). Incidence of GC visits post-F1 rose from C1 to C2 (7.3 to 41.6%, P < .0001) with visits specifically due to F1 increasing from C1 to C2A (7.3 to 32.7%, P < 0.0001) and even more from C1 to C2B (7.3 to 40.9%, P < 0.0001). Incidence of GL testing showed an increasing trend from C1 to C2A (11.0 to 14.4%, P = 0.091) with significance from C1 to C2B (11.0 to 27.8%, P < 0.0001). Finally, the number of pts found positive for GL mutation showed an increasing trend from C1 to C2A (1.4% to 2.2%, P = .22) with significance from C1 to C2B (1.4% to 6.0%, P = .0046). Conclusions: Integrating CCG with somatic NGS testing review significantly increased not only GC utilization but also the discovery of positive GL results. Although this approach should not substitute for documentation of a detailed family history, positive GL findings can be a direct consequence of somatic NGS and should be considered an independent clinical benefit of somatic NGS testing apart from therapeutic uses.