tbuckley/cabot-search huggingface dataset:
Multidisciplinary management of brain metastases from non-small cell lung cancer: A retrospective study of 251 patients
Authors: M. Shenglin, X. Yaping, Y. Xinmin, Y. Yang
Journal: Journal of Clinical Oncology (2009)

e19030 Background: The detection of brain metastasis(BM) is becoming increasingly common in patients with non-small cell lung cancer (NSCLC). The aim of this study was to evaluate clinical course, prognostic significance, and treatment efficacy in patients with brain metastasis. Methods: The records of all patients with BM from December 2003 to January 2007 were reviewed, and a retrospective study of 251 patients with cytologically and histologically diagnosed NSCLC and brain metastasis detected by cranial computed tomography or magnetic resonance imaging was performed. Variables analyzed included the recursive partitioning analysis (RPA) grouping, weight loss, LDH in blood serum, sex, age, time of brain metastasis (synchronous vs. metachronous), number of brain metastases, maximum diameter of largest brain lesion, Karnofsky performance status, histologic type (adenocarcinoma vs. other types of NSCLC), TNM stage (without consideration of brain involvement), and the treatment modality used for both the primary NSCLC tumor and brain metastasis. Results: The overall 1-, 2- and 3-year survival rates were 34.1%, 13.7% and 8.7% with a median survival time of 9.0 months (95% CI 8.04–9.97 months). On multivariate analysis, RPA grouping, weight loss, LDH in blood serum and treatment were independent prognostic factors. The median overall survival (OS) time of chemotherapy alone, whole brain radiotherapy (WBRT) alone, surgery alone, WBRT with chemotherapy, surgery with chemoradiation, WBRT with Gefitinib and others management was 6.0, 9.0, 12.0, 9.0, 22.0, 13.0 and 4.0 months, respectively, which were significantly different (X2=43.104, P=0.000). The stratify analysis indicated the median OS of patients received concurrent WBRT/chemotherapy (13.0 months) was longer than it of patients received sequential WBRT/chemotherapy (9.0 months) (X 2 =3.89,P=0.049). Conclusions: The main prognostic factors of BM from NSCLC of pretreatment are RAP grouping, weight loss and LDH in blood serum. The effect of combined treatment of surgery with chemoradiation is favorable and the choice of the patient is important. The survival are prolonged by active multidisciplinary management of brain metastases. [Table: see text]
Circular RNA circRHOT1 promotes hepatocellular carcinoma progression by initiation of NR2F6 expression
Authors: Liyan Wang, Haiyan Long, Qinghua Zheng, Xiaotong Bo, Xuhua Xiao, Bin Li
Journal: Molecular Cancer (2019)

Increasing evidence has revealed a close relationship between non-coding RNAs and cancer progression. Circular RNAs (circRNAs), a recently identified new member of non-coding RNAs, are demonstrated to participate in diverse biological processes, such as development, homeostatic maintenance and pathological responses. The functions of circRNAs in cancer have drawn wide attention recently. Until now, the expression patterns and roles of circRNAs in hepatocellular carcinoma (HCC) have remained largely unknown. Bioinformatics method was used to screen differentially expressed novel circRNAs in HCC. Northern blotting, qRT-PCR, in situ hybridization (ISH) and RNA-FISH were utilized to analyzed the expression of circRHOT1 in HCC tisues.CCK8, colony formation, EdU assays were used to analyze proliferation of HCC cells. Transwell assay was utilized to analyze HCC cell migration and invasion. FACS was used for apoptosis analysis. Xenograft experiments were used to analyze tumor growth in vivo. Mass spectrum, RNA pulldown, RIP and EMSA was utilized to test the interaction between circRHOT1 and TIP60. RNA-sequencing method was used to analyze the downstream target gene of circRHOT1. We identified circRHOT1 (hsa_circRNA_102034) as a conserved and dramatically upregulated circRNA in HCC tissues. HCC patients displaying high circRHOT1 level possessed poor prognosis. Through in vitro and in vivo experiments, we demonstrated circRHOT1 significantly promoted HCC growth and metastasis. Regarding the mechanism, we conducted a RNA pulldown with a biotin-labeled circRHOT1-specific probe and found that circRHOT1 recruited TIP60 to the NR2F6 promoter and initiated NR2F6 transcription. Moreover, NR2F6 knockout inhibited growth, migration and invasion, whereas rescuing NR2F6 in circRHOT1-knockout HCC cells rescued the proliferation and metastasis abilities of HCC cells. Taken together, circRHOT1 inhibits HCC development and progression via recruiting TIP60 to initiate NR2F6 expression, indicating that circRHOT1 and NR2F6 may be potential biomarkers for HCC prognosis.
Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases
Authors: Franziska Maria Ippen, Julia Katharina Grosch, Megha Subramanian, Benjamin Macfarlane Kuter, Bianca M Liederer, Emile G Plise, Joana Liliana Mora, Naema Nayyar, Stephen Paul Schmidt, Anita Giobbie-Hurder, Maria Martinez-Lage, Scott L Carter, Daniel P Cahill, Hiroaki Wakimoto, Priscilla Kaliopi Brastianos
Journal: Neuro-Oncology (2019)

Abstract Background Activating mutations in the pathway of phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) occur in 43–70% of breast cancer brain metastasis patients. To date, the treatment of these patients presents an ongoing challenge, mainly because of the lack of targeted agents that are able to sufficiently penetrate the blood–brain barrier. GDC-0068 is a pan-Akt inhibitor that has shown to be effective in various preclinical tumor models as well as in clinical trials. The purpose of this study was to analyze the efficacy of GDC-0068 in a breast cancer brain metastases model. Methods In in vitro studies, antitumor activity of GDC-0068 was assessed in breast cancer cells of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)–mutant and PIK3CA-wildtype breast cancer cell lines using cell viability and apoptosis assays, cell cycle analysis, and western blots. In vivo, the efficacy of GDC-0068 was analyzed in a PIK3CA-mutant breast cancer brain metastasis orthotopic xenograft mouse model and evaluated by repeated bioluminescent imaging and immunohistochemistry. Results GDC-0068 decreased cell viability, induced apoptosis, and inhibited phosphorylation of proline rich Akt substrate 40 kDa and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines compared with PIK3CA-wildtype cell lines. In vivo, treatment with GDC-0068 notably inhibited the growth of PIK3CA-mutant tumors and resulted in a significant survival benefit compared with sham, whereas no effect was detected in a PIK3CA-wildtype model. Conclusions This study suggests that the Akt inhibitor GDC-0068 may be an encouraging targeted treatment strategy for breast cancer brain metastasis patients with activating mutations in the PI3K pathway. These data provide a rationale to further evaluate the efficacy of GDC-0068 in patients with brain metastases.
Prospective study to measure the impact of MMprofiler on treatment intention in newly diagnosed multiple myeloma patients (PROMMIS).
Authors: Parameswaran Hari, Suzanne Lentzsch, David Samuel DiCapua Siegel, Saad Zafar Usmani, Binod Dhakal, Adriana C. Rossi, Cara Ann Rosenbaum, Siyang Leng, Divaya Bhutani, Noa Biran, David H. Vesole, Manisha Bhutani, Lisette Stork-Sloots, Femke De Snoo, Belinda C. Dumee, Martin Van Vliet, Ruben Niesvizky
Journal: Journal of Clinical Oncology (2019)

8030 Background: Multiple Myeloma (MM) is recognized as a heterogeneous group of patients with varying response and outcome of their disease, associated with various risk factors including genetic aberrations. Risk adapted treatment strategies are beginning to emerge (e.g. mSMART), which include gene expression signatures. SKY92, a 92-gene prognostic signature, classifies MM patients as “high” or “standard” risk. It has been reported to be a robust predictor for Overall and Progression Free Survival (Kuiper 2012, 2015). Here we report the preliminary impact of SKY92 on risk classification and treatment intention decisions in newly diagnosed MM patients enrolled in the PRospective Observational Multiple Myeloma Impact Study (PROMMIS). Methods: Patients with MM had their BM aspirate analyzed using the MMprofiler with SKY92. The physician completed questionnaires with his/her treatment intention, before and after knowing SKY92 results. Results: 39 MM patients were enrolled from 5 US centers. The SKY92 signature classified 15 patients (38%) as high risk. Prior to knowing SKY92 results, physicians regarded 20 (51%) patients as clinically high risk, for whom SKY92 indicated 12 patients to be standard risk. Upon revealing SKY92, 8 patients were then considered standard risk by the physician. For 2 patients with concordant high risk classification results, the confirmation of the risk classification was considered helpful. The impact of treatment intention decisions in clinical high risk patients was 40% (8 out of 20). In the 19 patients (49%) that were regarded clinically standard risk prior to knowing SKY92, SKY92 indicated 7 patients to be high risk. Physicians agreed to this classification. For 4 patients with concordant risk classification, the confirmation was found helpful. The impact of treatment intention decisions in clinical standard risk patients was 37% (7 out of 19). Conclusions: Preliminary results from the PROMMIS trial indicate that SKY92 impacts the physician’s treatment intention for 38% of patients with newly diagnosed MM. Moreover, the physicians found the SKY92 result useful for 54% of the patients. This underlines the relevance and need for assessment of SKY92 in MM patients, and associated risk stratified treatment paradigm. Clinical trial information: NCT02911571.
Approaching Clinical Trials in Childhood Interstitial Lung Disease and Pediatric Pulmonary Fibrosis
Authors: Robin R. Deterding, Emily M. DeBoer, Michal J. Cidon, Terry E. Robinson, David Warburton, Gail H. Deutsch, Lisa R. Young
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Section:ChooseTop of pageAbstract <<Childhood Interstitial Lu...Diagnosis of chILDPathophysiology of Fibros...Currently Available Treat...Challenges of Investigati...ConclusionsReferencesCITING ARTICLES
Cdc42 Deficiency Leads To Epidermal Barrier Dysfunction by Regulating Intercellular Junctions and Keratinization of Epidermal Cells during Mouse Skin Development
Authors: Min Zhang, Xueer Wang, Fukun Guo, Qin Jia, Nuyun Liu, Yinghua Chen, Yuan Yan, Mianbo Huang, Huiyi Tang, Ying Deng, Simin Huang, Zhitao Zhou, Lu Zhang, Lin Zhang
Journal: Theranostics (2019)

Rationale: Cdc42 is a Rho GTPase that regulates diverse cellular functions. Here, we used genetic techniques to investigate the role of Cdc42 in epidermal development and epidermal barrier formation. Methods: Keratinocyte-restricted Cdc42 knockout mice were generated with the Cre-LoxP system under the keratin 14 (K14) promoter. The skin and other tissues were collected from mutant and wild-type mice, and their cellular, molecular, morphological, and physiological features were analyzed. Results: Loss of Cdc42 in the epidermis in vivo resulted in neonatal lethality and impairment of epidermal barrier formation. Cdc42 deficiency led to the loss of epidermal stem cells. The absence of Cdc42 led to increased thickening of the epidermis, which was associated with increased proliferation and reduced apoptosis of keratinocytes. In addition, Cdc42 deficiency damaged tight junctions, adherens junctions and desmosomes. RNA sequencing results showed that the most significantly altered genes were enriched by the terms of "keratinization" and "cornified envelope" (CE). Among the differentially expressed genes in the CE term, several members of the small proline-rich protein (SPRR) family were upregulated. Further study revealed that there may be a Cdc42-SPRR pathway, which may correlate with epidermal barrier function. Conclusions: Our study indicates that Cdc42 is essential for epidermal development and epidermal barrier formation. Defects in Cdc42-SPRR signaling may be associated with skin barrier dysfunction and a variety of skin diseases.
HIF-1α/Wnt signaling-dependent control of gene transcription regulates neuronal differentiation of glioblastoma stem cells
Authors: Daniele Boso, Elena Rampazzo, Carlo Zanon, Silvia Bresolin, Francesca Maule, Elena Porcù, Alice Cani, Alessandro Della Puppa, Luca Trentin, Giuseppe Basso, Luca Persano
Journal: Theranostics (2019)

HIF-1α has been suggested to interplay with Wnt signaling components in order to activate a neuronal differentiation process in both normal brain and glioblastoma (GBM).Based on these data, we explored the molecular mechanisms underlying the observed capability of GBM cells to acquire a neuronal phenotype upon Wnt signaling stimulation and how the microenvironment, particularly hypoxia, modulates this process.Methods: here, the employment of ChIP-seq techniques together with co-immunoprecipitation approaches allowed to reconstruct the molecular interactions responsible for activating specific pro-differentiating transcriptional programs in GBM cells.Moreover, gene silencing/over-expression approaches coupled with the functional analysis of cell phenotype were applied to confirm ChIP-driven hypotheses.Finally, we combined the use of publicly available gene expression datasets with protein expression data by immunohistochemistry to test the clinical relevance of obtained results.Results: our data clearly suggest that HIF-1α is recruited by the β-catenin/TCF1 complex to foster neuronal differentiation gene transcription in hypoxic GBM cells.Conversely, at higher oxygen levels, the increased expression of TCF4 exerts a transcriptional inhibitory function on the same genomic regions, thus counteracting differentiation.Moreover, we demonstrate the existence of a positive correlation between the expression levels of HIF-1α, TCF1 and neuronal phenotype in GBM tumors, accompanied by the over-expression of several Wnt signaling components, finally affecting patient prognosis.Conclusion: we unveiled a peculiar mechanism by which TCF1 and HIF-1α can induce a reminiscent neuronal differentiation of hypoxic GBM cells, which is hampered, in normoxia, by high levels of TCF4, thus not only de facto controlling the balance between differentiation and stemness, but also impacting on intra-tumoral heterogeneity and eventually patient outcome.
Is Increasing Frequency of Marijuana Use Among Women of Reproductive Age a Cause for Alarm?
Authors: Torri D. Metz, Elaine H. Stickrath
Journal: JAMA Network Open (2019)

Kelly C. Young-Wolff, PhD, MPH; Varada Sarovar, PhD; Lue-Yen Tucker, BA; Amy Conway, MPH; Stacey Alexeeff, PhD; Constance Weisner, DrPH; Mary Anne Armstrong, MA; Nancy Goler, MD
Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non–germinal center B-cell–like DLBCL
Authors: Andre Goy, Radhakrishnan Ramchandren, Nilanjan Ghosh, Javier Munoz, David S. Morgan, Nam H. Dang, Mark Knapp, Maria Delioukina, Edwin Kingsley, Jerry Ping, Darrin M. Beaupre, Jutta K. Neuenburg, Jia Ruan
Journal: Blood (2019)
Glufosfamide (GLU) plus gemcitabine (GEM) in advanced solid tumors: Phase 1 results
Authors: E. G. Chiorean, T. Dragovich, J. T. Hamm, V. K. Langmuir, S. Kroll, D. T. Jung, A. B. Colowick, P. J. Loehrer
Journal: Journal of Clinical Oncology (2006)

14022 Background: Glufosfamide is glucose linked to isophosphoramide mustard, the active metabolite of ifosfamide. Cancer cells use glucose at a higher rate than normal cells, which may lead to preferential metabolic targeting by GLU. GLU has shown activity in patients (pts) with pancreatic cancer in Phase 1/2 studies with the dose-limiting toxicities (DLT) being nephrotoxicity and neutropenia. The MTD was 4500 mg/m 2 . In preclinical studies, GLU has shown additive activity when combined with GEM. The objectives of this study are to establish the maximum tolerated dose (MTD) and to evaluate the safety, efficacy and PK of GLU + GEM in advanced solid tumors. Methods: Eligible pts had Karnofsky Performance Status ≥70, no prior GEM, at least one lesion by RECIST, creatinine clearance (CrCL) ≥60 mL/min and acceptable hematologic and liver function. Cohorts of 3–6 patients were treated with GLU 1500–4500 mg/m 2 IV over 4 hours on Day 1 and GEM 1000 mg/m 2 IV over 30 minutes on Days 1, 8 and 15 of every 28-day cycle for up to 6 cycles. CT scans were obtained every 8 weeks. Detailed PK sampling was performed. Results: Nineteen pts with pancreatic (8), gall bladder (4) and other (7) cancers were enrolled. Two DLTs have occurred: Grade 3 fatigue at 2500 mg/m 2 and Grade 4 thrombocytopenia at 4500 mg/m 2 . Both cohorts were expanded. No DLTs occurred in the 1500 or 3500 mg/m 2 cohorts. Three pts completed all 6 cycles and 3 pts continue on study. Reasons for early discontinuation were progressive disease (10), clinical deterioration (1), AE (1) and death (1). Grade 3/4 neutropenia occurred in 7 pts (5 during Cycle 1) and Grade 3/4 thrombocytopenia in 5 pts (2 during Cycle 1). The CrCL fell below 60 mL/min in one patient. No objective tumor responses have been reported; 10 of 18 (56%) evaluable pts had stable disease (SD) at 8 weeks, including 1 pt with heavily pretreated ovarian cancer with ongoing SD after 8 months on therapy. PK analyses suggest no interaction between GLU and GEM. Conclusions: Phase 1 data indicate that full dose GLU (4500 mg/m 2 ) can be given safely in combination with GEM. Both early and delayed Grade 3/4 thrombocytopenia and neutropenia have been observed. A Phase 2 cohort of 28 pts with pancreatic adenocarcinoma is currently enrolling. Studies with GEM/GLU in other tumor types are planned. [Table: see text]
Liver metastases in carcinoma of the prostate as an indicator of aggressive subtype refractory to hormonal therapy and duration of response to docetaxel monotherapy: A single institution experience.
Authors: Arsh Singh, Muhammad I. Kafeel, Shams A. Shakil, Frederick Gulmi, Unni Mooppan, Jen C. Wang
Journal: Journal of Clinical Oncology (2013)

e16101 Background: Prostate cancer exhibits distinct pattern of metastasis with bone being the most common site of involvement. Liver is an uncommon site of metastasis and is associated with poor prognosis. Very few data is available on treatment with hormone including LHRH agonist (LA) and abiraterone (Ab) and chemotherapy. We retrospectively reviewed data of patients with liver metastasis with the primary objective of determining their clinical characteristics and treatment outcome from a single institution experience. Methods: Data of 5 patients with prostate cancer who developed liver metastases during the course of their disease was collected between 2007 and 2013. Four out of five patients had histological confirmation of prostatic origin adenocarcinoma while one had radiological confirmation. All patients except one had received prior LA and all were chemotherapy naïve prior to development of liver metastases. Objective biochemical response was defined as &gt;50% decrease in PSA value following therapy. Results: Gleason score was &gt;8 in 4/5 patients and unknown in one. Three out of five patients who progressed on LA received docetaxel, and despite achieving a more than 50% objective PSA response in all patients, it was of short duration, the mean duration of response was only 6 months. Two patients received Ab, after chemotherapy with docetaxel ,did not show any response and another two patients received LA therapy also failed ( one patient who presented with lung metastases developed liver metastases in &lt;6 months; one patient who presented with liver metastases expired in &lt;3 months despite LA therapy). Thus, four of five patients in this small series did not respond to hormone therapy. Conclusions: From this small series of study, it suggests that liver metastases in carcinoma of prostate represent an aggressive subset that does not respond to hormonal therapy including the LHRH agonist and abiraterone. Although they responded to docetaxel chemotherapy, the responses were of short duration. An alternative regimen should be explored for this particular subset of patients.
Diagnostic accuracy of droplet digital PCR analysis of cerebrospinal fluid for tuberculous meningitis in adult patients
Authors: Z. Li, L. Pan, L. Lyu, J. Li, H. Jia, B. Du, Q. Sun, Z. Zhang
Journal: Clinical Microbiology and Infection (2019)

Tuberculous meningitis (TBM) is difficult to diagnose. Digital PCR (dPCR) is a novel method which can quantify trace nucleic acids. This study sought to evaluate the diagnostic accuracy of dPCR analysis of cerebrospinal fluid (CSF) for TBM.We collected CSF specimens from hospitalized TBM and non-TBM patients. Total CSF DNA was purified and the concentrations of Mycobacterium tuberculosis insert sequence 6110 (IS6110) and gyrase subunit B (gyrB) were quantified using droplet dPCR. The receiver operating characteristic curves of dPCR were established and the diagnostic performances were obtained. We also compared the sensitivity of dPCR with routine diagnostic tests.A total of 101 patients were recruited, 68 of whom suffered from TBM (26 definite, 34 probable and eight possible TBM) and 33 from non-TBM. The sensitivity of IS6110-dPCR assay for total TBM was higher than that of gyrB-dPCR assay (57.4% (44.8-69.3%) vs. 22.1% (12.9-33.8%)), and there was no significant difference for specificity between them (97.0% (84.2-99.9%) vs. 100% (89.4-100.0%)). The sensitivity of IS6110-dPCR in definite TBM was higher than that in probable and possible TBM (73.1% vs. 52.9% and 25.0%, respectively). IS6110-dPCR assay showed a higher sensitivity than smear microscopy (53.3% vs. 6.7%), mycobacterial culture (50.0% vs. 12.5%), IS6110-quantitative PCR (53.1% vs. 21.9%) and Xpert MTB/RIF (70.4% vs. 29.6%). Long anti-tuberculosis treatment time was found to be significantly associated with negative dPCR results.CSF IS6110-dPCR assay is a rapid and sensitive molecular test, which has the potential to be used to enhance the diagnosis of TBM.
OTC drugs: push to cut prescribing fails to bring savings in some categories, <i>BMJ</i> analysis finds
Authors: Gareth Iacobucci
Journal: BMJ (2019)

A drive by NHS England to reduce GPs’ prescribing of drugs sold over the counter failed to deliver savings across some drug categories last year, a new analysis by The BMJ has shown. Although spending was reduced in some categories by as much as 40%, in others it increased by similar amounts (Table 1).

View this table:

Table 1 
Changes in spending on prescribed OTC treatments from 2017-18 to 2018-19



Experts said it may take longer for savings to materialise in some areas and that more work was needed to understand the reasons for the variation.

In April The BMJ reported that NHS England’s target to save £100m (€110m; $125m) a year through reductions in spending on OTC drugs delivered only modest savings of £25.9m in the year to January 2019.1 GP leaders said that this was because most GPs were already prescribing sensibly before NHS England’s policy push.

The BMJ ’s latest analysis looked more closely at prescribing trends across the different categories of OTC drugs before and after NHS …
Abstract 16395: Quantification of Circulating Leukocyte Subsets Based on Peripheral Blood RNA Expression in Patients With Acute Myocardial Infarction
Authors: Maarten Vanhaverbeke, Denise Veltman, Nico De Crem, Hilde Gillijns, Stefan Janssens, Peter Sinnaeve
Journal: Circulation (2017)

Introduction: Circulating leukocyte subtypes show a time-dependent activation during myocardial infarction (MI), and relate to outcome. However, isolation of leukocyte subsets is difficult in clini...