tbuckley/cabot-search huggingface dataset:
A methylated DNA marker panel for the sensitive detection of lung cancer in tissue.
Authors: Maria Giakoumopoulos, Tamara Sander, Carla Volkmann, Austin Oliphant, Evan Flietner, Brian Aizenstein, Drew Eckmayer, Abram Vaccaro, Vipul Rathore, Jennifer Carlson, Barry M. Berger, Tracy C. Yab, William R Taylor, Thomas C. Smyrk, Eric Edell, Douglas W. Mahoney, John B. Kisiel, David A. Ahlquist, Graham P. Lidgard, Hatim T. Allawi
Journal: Journal of Clinical Oncology (2016)

8527 Background: Lung cancer remains the #1 cancer killer in the US, and effective screening approaches are desperately needed. Lung cancer alone accounts for 221,000 deaths annually. DNA methylation profiling has shown unique patterns in DNA promoter regions with cancer and has potential application for detection of lung malignancies. However, optimally discriminant markers and marker panels are needed. The purpose of this study is to identify and validate in tissue, candidate methylated DNA markers for detecting lung cancer overall and by subtypes. Methods: Candidate methylated DNA markers were identified by unbiased whole methylome sequencing of selected lung cancer case and lung control tissues. The top 51 marker candidates were further evaluated in 255 independent patients with 119 controls, of which 37 were from benign nodules, and 136 cases inclusive of all lung cancer subtypes. DNA extracted from patient tissue samples was bisulfite treated and then candidate markers and ACTB as a normalizing gene were assayed by Quantitative Allele-Specific Real-time Target and Signal amplification (QuARTS). QuARTS chemistry requires perfect base pairing to minimize false signals due to un-methylated or partially methylated genes and yields high discrimination for methylated marker selection and screening. Results: On receiver operator characteristics analyses of individual marker candidates, areas under the curve (AUCs) ranged from 0.512 to 0.941. At 100% specificity, a combined panel of 8 methylation markers (SLC12A8, KLHDC7B, PARP15, OPLAH, BCL2L11, MAX.12.526, HOXB2, and EMX1) yielded a sensitivity of 98.5% across all subtypes of lung cancer. Furthermore, using the 8 markers panel, benign lung nodules yielded no false positives. Conclusions: A panel of novel methylated DNA markers assayed on tissue achieves extremely high discrimination for all types of lung cancer while remaining negative in normal lung tissue and benign nodules. Following technical optimization, this panel can be applied to blood or bodily fluid-based testing with applications in lung cancer screening and discrimination of malignant from benign nodules.
Novel platform for monitoring bladder cancer recurrence using expression analysis of small non-coding RNAs.
Authors: Ilija Aleksic, Winnie Wang, Tucker Conklin, Igor Sorokin, Hugh A.G. Fisher, Ronald P. Kaufman, Badar Mian, Barry Kogan, Brian McNeil, Andrew Winer, Raavi Gupta, A. Gregory DiRienzo, Martin Tenniswood
Journal: Journal of Clinical Oncology (2018)

12070 Background: Bladder cancer patients are routinely monitored after treatment by cystoscopy due to a high rate of recurrence. In the absence of an accurate non-invasive screening test to monitor recurrence, bladder cancer will remain the most expensive malignancy to manage. We have developed a non-invasive test that interrogates small non-coding RNAs (sncRNAs) present in urinary exosomes. Analyzing the urine exosome data with a novel statistical classification algorithm provides a platform that unequivocally differentiates between patients with no evidence of disease and those with recurrence. Methods: Urine samples were collected from patients previously treated for bladder cancer (n = 82) who are currently under routine surveillance cystoscopy. Patients without bladder cancer or without evidence of recurrent disease served as the control cohort. A Sentinel sncRNA signature specific for bladder cancer was generated by interrogation of urine exosomal RNAs on Affymetrix 4.0 arrays that probes for > 6600 sncRNAs. A customized platform to interrogate the most informative (~120) Sentinel sncRNAs, was then used to screen urine exosomal RNA derived from patients at risk for recurrent disease. Data were then analyzed using a statistical classification algorithm that provides the miR-BCPx (bladder cancer progression score). This novel analytical approach requires no a priori knowledge of the sncRNA function to generate an unbiased classification into those with stable disease versus those with recurrent tumor. Results: Bladder cancer patients have significantly elevated levels of exosomal RNA relative to control cohort. In a small blinded testing male cohort, comparison of the miR-BCPx score generated to the disease status demonstrates that the miR-BCPx identifies patients with recurrent tumor with 100% sensitivity (59/59) and 96% specificity (22/23). Conclusions: Implementation of the miR-BCPx as a surveillance screen for bladder cancer patients provides an affordable, non-invasive alternative to cystoscopy for monitoring disease stability, and can readily be deployed in the clinic to reduce the number of screening cystoscopies needed.
Prognostic ability of miR-744 expression in non-small cell lung cancer (NSCLC).
Authors: Xiaoxia Zhu, Na Li, Dianhe Li, Yiyi Li
Journal: Journal of Clinical Oncology (2016)

e20539 Background: MiR-744, previously-shown to be dysregulated in the serum or specimens of several cancers, haven’t been described in NSCLC on its expression pattern and potential clinic implications. Methods: MiR-744 expression was quantified by in situ hybridization (ISH) on 87 formalin-fixed paraffin-embedded (FFPE) NSCLC tissues (training set), or by using RNA sequencing data related to 456 primary NSCLC from The Cancer Genome Atlas (TCGA) (validation set). Associations between clinicopathological factors and survival outcome were analyzed by cox proportional hazards models. We further evaluated the associations of prognostic effects of miR-744 and clinicopathological factors by stratified analyses basing on the TCGA data. Results: Analysis of the training set identified that higher expression of miR-744 was tended to be more frequently presented in squamous cell carcinoma (SCC) (p = 0.064), this association was confirmed in validation set (p = 0.007). Survival analyses revealed that patients with higher levels of miR-744 showed shorter overall survival (OS) (traning set: p = 0.005; validation set: p = 0.002). The multivariate Cox regression analyses in two cohorts both revealed that higher expression of miR-744 is an independent unfavorable prognostic marker for OS (traning set: HR 2.294 [1.063-4.949], p = 0.034; validation set: HR 2.093 [1.386-3.160], p = 0.000). In addition to miR-744, only disease stage (traning set: HR 5.491, [2.771-10.881], P = 0.000; validation set: HR 1.320 [1.013-1.720], p = 0.039) retained an independent prognostic association with OS in both cohorts. Subgroup analysis in validation set also showed that higher expression of miR-744 was especially associated with worse OS among male group (median 38.5 vs 88.0 months, p = 0.001), over-60 age group (median 38.5 vs 71.1 months, p = 0.000), SCC group (median 35.6 vs 64.4 months, p = 0.001), T1/T2 group (median 41.9 vs 72.34 months, p = 0.005), and N0/N1 group (median 44.9 vs 66.4 months, p = 0.009). Conclusions: Our results suggest that miR-744 is a prognostic NSCLC marker and that its high level of expression in a large proportion in SCC of lung holds promise that targeted therapy directly against miR-744 may be effective for the treatment of SCC of lung.
Modified IPCW model: A method for adjusting for bias in the estimation of overall survival due to the use of second and third line therapies in locally advanced or metastatic pancreatic cancer patients.
Authors: N. E. Iznaga Escobar, Patricia Lorenzo Luaces, Lizet Sanchez Valdes, Carmen Valenzuela Silva, Tania Crombet Ramos, Dirk Strumberg, Beate Schultheis, Matthias Philip Ebert, Andrea Kerkhoff, Ralf Hofheinz, Dirk M. Behringer, Wolfgang E Schmidt, Erdem Goker, Sara De Dosso, Michael Kneba, Suayib Yalcin, Friedrich Overkamp, Frank Schlegel, Markus Dommach, Robert Rohrberg
Journal: Journal of Clinical Oncology (2017)

e15787 Background: Nimotuzumab, a unique and affinity differentiated anti-EGFR antibody had been used in combination with gemcitabine on the treatment of pancreatic cancer patients. The aim of the study was to evaluate overall survival. Methods: Patients with newly diagnosed, locally advanced or metastatic pancreatic cancer, KPS ≥ 70 %, 18-72 years old, with adequate renal and liver function were included. Pts received gemcitabine 1000 mg/m 2 and nimotuzumab or placebo fixed dose of 400 mg once a wk, for 3 wks, followed by a 1-wk rest (d1, 8, 15, q28) until disease progression or unacceptable toxicity. The primary endpoint was OS and secondary PFS, ORR, CBR, safety and QoL. For OS determination, a KM log-rank test was used and a modified IPCW with a cox regression as a secondary analysis. On this evaluation using a modified IPCW model, 41.7% of pts from treatment arm and 42.7% from control arm who received 2nd and 3rd line treatment were censored after progression, while pts that did not receive 2nd and 3rd line treatment were weighted to compensate for the bias created by censoring switchers to 2nd and 3rd line treatment. Results: 192 pancreatic cancer pts were recruited. Ninety-six pts (62 male and 34 female) with a median age of 67 years, range (31, 83) were randomized to treatment arm and 96 pts (57 male and 39 female) with a median age of 64 years, range (41, 82) were randomized to control arm. In the primary analysis, median OS [95% CI] in the treatment arm was 8.57 mo [5.93, 10.90] vs 6.03 mo [4.97, 7.60] in the control arm. The HR [95% CI], 0.83 [0.62, 1.12] and p = 0.23 and when a modified IPCW model as a secondary analysis was used to remove the effect of 2nd and 3rd line therapies, the median OS was statistically significant with a HR [95% CI], 0.81 [0.67, 0.98] and a p = 0.030. The median PFS [95% CI] was 4.43 mo [3.67, 6.00] in the treatment arm vs 3.47 mo [2.60, 4.03] in the control arm with a HR [95% CI] 0.68 [0.51, 0.92] and p = 0.012. Conclusions: A modified IPCW model had proven that addition of nimotuzumab to gemcitabine increases median overall survival of newly diagnosed chemotherapy-naïve locally advanced or metastatic pancreatic cancer patients. Clinical trial information: NCT00561990.
Customized or randomized trials for relapsed refractory pediatric Burkitt lymphomas? A retrospective analysis of two clinical cases with comprehensive molecular profiling: Possible explanation for different treatment outcomes after similar targeted therapies
Authors: K. Polaskova, A. Martincekova, Z. Krenova, D. Valik, H. Noskova, O. Slaby, V. Kanderova, O. Hrusak, G.L. Klement, J. Neradil, R. Veselska, J. Sterba
Journal: Annals of Oncology (2018)

Background: Current standard chemoimmunotherapy achieves survival in almost 95% children with mature B-NHL. However, children with relapses still carry very poor prognosis. Methods: Molecular profiling consisted of whole exome NGS, gene expression profiling and peripheral blood phosphoflow. Results: Both cases had identical clinical presentation and histology, progressed early during standard therapy and did not respond to intensive retrieval chemotherapy. In the first patient, a germ line variant of c.935C>G in the PI3K-delta subunit was found. Activation of PI3K downstream signaling pathway was detected using flow cytometry in patient´s peripheral blood lymphocytes. Increased levels of PI3K were confirmed also by gene expression profiling together with an increased expression of HR23B. Immunohistochemistry revealed strong expression of PD-1L. Therapy was changed to a single agent idelalisib window. In two weeks there was markedly decreased PI3K pathway activation in patient's lymphocytes, but the disease still showed a radiological progression. During the time, ibrutinib, valproic acid, nivolumab and metronomic cyclophosphamide was added and local 21Gy radiation to the site of the abdominal relapse was used. Partial remission was documented and personalized immunotherapy with autologous dendritic cell-based vaccine was given. Residual tumor resected after 11 months did not show any viable tumor and treatment was gradually tapered down. His 3rd EFS 31 months on personalized treatment is the longest he ever experienced. The second patient died 11 months form diagnosis. Conclusions: The first case was successfully treated with targeted and immune therapy that matched the molecular signature of the tumor, but in the second case, the therapy "missed" the target, because his molecular signature was not known at the time retrieval therapy. The findings suggest that molecular signatures among clinically and histologically similar patients could be unique, and a tissue biomarker-based customized therapy may be the best approach to address these poor prognosis patients. Legal entity responsible for the study: Department of Pediatric Oncology, University Hospital, Brno. Funding: AZV MZCR - 16-33209A, 16-34083A Masaryk University, Brno, Czech Republic - MUNI/A/1136/2017. Disclosure: All authors have declared no conflicts of interest.
Sensitization of glioblastoma to alkylating chemotherapy by ultrasound-mediated delivery of therapeutic liposomes.
Authors: Patrick Roth, Alexandros Papachristodoulou, Davide Brambilla, Rea Deborah Signorell, Beat Werner, Ernst Martin, Michael Weller, Jean-Christophe Leroux
Journal: Journal of Clinical Oncology (2018)

e14061 Background: Treatment options for patients with newly diagnosed glioblastoma comprise surgical resection, radiochemotherapy and maintencance chemotherapy with the alkylating agent, temozolomide. However, the median overall survival is only approximately 16 months. Importantly, the survival benefit derived from the addition of temozolomide is almost exclusively restricted to the rather small subgroup of patients with tumors harboring a methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter. Inhibition of MGMT activity to sensitize gliomas to temozolomide has been considered a promising therapeutic strategy but the clinical development of this approach was largely unsuccessful because of systemic toxicity. Methods: We synthesized several novel O6-(4-bromothenyl)guanine (O6BTG) derivatives and assessed them for their ability to reduce MGMT expression. Magnetic resonance image (MRI)-guided microbubble-enhanced low-intensity pulsed focused ultrasound (LIFU) was applied to transiently open the blood brain barrier in mice bearing MGMT-expressing experimental gliomas. We identified a promising MGMT inactivator that was encapsulated in liposomes and subsequently evaluated in various in vitro and in vivo models. Results: The newly generated O6BTG derivative efficiently targeted MGMT, thereby sensitizing murine and human glioma cells to temozolomide in vitro. LIFU mediated the delivery of this long-circulating liposomal MGMT inactivator in the tumor region resulting in potent MGMT depletion in vivo. Treatment with the liposomal MGMT inactivator facilitated by focal LIFU-mediated blood-brain barrier opening reduced tumor growth and significantly prolonged survival of glioma-bearing mice, when combined with temozolomide chemotherapy. Conclusions: These data demonstrate that MRI-guided LIFU allows for transient and circumscribed BBB opening in the tumor region which can be used for targeted MGMT downregulation. Overcoming MGMT-mediated alkylator resistance sensitizes gliomas in vivo to temozolomide, ultimately resulting in a survival benefit. Based on these data, a clinical assessment of this approach in human patients is warranted.
TCT-166 Predictors of Target Lesion Revascularization After Implantation of Second-Generation Drug-Eluting Stents in Randomized Trials and the “Real-World”: Analysis From Two Large Datasets
Authors: Behnood Bikdeli, Ajay Jayant Kirtane, Shmuel Chen, Martin Leon, Patrick Serruys, Pieter Smits, Clemens von Birgelen, Bernhard Witzenbichler, Giora Weisz, Michael Rinaldi, Ori Ben-Yehuda, Yangbo Liu, Bjorn Redfors, Thomas McAndrew, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
Efficacy and safety of the CDK4/6 inhibitor palbociclib during different lines of treatment in patients with advanced stage endocrine sensitive/HER2 negative breast cancer.
Authors: Jean-Philippe Zurcher, Veronica Aedo, Athina Stravodimou, Apostolos Sarivalasis, Khalil Zaman
Journal: Journal of Clinical Oncology (2018)

e13052 Background: Following the pivotal phase III randomized trials, benefit of the combination of CDK4/6 inhibitors-endocrine therapy (ET) is currently well known in early lines of treatment in advanced stage endocrine sensitive/HER2 negative breast cancer (ABC). Less data are available about the efficacy and safety in later lines. We are presenting real-life data from a single center. Methods: we retrospectively collected data of all our patients, who received at least one dose of a combination of palbociclib and ET. Palbociclib was obtained via an early access program until its registration in Switzerland. Results: From January 2016 to February 2018, 39 patients were identified. Median age was 67 (range 45-93). Visceral disease was present in 54% of patients. Patients received a median of 3.2 previous lines of systemic therapy (range 0-9) before starting palbociclib. The associated ET regimen were: fulvestrant (66.7%), letrozole (15.4%), exemestane (7.7%), tamoxifen (7.7%) and anastrozole (2.5%). 56% of the patients were pre-treated with chemotherapy and 28% with everolimus-ET. At the time of the data cutoff, 26 patients (66.7%) were still on treatment with palbociclib-ET. The median progression free survival (PFS) was not reached after a median follow up of 11.2 months. PFS seems altered by previous administration of chemotherapy or everolimus, but not by age younger/older than 75. The most common adverse event (AE) was neutropenia (96%). Grade 2 and 3 infections occurred in 4 and 3 patients, respectively. Deep venous thrombosis occurred in 4 patients on treatment (10.2 %). Definitive treatment interruption for AE occurred in one patient. At least one dose reduction was necessary in 41% of patients (2 dose reductions in 23%). Median time to the first dose modification was 3.4 months, and for second dose modification 2.8 months. Conclusions: Our data support a clinically meaningful benefit of the combination palbociclib-ET in patients older and more heavily pre-treated than in the pivotal trials. AEs were in line with the known safety profile of palbociclib and were effectively manageable with dose reductions.
Incidence, features and management of radionecrosis (RN) in melanoma patients (pts) treated with cerebral radiotherapy (RT) and anti-PD-1 antibodies (PD1).
Authors: Ines Esteves Domingues Pires Da Silva, Romany Anne Nilanthi Johnpulle, Patricia Diana Banks, G. Daniel Grass, Jess Louise Smith, Ashlyn S. Everett, Simone M. Goldinger, Rachel Roberts-Thomson, Michael Millward, Isabella Claudia Glitza, Lauren Elaine Haydu, Victoria Atkinson, Tim Wang, Zeynep Eroglu, Robert Martin Conry, Mark J. Shackleton, Angela Hong, Georgina V. Long, Douglas Buckner Johnson, Alexander M. Menzies
Journal: Journal of Clinical Oncology (2017)

9513 Background: Melanoma brain metastases confer poor prognosis, with various treatments used including RT and PD1. While RT and PD1 may have a synergistic effect to improve efficacy, RN may complicate RT, and whether PD1 potentiates this is unknown. We examined the incidence and features of RN and other neurotoxicities in melanoma pts treated with PD1 and whole brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS). Methods: Pts treated with PD1 who received WBRT/SRS during or within 1 year (y) of PD1 who survived &gt; 1y were examined for short and long term neurotoxicity. 2 cohorts were included: (A) consecutive pts fulfilling eligibility criteria from 8 melanoma centers, (B) additional cases of RN from 3 centers. Pt demographics, disease features, treatment details, neurotoxicity, and outcome data were collected. Results: Cohort A included 118 pts, with median follow-up of 24.3 months (mo). Median age was 56yo, 51% had mutant BRAF, 41% elevated LDH and 65% were ECOG 1-2 at PD1 start. 58% had prior ipilimumab and 43% prior MAPK inhibitors. 85% were treated with pembrolizumab, 10% nivolumab and 5% combination ipilimumab/nivolumab. Most pts (82, 69%) had SRS, 22 (19%) had WBRT alone and 14 pts (12%) had both. Median PFS was 24mo and OS was 45.8mo. 21 pts (18%) developed RN, (14/82) 17% after SRS, (2/22) 9% after WBRT and (5/14) 36% after both. With 13 further cases from cohort B (total 34), all had radiological signs on MRI, 78% had neurological symptoms and 56% had pathological confirmation of RN. Median time to symptom onset and to first radiological sign was 9.8mo and 10.8mo, respectively. 52% were treated with steroids and 30% had bevacizumab, with clinical improvement in 64% and 100%, respectively. Updated analysis including clinical variables associated with RN development will be presented, including RT dose and schedule. Conclusions: RN is a significant toxicity in melanoma pts with brain metastases treated with RT and PD1, particularly in long term survivors. Further research to identify those at risk of RN, those who do not require RT, and studies exploring RT and PD1 schedules are required.
Role in carcinogenesis and clinical significance of Merkel cell polyomavirus in non-small cell lung cancer.
Authors: Deok Heon Lee, Jae-Ho Lee, Gun-Jik Kim
Journal: Journal of Clinical Oncology (2016)

e20034 Background: Recently, an association of Merkel cell polyomavirus (MCPyV) with epidermal growth factor receptor (EGFR) mutation rate and tumorigenesis in non-small cell lung cancer (NSCLC) has been suggested. However, the underlying carcinogenic effects and the prognosis related to MCPyV are still elusive. The aim of the present study was to clarify the incidence and prognosis related to MCPyV infection in NSCLC. Methods: A total 167 patients with NSCLC including 92 with squamous cell carcinomas (SCC) and 75 with adenocarcinomas were enrolled in this study. We analyzed the presence of MCPyV and EGFR mutation by using a polymerase chain reaction and direct sequencing, respectively. The clinicopathological characteristics, recurrence-free survival rate, and overall survival rate were also analyzed for each parameter in accordance with the presence of MCPyV. Results: There were 124 men (74.3%) with a mean age of 64.7 ± 8.1 years. The mean follow-up period was 34.8 ± 22.3 months. MCPyV DNA was detected in 30 of the 167 patients (18.0%), and EGFR mutation was found in 31. EGFR mutations were more frequently detected in the MCPyV-positive patients; however, this did not reach statistical significance (p = 0.075). Fifty-six patents had recurrent disease, and 47 died after surgery, during the follow-up period. There was no statistically significant difference in the overall survival rate due to any of the parameters between those with and without MCPyV. The recurrence-free survival rate of patients with MCPyV was statistically significantly lower than that of patients without MCPyV in the pN0 stage group (p = 0.036), SCC group (p = 0.042) and positive EGFR mutation group (p= 0.050). Conclusions: To our knowledge, this is the first study to report a relationship between MCPyV infection and cancer prognosis in subgroups of NSCLC. Although the prevalence of MCPyV infection was relatively low, the presence of MCPyV DNA was significantly correlated with cancer prognosis in subgroups of NSCLC. These results suggest that MCPyV may be partly associated with pathogenesis in some cases of NSCLC.