tbuckley/cabot-search huggingface dataset:
Differences in outcome between colorectal cancer (CRC) patients (pts) with Lynch syndrome (LS) versus <i>MLH1</i> hypermethylation (<i>MLH1</i> HM).
Authors: Sigurdis Haraldsdottir, Christina Sing-Ying Wu, Xueliang Jeff Pan, Heather Hampel, Richard M. Goldberg, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2013)

1556 Background: In ~15% of CRC tumors mismatch repair deficiency (dMMR) is observed and is usually caused by LS (germline mutations in MLH1, MSH2, MSH6 or PMS2) or sporadic inactivation of MLH1 (hypermethylation [HM] of MLH1 gene promoter). The objective of this study was to retrospectively compare clinical factors and outcomes in pts with dMMR with LS to those without LS. Methods: This cohort includes pts with CRC diagnosed between 5/98 and 5/12 with dMMR on immunohistochemistry (IHC) staining. Prior to 2006 pts came from the Columbus area HNPCC study. After 2006, we included all CRC pts at OSU as universal IHC was initiated. Chi-square was used to compare nominal parameters and log-rank to compare overall survival (OS). Results: A total of 189 pts had dMMR per IHC staining (see characteristics in table). In 36 pts (19.0%) a diagnosis of LS was made after germline testing, in 59 pts (31.2%) a diagnosis of MLH1 HM was made with methylation or BRAF testing, in 65 pts (34.4%) a LS or MLH1 HM diagnosis was assumed based on clinical criteria. Median OS was 159 mos in the LS group and 49 mos in the MLH1MH group (p=0.003) and OS was significantly longer in the LS group across all 4 stages (p=0.002) (see Table). Conclusions: Pts with LS-associated CRC had longer OS than pts with MLH1 HM-associated CRC, even in the setting of a higher incidence of other cancers (44.1% vs. 28%). This is likely related to younger age in the LS group. The MLH1HM group was older at diagnosis and more often female. There are a number of limitations to our study including the potential for survivorship bias and lack of a definitive diagnosis in ~50% of patients despite using clinical criteria to define these pts. [Table: see text]
Deoxycytidine Release from Pancreatic Stellate Cells Promotes Gemcitabine Resistance
Authors: Simona Dalin, Mark R. Sullivan, Allison N. Lau, Beatrice Grauman-Boss, Helen S. Mueller, Emanuel Kreidl, Silvia Fenoglio, Alba Luengo, Jacqueline A. Lees, Matthew G. Vander Heiden, Douglas A. Lauffenburger, Michael T. Hemann
Journal: Cancer Research (2019)

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths in the United States. The deoxynucleoside analogue gemcitabine is among the most effective therapies to treat PDAC, however, nearly all patients treated with gemcitabine either fail to respond or rapidly develop resistance. One hallmark of PDAC is a striking accumulation of stromal tissue surrounding the tumor, and this accumulation of stroma can contribute to therapy resistance. To better understand how stroma limits response to therapy, we investigated cell-extrinsic mechanisms of resistance to gemcitabine. Conditioned media from pancreatic stellate cells (PSC), as well as from other fibroblasts, protected PDAC cells from gemcitabine toxicity. The protective effect of PSC-conditioned media was mediated by secretion of deoxycytidine, but not other deoxynucleosides, through equilibrative nucleoside transporters. Deoxycytidine inhibited the processing of gemcitabine in PDAC cells, thus reducing the effect of gemcitabine and other nucleoside analogues on cancer cells. These results suggest that reducing deoxycytidine production in PSCs may increase the efficacy of nucleoside analog therapies. SIGNIFICANCE: This study provides important new insight into mechanisms that contribute to gemcitabine resistance in PDAC and suggests new avenues for improving gemcitabine efficacy.
Comprehensive Next-Generation Sequencing Unambiguously Distinguishes Separate Primary Lung Carcinomas From Intrapulmonary Metastases: Comparison with Standard Histopathologic Approach
Authors: Jason C. Chang, Deepu Alex, Matthew Bott, Kay See Tan, Venkatraman Seshan, Andrew Golden, Jennifer L. Sauter, Darren J. Buonocore, Chad M. Vanderbilt, Sounak Gupta, Patrice Desmeules, Francis M. Bodd, Gregory J. Riely, Valerie W. Rusch, David R. Jones, Maria E. Arcila, William D. Travis, Marc Ladanyi, Natasha Rekhtman
Journal: Clinical Cancer Research (2019)

In patients with >1 non-small cell lung carcinoma (NSCLC), the distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is a common diagnostic dilemma with critical staging implications. Here, we compared the performance of comprehensive next-generation sequencing (NGS) with standard histopathologic approaches for distinguishing NSCLC clonal relationships in clinical practice.
Evaluation of outcome and prognostic factors in paediatric extraskeletal ewings sarcoma: A single institution experience.
Authors: Vijay Kumar Srinivasalu, Hari Sankaran, Narayana Subramaniam, Arun Philip, Wesley Mannirathil Jose, Pavithran Keechilat
Journal: Journal of Clinical Oncology (2019)

e21507 Background: Ewing's sarcoma (ES) represent the most frequent small and round cell bone tumors of childhood and adolescence. Data on extraskeletal ewings sarcoma (EES) with uniform chemotherapy protocol are very minimal. We aimed to assess this aspect in our patients and identify prognostic factors in patients with extraskeletal ewings sarcoma. Methods: A retrospective analysis of data was done between January 2005 and January 2016. These paediatric EES patients who received chemotherapy with VAC-IE regimen were evaluated for their response, overall survival (OS) and Event free survival (EFS). The prognostic factors which influenced their overall survival were also analysed. Results: Fourty one paediatric EES patients were diagnosed at our institute out of which 31 patients received treatment at our hospital. 25.8% (8) were metastatic at presentation. The mean age was 12.37 years (1-18 years) with a predominant female preponderance 54.8%. The commonest site at presentation was presacral mass (7) and mass in the brain parenchyma (8). Rare sites of presentation as a nasal mass and parotid mass was seen in one patients each. 78% received chemotherapy with VAC-IE regimen. The ORR was 71% (8 CR + 9 PR). Toxicity was grade III neutropenia in 5 (20.8%). 8 patients received local RT. The 3 year OS and EFS in the localized EES were 55% and 39% and in metastatic EES were 35% and 24% respectively. Low hemoglobin (P = 0.05) and high LDH (P = 0.01) predicted inferior OS for the entire EES cohort on multivariate analysis. Conclusions: High LDH and low hemoglobin is associated with poor OS for patients with EES ewings sarcoma. VAC-IE is a very effective and a safe chemotherapy regimen and should be considered in patients with extraskeletal ewings sarcoma.
Outbreak of Electronic-Cigarette–Associated Acute Lipoid Pneumonia — North Carolina, July–August 2019
Authors: Kevin Davidson, Alison Brancato, Peter Heetderks, Wissam Mansour, Edward Matheis, Myra Nario, Shrinivas Rajagopalan, Bailey Underhill, Jeremy Wininger, Daniel Fox
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

On September 6, 2019, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr). Electronic cigarettes (e-cigarettes) produce an aerosol by heating a liquid that usually contains nicotine, flavorings, and other chemicals that users inhale, a behavior commonly referred to as "vaping." E-cigarettes can also be used to deliver marijuana and other drugs. In recent months, more than 200 possible cases of acute lung injury potentially associated with vaping were reported from 25 states (1). During July and August 2019, five patients were identified at two hospitals in North Carolina with acute lung injury potentially associated with e-cigarette use. Patients were adults aged 18-35 years and all experienced several days of worsening dyspnea, nausea, vomiting, abdominal discomfort and fever. All patients demonstrated tachypnea with increased work of breathing on examination, hypoxemia (pulse oximetry <90% on room air), and bilateral lung infiltrates on chest x-ray. All five patients shared a history of recent use of marijuana oils or concentrates in e-cigarettes. All of the products used were electronic vaping pens/e-cigarettes that had refillable chambers or interchangeable cartridges with tetrahydrocannabinol (THC) vaping concentrates or oils, which were all purchased on the street. Three of the patients also used nicotine-containing e-cigarettes, and two of the patients smoked marijuana or conventional cigarettes, although none used other illicit drugs. All five patients were hospitalized for hypoxemic respiratory failure; three required intensive care for acute respiratory distress syndrome, one of whom required intubation and mechanical ventilation. All of the patients survived.
Real-World and Clinical Trial Data in Relapsed/Refractory Multiple Myeloma (RRMM): Evaluating Treatment Duration and Comparing Effectiveness and Efficacy
Authors: Paul G Richardson, Jesus F. San Miguel, Philippe Moreau, Roman Hajek, Meletios A. Dimopoulos, Antonio Palumbo, Katarina Luptakova, Tomas Skacel, Shaji K Kumar, Kenneth C Anderson
Journal: Blood (2017)
OS9.1 Clinical significance of hypermutation in gliomas
Authors: M Touat, Y Li, A Boynton, L Spurr, B Iorglescu, J Geduldig, C Birzu, M Lim Fat, S Santagata, F Coulet, F Beuvon, K Mokhtari, M Giry, S Block, E Guillerm, A Carpentier, R Huang, J Delattre, K Hoang-Xuan, M Sanson, A Duval, A Cherniack, D Reardon, P Wen, A Idbaih, A Marabelle, P Bandopadhayay, R Beroukhim, F Bielle, K Ligon
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Among patients with glioma, little is known about the clinical significance of hypermutation. We sought to define the determinants of hypermutation in gliomas, and to assess the value of this biomarker for predicting response to standard of care and immune checkpoint blockade. MATERIAL AND METHODS We performed comprehensive molecular characterization of 2420 pediatric and adult gliomas with clinical annotation. We determined the clinical and molecular characteristics associated with hypermutation, and assessed the relationship between hypermutation and clinical response to cancer therapies. RESULTS Overall, 114 hypermutated gliomas were identified. Hypermutation occurred predominantly in therapy-responsive subtypes characterized by methylated MGMT promoter, IDH1/2mutation or 1p/19q co-deletion. Hypermutation was almost always associated with prior treatment with temozolomide and molecular defects in DNA mismatch repair (MMR), which were identified in one-third of IDH1/2-mutated recurrent gliomas and was associated with shorter survival in multivariate analyses (hazard ratio 2.11 [95% CI 1.24–3.6], P=0.006). The molecular mechanisms whereby gliomas undergo hypermutation during therapy with alkylating agents were dissected using patient-derived glioma models in vitro and in vivo. Outcomes of hypermutated gliomas treated with immune checkpoint blockade or with standard of care agents will be presented at the conference. CONCLUSION This study establishes that mutation burden and mutation signatures are clinically and biologically significant biomarkers that can be used to predict therapy response and guide treatment decisions in gliomas.
Optical and Electromagnetic Tracking Systems for Biomedical Applications: A Critical Review on Potentialities and Limitations
Authors: Angela Sorriento, Maria Bianca Porfido, Stefano Mazzoleni, Giuseppe Calvosa, Miria Tenucci, Gastone Ciuti, Paolo Dario
Journal: IEEE Reviews in Biomedical Engineering (2019)

Optical and electromagnetic tracking systems represent the two main technologies integrated into commercially-available surgical navigators for computer-assisted image-guided surgery so far. Optical Tracking Systems (OTSs) work within the optical spectrum to track the position and orientation, i.e., pose of target surgical instruments. OTSs are characterized by high accuracy and robustness to environmental conditions. The main limitation of OTSs is the need of a direct line-of-sight between the optical markers and the camera sensor, rigidly fixed into the operating theatre. Electromagnetic Tracking Systems (EMTSs) use electromagnetic field generator to detect the pose of electromagnetic sensors. EMTSs do not require such a direct line-of-sight, however the presence of metal or ferromagnetic sources in the operating workspace can significantly affect the measurement accuracy. The aim of the proposed review is to provide a complete and detailed overview of optical and electromagnetic tracking systems, including working principles, source of error and validation protocols. Moreover, commercial and research-oriented solutions, as well as clinical applications, are described for both technologies. Finally, a critical comparative analysis of the state of the art which highlights the potentialities and the limitations of each tracking system for a medical use is provided.
P14.37 Depression in patients with primary brain tumors: Relation to clinical variables and tumor characteristics
Authors: F John, G R Barger, S Mittal, C Juhasz
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Patients with brain tumor have an increased risk for depressive disorder, however, the association between depression and clinical or tumor-related variables remains mostly unclear. In this study, we analyzed the relation of depression to several clinical and tumor-related characteristics in patients with primary brain tumors. MATERIAL AND METHODS Sixty patients with newly-diagnosed (n=34) or recurrent (n=26) primary brain tumors (50 gliomas, 10 meningiomas) underwent testing with the Beck Depression Inventory-II (BDI-II). Relation of BDI-II scores to clinical and tumor-related characteristics, including age, Karnofsky Performance Status (KPS) scores, presence of antiepileptic, antidepressant, or steroid treatment, as well as tumor grade, lateralization, and lobar localization, were analyzed. In a subset of recurrent malignant glioma patients, the prognostic value of BDI-II scores on overall survival was also analyzed. RESULTS The mean total BDI-II score was 10±8 (range: 0–37); while 27% of patients (n=16) had BDI-II scores indicating at least mild depressive disorder (≥13), only a portion of them (17%) was on antidepressant treatment. No BDI-II difference was found between gliomas vs. meningiomas or newly-diagnosed vs. recurrent tumors; also, no association was found with any tumor-related characteristics. Antiepileptic or steroid therapy had no association with BDI-II scores, while higher BDI-II scores were observed in patients with ongoing antidepressant therapy (15±10 vs. 8±7, p=0.017). Higher BDI-II total and somatic subscale scores correlated with lower KPS scores (r=-0.32, p=0.014 and r=-0.31, p=0.017, respectively). In recurrent malignant glioma patients (n=18), higher depression scores were associated with shorter survival (hazard ratio: 3.7; 95% confidence interval: 1.0–13.6; p=0.048). CONCLUSION Depression affected more than ¼ of patients with primary brain tumors in this single-center cohort and was independent from most clinical and tumor-related characteristics, except KPS scores. Although most of these patients have mild depression that is often overlooked without targeted screening, higher BDI-II scores may predict shorter overall survival in recurrent malignant glioma patients. These data reinforce the importance of early recognition and treatment of depressive symptoms in patients with primary brain tumors.
Cyclooxygenase-2 expression levels correlate with susceptibility to mouse skin tumorigenesis
Authors: Joyce Rundhaug, Amy Pavone, Carol Mikulec, Susan Fischer
Journal: Cancer Research (2007)

5664  Cyclooxygenase (COX) enzymes catalyze the rate-limiting step in the conversion of arachidonic acid to prostaglandins. While COX-1 is constitutively expressed in most tissues and is involved in tissue homeostasis, COX-2 is highly inducible, is frequently overexpressed in cancers, and plays roles in inflammation, immune function, angiogenesis, and tumor invasiveness. Both general COX inhibitors, as well as COX-2-specific inhibitors, have been shown to inhibit carcinogenesis in a number of animal models. However, COX inhibitors have been shown to have COX-independent effects. So we have used both COX-2 transgenic and COX-2 knockout mice to determine the role of COX-2 in carcinogenesis using the mouse skin model. FVB mice overexpressing COX-2 in the skin via the keratin 14 (K14) promoter were initially shown to be resistant to skin tumorigenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) initiation and 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. However, using DMBA only or using the nonphorbol ester tumor promoter, anthralin, with DMBA, K14.COX2 transgenic mice developed many more tumors (3.7 and 5.5 fold, respectively) than wild type FVB mice. Thus, overexpression of COX-2 appears to promote skin tumorigenesis and resistance to tumorigenesis is limited specifically to TPA tumor promotion, which correlated to a reduced TPA induction of proliferation, ornithine decarboxylase, interleukin-1α, and tumor necrosis factor-α expression in transgenic versus wild type mice. Similarly, when SKH-1 hairless mice overexpressing COX-2 in the skin via the keratin 5 (K5) promoter were subjected to ultraviolet (UV) light-induced tumorigenesis, transgenic mice developed 2.5 fold more tumors/mouse than wild type SKH-1 mice. To complement these studies with transgenic overexpressing mice, COX-1 and COX-2 knockout mice were backcrossed onto the SKH-1 background for UV carcinogenesis studies (others have already shown that COX-1 and COX-2 knockout mice are resistant to DMBA/TPA skin tumorigenesis; Cancer Res., 62:3395, 2002). However, since homozygous COX-2 -/- mice do not survive beyond ~6 weeks of age on the SKH-1 background, heterozygous COX-1 +/- and COX-2 +/- mice were used. While COX-1 +/- mice developed UV-induced tumors similarly to wild type SKH-1 mice, COX-2 +/- mice developed 3 fold fewer tumors/mouse with a 10-week increase in latency compared to wild type mice. Thus, loss of only one allele of COX-2 was enough to decrease tumorigenesis in this system. Overall, mouse skin COX-2 expression levels were directly correlated to susceptibility to tumorigenesis. Supported by NIH grants CA100140, ES07784.
Phase 1 study of pevonedistat (MLN4924) in combination with temozolomide (TMZ) and irinotecan (IRN) in pediatric patients with recurrent or refractory solid tumors (ADVL1615).
Authors: Jennifer Foster, Jodi Ann Muscal, Charles G. Minard, Xiaowei Liu, Joel M. Reid, Stacey L. Berg, Elizabeth Fox, Brenda Weigel
Journal: Journal of Clinical Oncology (2019)

e21521 Background: Pevonedistat, a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m 2 . Antitumor activity of pevonedistat has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for pevonedistat in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended phase 2 dose of pevonedistat in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: Using a rolling six design, we conducted a phase 1 trial of pevonedistat in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m 2 ) and TMZ (orally, 100mg/m 2 ), on days 8-12 of a 28 day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Results: 18 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 11 (61%) were male. Six pts had brain tumors, and 12 pts had solid tumors. Six pts each enrolled on pevonedistat dose levels 1 (15mg/m 2 ), 2 (20mg/m 2 ), and 3 (25mg/m 2 ). There were no DLTs; DLT assessment is pending for 1 pt on dose level 3. Grade 3/4 toxicities included grade 4 lymphocyte count decreased (n = 2), grade 3 white blood cell decreased (n = 2), and 1 pt each with grade 3 anemia, elevated AST, and elevated ALT. The most frequent AEs were anemia (83%), nausea (61%), elevated AST (61%), and diarrhea (61%). Pharmacokinetic analysis is pending. Conclusions: Pevonedistat in combination with IRN and TMZ is well tolerated in pts with solid or brain tumors. PK and PD analyses are ongoing to establish the recommended dose. Clinical trial information: NCT03323034.
Timeless-Stimulated miR-5188-FOXO1/β-Catenin-c-Jun Feedback Loop Promotes Stemness via Ubiquitination of β-Catenin in Breast Cancer
Authors: Yujiao Zou, Xian Lin, Junguo Bu, Zelong Lin, Yanjuan Chen, Yunhui Qiu, Haiyue Mo, Yao Tang, Weiyi Fang, Ziqing Wu
Journal: Molecular Therapy (2019)

MicroRNAs (miRNAs) play an essential role in the self-renewal of breast cancer stem cells (BCCs). Our study aimed to clarify the role of proto-oncogene c-Jun-regulated miR-5188 in breast cancer progression and its association with Timeless-mediated cancer stemness. In the present study, we showed that miR-5188 exerted an oncogenic effect by inducing breast cancer stemness, proliferation, metastasis, and chemoresistance in vitro and in vivo. The mechanistic analysis demonstrated that miR-5188 directly targeted FOXO1, which interacted with β-catenin in the cytoplasm, facilitated β-catenin degradation, and impaired the nuclear accumulation of β-catenin, thus stimulating the activation of known Wnt targets, epithelial-mesenchymal transition (EMT) markers, and key regulators of cancer stemness. Moreover, miR-5188 potentiated Wnt/β-catenin/c-Jun signaling to promote breast cancer progression. Interestingly, c-Jun enhanced miR-5188 transcription to form a positive regulatory loop, and Timeless interacted with Sp1/c-Jun to induce miR-5188 expression by promoting c-Jun-mediated transcription, which further activated miR-5188-FOXO1/β-catenin-c-Jun loop and facilitated breast cancer progression. Importantly, miR-5188 was upregulated in breast cancer and was positively correlated with poor patient prognosis. This study identifies miR-5188 as a novel oncomiR and provides a new theoretical basis for the clinical use of miR-5188 antagonists in the treatment of breast cancer.Graphical abstract
The supply chain of human pancreatic β cell lines
Authors: Raphael Scharfmann, Willem Staels, Olivier Albagli
Journal: Journal of Clinical Investigation (2019)

Patients with type 1 or type 2 diabetes have an insufficiency in their functional β cell mass. To advance diabetes treatment and to work toward a cure, a better understanding of how to protect the pancreatic β cells against autoimmune or metabolic assaults (e.g., obesity, gestation) will be required. Over the past decades, β cell protection has been extensively investigated in rodents both in vivo and in vitro using isolated islets or rodent β cell lines. Transferring these rodent data to humans has long been challenging, at least partly for technical reasons: primary human islet preparations were scarce and functional human β cell lines were lacking. In 2011, we described a robust protocol of targeted oncogenesis in human fetal pancreas and produced the first functional human β cell line, and in subsequent years additional lines with specific traits. These cell lines are currently used by more than 150 academic and industrial laboratories worldwide. In this Review, we first explain how we developed the human β cell lines and why we think we succeeded where others, despite major efforts, did not. Next, we discuss the use of such functional human β cell lines and share some perspectives on their use to advance diabetes research.