tbuckley/cabot-search huggingface dataset:
Competing risks analysis of microsatellite instability as a prognostic factor in colorectal cancer
Authors: K. Spring, J. Toh, P. Chapuis, L. Bokey, C. Chan, O. Dent
Journal: Annals of Oncology (2018)

Introduction: Despite an extensive literature suggesting that high microsatellite instability (MSI-H) enhances survival and protects against recurrence after colorectal cancer (CRC) resection such effects remain controversial as many studies show no or only a weak bivariate association or no multivariable association. This study examined the association between MSI-H and recurrence and death due to CRC adjusting for death due to other cause as a competing risk. Methods: Data were drawn from a prospective hospital registry of consecutive resections for CRC, which contains detailed clinical, operative, pathology, adjuvant therapy and follow-up information. The cumulative incidence of recurrence and CRC-specific death were evaluated by competing risks regression. Results: Among 1009 patients who had a resection between August 2002 and December 2008 and were followed to at least December 2013 there were 114 (11.3%) with MSI-H. After potentially curative resection and adjustment for 19 other prognostic variables and accounting for non-CRC death as a competing risk there was no association between MSI-H and recurrence (HR 0.8 95% CI 0.42-1.57) or CRC-specific death (HR 0.73 CI 0.39-1.35). For palliative resections there was no association between MSI-H and CRC-specific death (HR 0.65, CI 0.21-2.04). For both curative and palliative resections MSI-H had a bivariate association with non-CRC death (HR 1.55 CI 1.04-2.30 and HR3.80 CI 1.32-11.00 respectively) but this disappeared in multivariable models. Conclusion: These results contradict the suggested protective association between MSI-H and recurrence or survival reported in other studies. MSI status may not be an independent prognostic variable for CRC.
The prognostic values of tumor characteristics and clinical factors of neuroendocrine tumors: Two centers experience
Authors: E. Sezer, K. Eser, V. Ercolak, Y. Acıkgoz, B. Ozturk
Journal: Annals of Oncology (2018)

Introduction: Neuroendocrine tumors are large, heterogeneous tumors. Prognostic factors were not clearly established yet. We aimed to investigate clinical and pathological findings of our pts with NETs and detect most reliable factor on prognosis of NETs. Methods: A retrospective study with neuroendocrine tumors (NETs) performed in two different centers. The effects of clinic and pathologic factors on survival were investigated using the log rank test. The Kaplan- Meier survival estimates were calculated. Cox regression analyses were performed to investigate predictive factors on survival. Results: A total of 100 (F/M=36/64) pts were included to study. Median age was 59±14.6 (range: 31-90) years. Most of pts were gastro-entero-pancreatic (GEPNET) (57%), long and other localizations were 20 and 15%, respectively. According to WHO grading system, 27 pts were NET G1, 24 pts, NET G2, 37 pts were neuroendocrine carcinoma (NEC). At the time of diagnosis, 33% pts were metastatic. Median PFS was 9.2±2.3 and OS was 20.1±8.4 months. According to tumor grades, median PSF times were 18.5, 9.2 and 7.3 months (log rank p = 0.066) and OS were 103.3, 53.1 and 10.1 months (log rank p < 0.0001), respectively. Median PFS and OS were longer in GEPNETs than lung and other NETs (log rank p < 0.05). Only tumor grade was found as an independent prognostic factor for OS; age, sex, primary tumor localization and tumor stage had no significant effect on survival. Conclusion: Despite of rarity of disease, we collected a total of 100 pts with NETs data. Most of pts were GEPNET. Tumor grade was independent prognostic factor on survival. GEPNETs and grade 1 tumors had best survival rates.
Human Cytomegalovirus Protein UL31 Inhibits DNA Sensing of cGAS to Mediate Immune Evasion
Authors: Zhe-Fu Huang, Hong-Mei Zou, Bo-Wei Liao, Hong-Yan Zhang, Yan Yang, Yu-Zhi Fu, Su-Yun Wang, Min-Hua Luo, Yan-Yi Wang
Journal: Cell Host & Microbe (2018)
DIPG-45. RADIATION DOSE RESPONSE OF NEUROLOGIC SYMPTOM IMPROVEMENT DURING RADIOTHERAPY FOR DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Christopher Tinkle, Kristen Campbell, Brandon Bianski, Yimei Li, Yuanyuan Han, Alberto Broniscer, Zsila Sadghi, Thomas Merchant
Journal: Neuro-Oncology (2018)

To investigate the association between radiation dose response and neurologic symptom improvement and survival outcomes in patients with diffuse intrinsic pontine glioma (DIPG). METHODS AND 108 patients with newly-diagnosed DIPG were treated with conventionally-fractionated radiation therapy (RT) to 54Gy (median) at our institution from 2006 to 2014. The presence and severity of neurological symptoms related to cranial neuropathy (CN) and cerebellar (CB) and long tract (LT) signs prior to and weekly during RT was reviewed for each patient. The incidence and rate of change of each symptom category was evaluated to determine the impact of clinical variables and brain sub-region volumes using Cox proportional hazard models. Median dose to first sign of symptomatic improvement was 16.2Gy (CN), 21.6Gy (CB) and 19.8Gy (LT). Most patients showed any improvement by 20Gy. Black race was associated with improved LT signs at significantly lower cumulative RT doses (P=0.027). Larger uninvolved brainstem volume alone and normalized to total brain (TB) or posterior fossa volume (PF) was associated with a shorter time to LT sign improvement (P=0.044, P=0.033, and P=0.05, respectively). Patients with any improvement in CN experienced significantly prolonged progression-free (PFS) and overall survival (OS) (P=0.002 and P=0.008, respectively). Tumor volume, with or without normalization to TB or PF, was not significantly associated with PFS or OS. Low cumulative doses of RT provided neurologic improvement in the majority of patients with DIPG. Brain sub-region volumes influenced time to symptomatic improvement, while neurologic improvement was associated with superior survival outcomes.
Accuracy of a Novel Handheld Wireless Platform for Detection of Cardiac Dysfunction in Anthracycline-Exposed Survivors of Childhood Cancer
Authors: Saro H. Armenian, Derek Rinderknecht, Kaylene Au, Lanie Lindenfeld, George Mills, Aida Siyahian, Claudia Herrera, Karla Wilson, Kalyanasundaram Venkataraman, Kristen Mascarenhas, Peyman Tavallali, Marianne Razavi, Niema Pahlevan, Jon Detterich, Smita Bhatia, Morteza Gharib
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Childhood cancer survivors are at risk for anthracycline-related cardiac dysfunction, often developing at a time when they are least engaged in long-term survivorship care. New paradigms in survivorship care and chronic disease screening are needed in this population. We compared the accuracy of a novel handheld mHealth platform (Vivio) as well as echocardiography for assessment of cardiac function [left ventricular ejection fraction (EF)] in childhood cancer survivors with cardiac magnetic resonance (CMR) imaging (reference). Experimental Design: Cross-sectional study design was used. Concurrent evaluation of EF was performed using Vivio, two-dimensional (2D) echocardiography, and CMR. Differences in mean EF (2D echocardiography vs. CMR; Vivio vs. CMR) were compared using Bland–Altman plots. Linear regression was used to evaluate proportional bias. Results: A total of 191 consecutive survivors participated [50.7% female; median time from diagnosis: 15.8 years (2–44); median anthracycline dose: 225 mg/m2 (25–642)]. Echocardiography overestimated mean EF by 4.9% (P &amp;lt; 0.001); linear regression analysis confirmed a proportional bias, when compared with CMR (t = 3.1, P &amp;lt; 0.001). There was no difference between mean EF derived from Vivio and from CMR (–0.2%, P = 0.68). The detection of cardiac dysfunction via echocardiography was poor when compared with CMR [Echo EF &amp;lt; 45% (sensitivity 14.3%), Echo EF &amp;lt; 50% (sensitivity 28.6%)]. Sensitivity was substantially better for Vivio-based measurements [EF &amp;lt; 45% or EF &amp;lt; 50% (sensitivity 85.7%)]. Conclusions: This accessible technology has the potential to change the day-to-day practice of clinicians caring for the large number of patients diagnosed with cardiac dysfunction and heart failure each year, allowing real-time monitoring and management of their disease without the lag-time between imaging and interpretation of results. Clin Cancer Res; 24(13); 3119–25. ©2018 AACR.
EMBR-02. RECURRENT HOMOZYGOUS DELETION OF DROSHA AND MICRODUPLICATION OF PDE4DIP CONTAINING THE ANCESTRAL DUF1220 DOMAIN IN PINEOBLASTOMA
Authors: Matija Snuderl, Kasthuri Kannan, Elke Pfaff, Shiyang Wang, James Stafford, Jonathan Serrano, Adriana Heguy, Karina Ray, Arline Faustin, Olga Aminova, Igor Dolgalev, Stacie Stapleton, David Zagzag, Luis Chiriboga, Sharon Gardner, Jeffrey Wisoff, John Golfinos, David Capper, Volker Hovestadt, Marc Rosenblum, Dimitris Placantonakis, Sarah LeBoeuf, Thales Papagiannakopoulos, Lukas Chavez, Sama Ahsan, Charles Eberhart, Stefan Pfister, David Jones, Matthias Karajannis
Journal: Neuro-Oncology (2018)

Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. We analyzed pediatric and adult pineoblastoma samples (n=23) using integrated genomic studies, including genome-wide DNA methylation profiling, whole-exome or whole-genome sequencing, and whole-transcriptome analysis. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower grade pineal tumors and normal pineal gland. Recurrent somatic mutations were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expression of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain. Whole-transcriptome analysis showed that homozygous loss of DROSHA led to distinct changes in RNA expression profile. Disruption of the DROSHA locus in human neural stem cells using the CRISPR/Cas9 system, led to decrease of the DROSHA protein, and massive loss of miRNAs. We identified recurrent homozygous deletions of DROSHA in pineoblastoma, suggesting that different mechanisms disrupting miRNA processing are involved in the pathogenesis of familial versus sporadic pineoblastoma. Furthermore, a novel microduplication of PDE4DIP leading to upregulation of DUF1220 protein suggests DUF1220 as a novel oncogenic driver in pineoblastoma.
Association of Body Mass Index and Age With Subsequent Breast Cancer Risk in Premenopausal Women
Authors: Minouk J. Schoemaker, Hazel B. Nichols, Lauren B. Wright, Mark N. Brook, Michael E. Jones, Katie M. O’Brien, Hans-Olov Adami, Laura Baglietto, Leslie Bernstein, Kimberly A. Bertrand, Marie-Christine Boutron-Ruault, Tonje Braaten, Yu Chen, Avonne E. Connor, Miren Dorronsoro, Laure Dossus, A. Heather Eliassen, Graham G. Giles, Susan E. Hankinson, Rudolf Kaaks, Timothy J. Key, Victoria A. Kirsh, Cari M. Kitahara, Woon-Puay Koh, Susanna C. Larsson, Martha S. Linet, Huiyan Ma, Giovanna Masala, Melissa A. Merritt, Roger L. Milne, Kim Overvad, Kotaro Ozasa, Julie R. Palmer, Petra H. Peeters, Elio Riboli, Thomas E. Rohan, Atsuko Sadakane, Malin Sund, Rulla M. Tamimi, Antonia Trichopoulou, Giske Ursin, Lars Vatten, Kala Visvanathan, Elisabete Weiderpass, Walter C. Willett, Alicja Wolk, Jian-Min Yuan, Anne Zeleniuch-Jacquotte, Dale P. Sandler, Anthony J. Swerdlow
Journal: JAMA Oncology (2018)

The association between increasing body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and risk of breast cancer is unique in cancer epidemiology in that a crossover effect exists, with risk reduction before and risk increase after menopause. The inverse association with premenopausal breast cancer risk is poorly characterized but might be important in the understanding of breast cancer causation.
LncRNA–FEZF1-AS1 Promotes Tumor Proliferation and Metastasis in Colorectal Cancer by Regulating PKM2 Signaling
Authors: Zehua Bian, Jiwei Zhang, Min Li, Yuyang Feng, Xue Wang, Jia Zhang, Surui Yao, Guoying Jin, Jun Du, Weifeng Han, Yuan Yin, Shenglin Huang, Bojian Fei, Jian Zou, Zhaohui Huang
Journal: Clinical Cancer Research (2018)

Purpose: Long non-coding RNAs (lncRNAs) play key roles in human cancers. Here, FEZF1-AS1, a highly overexpressed lncRNA in colorectal cancer, was identified by lncRNA microarrays. We aimed to explore the roles and possible molecular mechanisms of FEZF1-AS1 in colorectal cancer.Experimental Design: LncRNA expression in colorectal cancer tissues was measured by lncRNA microarray and qRT-PCR. The functional roles of FEZF1-AS1 in colorectal cancer were demonstrated by a series of in vitro and in vivo experiments. RNA pull-down, RNA immunoprecipitation and luciferase analyses were used to demonstrate the potential mechanisms of FEZF1-AS1.Results: We identified a series of differentially expressed lncRNAs in colorectal cancer using lncRNA microarrays, and revealed that FEZF1-AS1 is one of the most overexpressed. Further validation in two expanded colorectal cancer cohorts confirmed the upregulation of FEZF1-AS1 in colorectal cancer, and revealed that increased FEZF1-AS1 expression is associated with poor survival. Functional assays revealed that FEZF1-AS1 promotes colorectal cancer cell proliferation and metastasis. Mechanistically, FEZF1-AS1 could bind and increase the stability of the pyruvate kinase 2 (PKM2) protein, resulting in increased cytoplasmic and nuclear PKM2 levels. Increased cytoplasmic PKM2 promoted pyruvate kinase activity and lactate production (aerobic glycolysis), whereas FEZF1-AS1-induced nuclear PKM2 upregulation further activated STAT3 signaling. In addition, PKM2 was upregulated in colorectal cancer tissues and correlated with FEZF1-AS1 expression and patient survival.Conclusions: Together, these data provide mechanistic insights into the regulation of FEZF1-AS1 on both STAT3 signaling and glycolysis by binding PKM2 and increasing its stability. Clin Cancer Res; 24(19); 4808-19. ©2018 AACR.
Turning Toxicants into Safe Therapeutic Drugs: Cytolytic Peptide−Photosensitizer Assemblies for Optimized In Vivo Delivery of Melittin
Authors: Hao‐Ran Jia, Ya‐Xuan Zhu, Ke‐Fei Xu, Fu‐Gen Wu
Journal: Advanced Healthcare Materials (2018)

Abstract Melittin (MEL) is recognized as a highly potent therapeutic peptide for treating various human diseases including cancer. However, the clinical applications of MEL are largely restricted by its severe hemolytic activity and nonspecific cytotoxicity. Here, it is found that MEL can form a stable supramolecular nanocomplex of ≈60 nm with the photosensitizer chlorin e6 (Ce6), which after hyaluronic acid (HA) coating can achieve robust, safe, and imaging‐guided tumor ablation. The as‐designed nanocomplex (denoted as MEL/Ce6@HA) shows largely reduced hemolysis and selective cytolytic activity toward cancer cells. Upon laser irradiation, the loaded photosensitive Ce6 can synergistically facilitate the membrane‐lytic efficiency of melittin and greatly increase the tumor penetration depth of the complexes in multicellular tumor spheroids. In vivo experiments reveal that MEL/Ce6@HA can realize enhanced tumor accumulation, reduced liver deposition, and rapid body clearance, which are beneficial for highly efficient and safe chemo‐photodynamic dual therapy. This work develops a unique supramolecular strategy for optimized in vivo delivery of melittin and may have implications for the development of peptide‐based theranostics.
DDX3 Activates CBC-eIF3–Mediated Translation of uORF-Containing Oncogenic mRNAs to Promote Metastasis in HNSCC
Authors: Hung-Hsi Chen, Hsin-I Yu, Muh-Hwa Yang, Woan-Yuh Tarn
Journal: Cancer Research (2018)

Abstract Mutated or dysregulated DDX3 participates in the progression and metastasis of cancer via its multiple roles in regulating gene expression and cellular signaling. Here, we show that the high expression levels of DDX3 in head and neck squamous cell carcinoma (HNSCC) correlate with lymph node metastasis and poor prognosis and demonstrate that DDX3 is essential for the proliferation, invasion, and metastasis of oral squamous cell carcinoma (OSCC) cells. Microarray analyses revealed that DDX3 is required for the expression of a set of pro-metastatic genes, including ATF4-modulated genes in an aggressive OSCC cell line. DDX3 activated translation of ATF4 and a set of its downstream targets, all of which contain upstream open reading frames (uORF). DDX3 promoted translation of these targets, likely by skipping the inhibitory uORF. DDX3 specifically enhanced the association of the cap-binding complex (CBC) with uORF-containing mRNAs and facilitated recruitment of the eukaryotic initiation factor 3 (eIF3). CBC and certain eIF3 subunits contributed to the expression of metastatic-related gene expression. Taken together, our results indicate a role for the novel DDX3–CBC–eIF3 translational complex in promoting metastasis. Significance: The discovery of DDX3-mediated expression of oncogenic uORF-containing genes expands knowledge on translational control mechanisms and provides potential targets for cancer therapy. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4512/F1.large.jpg Cancer Res; 78(16); 4512–23. ©2018 AACR.
NSRG-01. PRIMARY GLIOBLASTOMA IN THE PINEAL REGION OF A PEDIATRIC PATIENT: A CASE REPORT AND REVIEW OF THE LITERATURE
Authors: Lee Hwang, Gabrielle Yeaney, Tanya Tekautz, Kaine Onwuzulike, Violette Recinos
Journal: Neuro-Oncology (2018)

Glioblastoma, a very aggressive type of astrocytoma (WHO grade IV), is extremely rare in the pineal region particularly in the pediatric population. With only 5 pediatric cases reported since 1972, we present another report in the setting of technological advances in neurosurgical intervention. As in this case, patients usually present with non-specific symptoms such as headache, nausea, visual changes, and altered mental status. A complete evaluation includes an MRI of the entire neuro-axis. Neurosurgical management of more acute concerns related to increased intracranial pressure can initially consist of a less invasive endoscopic third ventriculostomy (ETV), even if a more invasive microsurgical resection is ultimately required. Furthermore, thorough molecular and histological analyses can guide postoperative adjuvant therapies. Unfortunately, the overall prognosis of a patient with pineal glioblastoma is poor. Despite aggressive treatment with surgery and adjuvant therapies, the average survival rate is less than one year after diagnosis. The potential benefits and risks of a lengthy and complex microsurgical resection of a pineal glioblastoma must be extensively discussed with patients and/or their families. Moreover, due to the aggressive nature of glioblastomas, these patients must be closely monitored postoperatively for progression or recurrence. Though extremely rare, pineal glioblastomas are amenable to neurosurgical intervention for CSF diversion, both ETV and shunt, as well as microsurgical resection. Furthermore, as with any pediatric case, involvement of the patient’s family, pediatrician, and oncologist is crucial in providing comprehensive and long-term supportive care.
RAS status in metastatic colorectal cancer: What is the relationship to epidemiological and anatomo-clinical factors?
Authors: M. Haffadi, N. Tawfiq, M. Karkouri, Z. Bouchbika, N. Benchakroun, H. Jouhadi, S. Sahraoui, A. Benider
Journal: Annals of Oncology (2018)

Introduction: In Morocco, colorectal cancer (CRC) is the first digestive cancer. The identification of RAS status has modified the management of metastatic colorectal cancer (mCRC). Very few RAS status studies in the mCRC have been conducted in developing countries, such as Morocco, to identify the profile of its patients. The aim of this study is to evaluate the epidemiological and anatomo-clinical profile of mCRC patients based on the RAS status. Methods: It is a cross-sectional study, conducted from March 2017 to February 2018 and involving 65 patients with mCRC in the Mohammed VI Center for the treatment of Cancers of Casablanca. The testing RAS status was requested at the time of mCRC diagnostic. The main criteria studied were age, sex, family history of CRC, BMI, tumor location, histological type and metastatic site. Results: RAS status was wild in 48% of cases and mutated in 52%. The median age in the wild-type RAS group was 55 years and 57 years in the mutated RAS group. There was no difference in sex between the two groups (wild-type and mutated RAS). A familial history of CRC was noted in 26% of cases in the mutated RAS group in 9% in the wild type RAS group. The BMI> 25kg/m2 was observed in 44% and 41% of patients in the mutated RAS group and wild-type respectively. The colon was the most frequent seat in our series with a predominance of the left colon in both groups. The most common histological type in both groups was Lieberkühn adenocarcinoma with good to moderate differentiation. Metastases were synchronous in 80% in both groups. The most predominant metastatic site was the liver in both groups. Conclusion: According to our series, we note that the patients in the two groups (RAS wild type and RAS mutated) share the majority of epidemiological and anatomo-clinical criteria.