tbuckley/cabot-search huggingface dataset:
Intraoperative assistive technologies and insular gliomas surgery: Results from a volumetry-based retrospective cohort.
Authors: Guilherme Lepski, Breno Jose Alencar Pires Barbosa, Artemisia Dimostheni, Manoel Jacobsen Teixeira, Marcos Tatagiba
Journal: Journal of Clinical Oncology (2016)

e13525 Background: In the field of Glioma surgery, there has been an increasing interest in the use of assistive technologies to overcome the difficulty of preserving brain function while improving surgical radicality. In most reports, tumor localization has seldom been considered a variable and the role of intraoperative adjuncts is yet to be determined for gliomas of the insula. The present study aims to evaluate the efficacy of fluorescence-guided resection, neurophysiological monitoring, neuronavigation, and tractography in the Extent of Resection (EOR), functionality scores, overall survival and progression-free survival in a retrospective cohort of insular gliomas. Methods: We reviewed all cases of insular tumors operated on at the Department of Neurosurgery, University Hospital of Tübingen – Germany, between May 2008 and November 2013. Extent of resection was determined by comparative volumetric analysis. Mann Whitney, Chi-square and Kaplan-Meier functions were used for assessment of each technology’s effect on primary and secondary outcomes. Results: 28 cases (18 men (64%) and 10 women (36%); median age at diagnosis: 52,5 years, range 12 - 59) were considered eligible for the retrospective cohort. High grade gliomas accounted for 20 cases (71%) and the remaining 8 cases (29%) were low grade gliomas. The most used technologies were Intraoperative Neurophysiological Monitoring (64%) and Neuronavigation (68%). Fluorescence-guided resection with 5-ALA was the only technique associated with resections > 90% (p = 0,04). Secondarily, tractography determined higher rates of improvement in the postoperative Karnofsky performance status (50% vs 5%, p = 0,02); Conclusions: We demonstrate for the first time that for insular gliomas Intraoperative fluorescence with 5-ALA and DTI-based tractography may play a significant role in achieving higher EOR while preserving patients functionality.
Moderate influenza vaccine effectiveness in Victoria, Australia, 2011
Authors: J E Fielding, K A Grant, T Tran, H A Kelly
Journal: Eurosurveillance (2012)

We used a sentinel general practitioner (GP) network to conduct surveillance for laboratory-confirmed influenza amongst patients presenting with influenza-like illness (ILI) in Victoria, Australia in 2011. The test-negative variation of the case control study design was used to estimate effectiveness for seasonal trivalent influenza vaccine. Cases and controls were ILI patients that tested positive and negative for influenza, respectively. Vaccination status was recorded by GPs and vaccine effectiveness (VE) was calculated as (1-adjusted odds ratio)x100%. There were 529 patients included in the study, of which 29% were influenza-positive. Twelve percent of study participants were reported as vaccinated, 6% of cases and 15% of controls. Adjusted VE against all influenza was 56%, but not statistically significant. There was generally little variation in VE estimates when stratified by virus type and subtype, which is consistent with good matches between circulating strains and the vaccine strains. The VE was higher among adults of working age than among children.
Clinically Ascertained Monoclonal B-Cell Lymphocytosis: Risk of Progression to Chronic Lymphocytic Leukemia Requiring Therapy and Outcomes
Authors: Sameer A. Parikh, Kari G Chaffee, Timothy G. Call, Jose F. Leis, Wei Ding, Saad S Kenderian, Asher A. Chanan-Khan, Deborah A. Bowen, Michael J Conte, Susan M. Schwager, Susan L. Slager, Curtis A. Hanson, Neil E. Kay, Tait D. Shanafelt
Journal: Blood (2016)
Biomarker discovery and preclinical validation using mouse models of lung cancer.
Authors: Alice T. Shaw, Michael A. Gillette, James A. Dowdle, Betty Chang, Veronica Saenz-Vash, Karl Clauser, Jacob Jaffe, Steven A. Carr, Tyler Jacks
Journal: Cancer Research (2006)

5740  Early detection represents one of the most promising approaches to improve lung cancer survival. To date, no reliable circulating biomarkers of lung cancer have been identified that allow early diagnosis. With the advent of gene targeting technologies, new genetically engineered mouse models of lung cancer have been created that closely recapitulate the pathobiology of the human disease. Given the variability, complexity, and dynamic range of human plasma, we hypothesized that the use of appropriate animal models might provide a unique entry point for the discovery of early lung cancer biomarkers. To test this hypothesis, we obtained plasma from three groups of mice, a control group with no lung tumors, a second group with lung tumors induced by expression of oncogenic K-ras (K-rasG12D), and a third group with lung tumors driven by both oncogenic K-ras and mutant p53. Plasma samples were first depleted of highly abundant proteins using an Agilent MARS M3 column. The depleted samples were then reduced, alkylated, and fractionated at the protein level by size exclusion chromatography (SEC). SEC fractions were digested with trypsin and sub-fractionated by gradient strong cation exchange (SCX). Collected fractions were analyzed by LC-MS/MS using a linear ion trap-Fourier transform ion cyclotron resonance tandem mass spectrometer. The resulting LC-MS/MS data were analyzed using SpectrumMill. All analyses were performed as complete replicates. We identified close to 500 proteins with a high degree of confidence. Of these, approximately one-quarter were increased at least two fold in one or both of the lung cancer-bearing groups compared to cancer-free controls. These candidate biomarkers include the expected acute phase reactants as well as a variety of coagulation cascade components. Potential biomarkers of interest include proteins involved in extracellular maintenance and degradation, lung-specific proteins, and tumor endothelial markers. To validate candidate biomarkers of lung cancer, we have performed immunoblotting of individual mouse plasma samples using commercially available antibodies directed against potential biomarkers. We are also performing quantitative analysis of candidate biomarkers using labeled peptides and multiple reaction monitoring. These preliminary studies highlight the potential utility of combining mouse models with innovative technologies to facilitate the discovery of clinically relevant biomarkers of lung cancer. These studies may ultimately lead to the identification of one or a panel of markers for formal evaluation in clinical trials.
Pharmaco-kinetics/dynamics (PK/PD) evaluation and individual patient cross-over studies with growth trajectory assessment to adaptively develop ilorasertib.
Authors: Michael L. Maitland, Manish Sharma, Binsheng Zhao, Mark D. McKee, Sanja Karovic, Vasiliki Thomeas, Malcom McIver, Hao Yang, Sarina Anne Piha-Paul, Gerald Steven Falchook, Theodore Karrison, Razelle Kurzrock, Linda A. Janisch, Elizabeth Hoening, Shekman Wong, Wijith Munasinghe, Peter J Ansell, Mark J. Ratain, Lawrence H. Schwartz, David S. Hong
Journal: Journal of Clinical Oncology (2017)

2563 Background: We evaluated PK/PD of the AURK B/VEGFR2 inhibitor ilorasertib. To detect activity in CDKN2A-deficient tumors, we measured changes-in-tumor-burden by CT-volume before, during, and after discontinuation of therapy. Methods: Study 1: open-label, dose-escalation, phase 1 in 58 patients (pts) with advanced solid tumors. Arms I, II, and III assigned: 23 pts (10–180 mg oral QD), 28 pts (40–340 mg oral BID), and 7 pts (8–32 mg i.v. QD), to ilorasertib monotherapy Days 1, 8, and 15 every 28 days. We evaluated PK/PD for validated biomarkers: change-in-diastolic blood pressure (ΔDBP), change-in-plasma [PlGF] (ΔPlGF), and change-in phosphorylated histone H3 (Δ%pHH3) in skin biopsies. Study 2: open-label trial, of 10 solid tumor pts with CLIA-lab-detected CDKN2A disruption. Pts received ilorasertib 250 mg oral BID on same schedule. On CT images collected prior to screening, and ~ study days -7, 49, and 98 individual lesion volumes were determined by central lab semi-automated segmentation algorithms on DICOM files. Pts who tolerated ilorasertib with RECIST-stable disease at day 98 discontinued ilorasertib for 42 days and underwent re-imaging before restarting ilorasertib. Results: Study 1: the DLTs and frequent adverse events reflected VEGFR2 inhibition. PK/PD analysis showed peak VEGFR2 inhibition on ΔDBP and ΔPlGF at lower systemic concentrations than for peak AURKB-inhibition detected with Δ%pHH3. Two pts in Arm II had partial response; one had homozygous deletion of CDKN2Aby FISH. Pre-clinically the CDKN2A-deficient cell lines (OVCAR5, MDA MB 231, A549) were among the most ilorasertib-sensitive. At time of submission, Study II enrolled 10 pts, with 5 evaluable for longitudinal tumor burden assessments. Three pts had sustained negative growth trajectories after ilorasertib therapy; one of these had positive growth after cessation of treatment but restabilization of disease after restarting ilorasertib. Conclusions: The development plan adapted to the in-human PK/PD assessment. We prospectively conducted individual change-in-tumor burden cross-over studies to assess clinically the sensitivity of CDKN2A-deficient tumors. Clinical trial information: NCT02540876 and NCT01110486.
Axitinib plus crizotinib in patients with advanced solid tumors and metastatic renal cell carcinoma (mRCC): Preliminary phase 1b results.
Authors: M Dror Michaelson, Shilpa Gupta, Neeraj Agarwal, Russell Zelig Szmulewitz, Thomas Powles, Roberto Pili, Justine Yang Bruce, Ulka N. Vaishampayan, James M. G. Larkin, Brad Rosbrook, Mariajose Lechuga, Olga Valota, Jamal Christo Tarazi, Dale Randall Shepard
Journal: Journal of Clinical Oncology (2017)

2551 Background: Axitinib (AX) is a tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) and a standard treatment for mRCC. Upregulation of mesenchymal-epithelial transition factor (c-MET) is implicated in resistance to VEGFR-directed therapy. An ongoing ph Ib study (NCT01999972) evaluated the safety and efficacy of AX + crizotinib (CZ), a TKI of c-MET, anaplastic lymphoma kinase (ALK), and ROS1. Methods: mRCC patients (pts) with advanced solid tumors were treated with AX + CZ in a dose escalation phase (DESC). After determining maximum tolerated dose (MTD) (modified toxicity probability interval), mRCC pts were enrolled into 2 cohorts in a dose expansion phase (DEXP). Cohort 1 (C1) was treatment-naïve and C2 had 1–2 prior therapies. The primary objectives were to assess the tolerability of AX + CZ, to obtain the MTD, and to select the recommended phase II dose. Results: As of Aug 5, 2016, 24 pts were screened and 22 pts treated in the DESC. Pts received AX 3 mg twice daily (BID) + CZ 200 mg BID (n = 5); AX 3 mg BID + CZ 250 mg BID (n = 3); AX 5 mg BID + CZ 200 mg BID (n = 4); or AX 5 mg BID + CZ 250 mg BID (n = 10) in a median 4 (range 1–23) cycles. There were no cycle 1 dose-limiting toxicities. One pt discontinued due to an AX-related alanine aminotransferase increase. Fifteen (68.2%) pts experienced Grade 3–4 adverse events (AEs), none in ≥2 pts; 1 pt had a Grade 5 AE (disease progression). AX 5 mg BID + CZ 250 mg BID was established as the MTD. Most frequent AEs in the MTD group were fatigue (70.0%), nausea (70.0%) and diarrhea (60.0%). In the ongoing DEXP, 15 pts have been treated at the MTD (n = 11 in C1, and 4 C2). Response evaluation (RECIST) is ongoing, with 1 complete response (CR), 3 partial responses (PR) and 4 stable disease (SD) in 10 pts in C1, and 1 PR and 2 SD in 4 pts in C2. Overall, 10 (66.7%) pts experienced Grade 3–4 AEs and 1 pt had a Grade 5 AE (disease progression). Most frequent AEs (≥60% pts) were nausea and diarrhea. Conclusions: We have identified AX 5 mg BID + CZ 250 mg BID as the MTD for combination therapy. This regimen has manageable toxicities and exhibits antitumor activity in treatment-naïve and pretreated mRCC. Further studies in VEGFR, c-MET, ALK and ROS1 tumor types are warranted. Clinical trial information: NCT01999972.
Seroprevalence and susceptibility to hepatitis A in the European Union and European Economic Area: a systematic review
Authors: Paloma Carrillo-Santisteve, Lara Tavoschi, Ettore Severi, Sandro Bonfigli, Michael Edelstein, Emma Byström, Pierluigi Lopalco, Valeria Alfonsi, Roman Chilbek, Angela Dominguez, Emmanouil Galanakis, Denisa Janta, Mira Kojouharova, Jördis J Ott, Noele Nelson, Vassiliki Papaevangelou, Daniel Shouval, Ingrid Uhnoo, Vytautas Usonis
Journal: The Lancet Infectious Diseases (2017)
Prognostic value of a BCSC-associated microRNA signature in hormone receptor-positive HER2-negative breast cancer.
Authors: Chang Gong, Weige Tan, Kai Chen, Na You, Shan Zhu, Wei Luo, Xinhua Xie, Yunjie Zeng, Nengtai Ouyang, Zhihua Li, Musheng Zeng, Shimei Zhuang, Wan-Yee Lau, Qiang Liu, Fengxi Su, Xueqin Wang, Erwei Song
Journal: Journal of Clinical Oncology (2016)

532 Background: Breast cancer patients with high proportion of cancer stem cells (BCSCs) are more chemotherapy-resistant and have unfavorable clinical outcomes. MicroRNAs (miRNAs) can function as oncogenes or tumor suppressor genes, which regulate key features of BCSCs. Since BCSCs have unique miRNA expression profile, we hypothesized that a biology-driven model based on BCSC-associated miRNAs could provide prognostic information for low recurrent-risk HR+HER2- breast cancer patients. Methods: A systematic literature reviewing suggested 50 BCSC-associated miRNAs that regulate the BCSC features. We excluded 15 of these miRNAs as they were not constantly detectable in the 40 paraffin embedded tumor samples by qRT-PCR (A pilot assay). A total of 35 BCSC-associated miRNAs were identified. We randomly assigned 303 patients into a training group (n = 202) and an internal validation (n = 101) group. We built a 10-miRNA-based classifier using a LASSO Cox model in the training group and validated its prognostic in the internal validation group, and two external independent groups of 308 patients. Results: In this multicenter study, we developed build a 10-miRNA classifier to predict disease-relapse free survival (DRFS). With this classifier, HR+HER2- breast cancer patients were classified into high-risk and low-risk group of recurrence. The DRFS was significantly different between these two groups in all of the patient groups. In the training group, the 5-year DRFS was 90.83 % and 35.0% for the low- and high-risk group, respectively (hazard ratio [HR] 15.85, 95% CI 8.15-30.82; p < 0•0001). In the internal validation group, the 5-year DRFS was 91.95% and 7.14% for the low- and high-risk group, respectively (HR 20.62, 95% CI 8.31-51.20; p < 0•0001). Furthermore, in the 1st external validation group, the 5-year DRFS for low-risk group and high-risk group were 87.50% and 37.50%, respectively (HR 6.623, 95% CI 3.54-12.39; p < 0•0001). In the 2nd external validation group, it was 91.74% for the low- group and 57.14% for the high-risk group (HR 6.99, 3.12-15.64; p < 0•0001). Conclusions: Our 10-miRNA-based classifier provides a reliable prognostic model for disease recurrence in HR+HER2- breast cancer patients.
Phase II trial with tamoxifen in combination with vorinostat and pembrolizumab in estrogen receptor (+) hormone therapy resistant metastatic breast cancer patients (NCT02395627).
Authors: Manuela Terranova Barberio, Scott Thomas, Amy Jo Chien, Hope S. Rugo, Michelle E. Melisko, Austin Nicholas Angelidakis, Nela Pawlowska, Travis Deal, Pamela N. Munster
Journal: Journal of Clinical Oncology (2016)

TPS620 Background: Immunotherapy with checkpoint inhibitors in estrogen receptor (ER) + breast cancer has been less effective than in other diseases. This in part is due to the scarcity of tumor infiltrating lymphocytes (TILs) and low PD-L1 expression.Histone deacetylase inhibitors (HDACi) represent a new class of anticancer agents that can reverse hormone therapy resistance, resulting in prolonged anti-tumor responses in patients. In addition to their effects on ER signaling, HDACi have immune-modulatory functions, including modulation of regulatory T-cells, Foxp3 expression, changes in TILs composition, induction of PD-L1 and PD-1 expression. Thus, inhibiting PD-1/PD-L1 interactions may prevent T-cell suppression and reactivate immune-surveillance. Methods: We propose a randomized two arm trial to evaluate the response of hormone therapy resistant breast cancer to epigenetic immune priming, and to test the optimal sequence and dosing of tamoxifen in combination with vorinostat and pembrolizumab. Pre or postmenopausal patients with ER+ metastatic breast cancer, who have progressed on multiple prior therapies, are eligible for the study. Both arms start with tamoxifen (20 mg daily orally) and vorinostat (400 mg 5/7 days orally) on cycle 1, while pembrolizumab (200 mg ever 3 weeks intravenously) starts on cycle 1 (Arm A) or cycle 2 (Arm B) to evaluate sequential priming. 16 of the planned 58 patients have been enrolled. Evaluation of overall response rate and adverse events are the primary outcomes. Comprehensive flow-cytometric immunophenotyping will be performed on tumor and blood specimens. Immunoprofiling will be accomplished together with histone acetylation evaluation and correlated with response. Clinical trial information: NCT02395627.
Phase I Trial of Targeted Alpha-Particle Therapy with Actinium-225 (225Ac)-Lintuzumab and Low-Dose Cytarabine (LDAC) in Patients Age 60 or Older with Untreated Acute Myeloid Leukemia (AML)
Authors: Joseph G. Jurcic, Moshe Yair Levy, Jae H. Park, Farhad Ravandi, Alexander E. Perl, John M. Pagel, B. Douglas Smith, Elihu H. Estey, Hagop Kantarjian, Dragan Cicic, David A. Scheinberg
Journal: Blood (2016)
Values of tumor-infiltrating lymphocytes (TILs), CD8+ TILs, and PDL-1 for predicting pathological complete response and prognosis in HER2-positive breast cancer receiving neoadjuvant chemotherapy with trastuzumab.
Authors: Sasagu Kurozumi, Kenichi Inoue, Masafumi Kurosumi, Hiroshi Matsumoto, Yuji Hayashi, Katsunori Tozuka, Kazuyuki Kubo, Kei Komatsu, Ken Takai, Shigenori E. Nagai, Hanako Oba, Jun Horiguchi
Journal: Journal of Clinical Oncology (2016)

589 Background: The predictive and prognostic values of tumor-infiltrating lymphocytes(TILs) in neoadjuvant chemotherapy have also been demonstrated in triple negative as well as HER2-positive breast cancer (BC). In the present study, we investigated the relationship between the expression and degree of stromal (str)-TILs, CD8+ TILs, and PDL-1 positive cancer cells, and evaluated the values of these 3 factors for predicting pCR and prognosis in HER2-positive BC patients receiving neoadjuvant chemotherapy with trastuzumab. Methods: A total of 128 Japanese HER2-positive BC received taxanes followed by FEC, with the concomitant administration of trastuzumab. The grades of str-TILs were evaluated using the criteria of the International Working Group for TILs in BC, with a high grade being defined as > 40%. Immunohistochemically, positive cancer cells for PDL-1 was defined as > 1%, and high CD8+ was defined as the number of CD8+ TILs > 25 / 1 high power field. The relationship between the expression and degree of str-TILs, CD8+ TILs, and PDL-1 was investigated, as was that with pCR. In addition, the relationships of relapse-free survival (RFS) and overall survival (OS) with str-TILs, CD8+ TILs, and PDL-1 were examined. Results: pCR was achieved in 83 patients (pCR rate, 64.8%) who received NAC with trastuzumab, and RFS was significantly better in the pCR group than in the non-pCR group (p = 0.0071). A high degree of str-TILs correlated with high CD8+ (p = 0.0022) and positive PD-L1 (p < 0.0001). pCR rates correlated with the grades of str-TILs (high, 83.3% vs. low, 60.6%; p = 0.035) and PD-L1 expression (positive, 86.4% vs. negative, 61.5%; p = 0.026), but not with the density of CD8+ TILs (high, 70.1% vs. low, 56.6%; p = 0.18). In PD-L1-negative patients, survival was significantly better in the high CD8+ group than in the low CD8+ group (RFS: p = 0.0013; OS: p = 0.015). Conclusions: High-grade str-TILs and positive PD-L1 were identified as predictive factors of pCR in patients receiving NAC with trastuzumab, and high CD8+ TILs was a predictive factor of better survival in PDL1-negative and HER2-positive BC.
Drainage biliaire, photothérapie dynamique et chimiothérapie comme traitement palliatif du cholangiocarcinome non opérable – Résultats à court et moyen termes
Authors: D Fuks, E Bartoli, R Delcenserie, T Yzet, P Cellisse, C Sabbagh, D Chatelain, JP Joly, JL Dupas, JM Regimbeau
Journal: Endoscopy (2009)

Introduction: La photothérapie dynamique (PTD) semble apporter un bénéfice réel sur la survie des patients avec un cholangiocarcinome (CC) irrésécable. L'objectif de ce travail est d'évaluer l'efficacité de la PTD dans notre centre.
Can 18 FDG whole body PET-CT substitute conventional imaging for initial staging of patients with locally advanced breast cancer?
Authors: Narendra Hulikal, sivanath Reddy GV, Kalawat TC, Lakshmi Ay
Journal: Journal of Clinical Oncology (2014)

e11545 Background: The locally advanced breast cancer (LABC) patients have high rate of systemic relapse, which may in part be due to failure of initial staging evaluation to detect systemic disease. Consequently, there is a need for a single and more sophisticated staging procedure. The 18 FDG PET/CT by combining anatomical and metabolic imaging may in theory, detect distant metastases more accurately than the conventional methods. Methods: This study included patients with biopsy proven newly suspected LABC during one year period. The metastatic work up consisted of a liver function test, chest radiograph, contrast enhanced tomography of chest and abdomen (CECT), ultrasound of abdomen and pelvis, bone scintigraphy and a whole body 18 FDG PET/CT. The objective was to know whether PET/CT can substitute the conventional imaging modalities for picking up the metastatic sites. Results: There were 38 patients, the age ranged from 27 to 73 years and median age was 48. On physical examination, 15 patients belonged to the AJCC/TNM stage III A, 19 were III B and 4 were III C. The chest radiograph was normal in all patients; CECT was reported normal in 26 patients, detected metastasis in 8 patients and was suspicious of metastasis in 4 patients. The bone scinitigraphy suggested osseous secondaries in 8 patients.The PET/CT could not detect any site of distant metastasis in 27 patients. Two patients had uptake in internal mammary nodes which was not detected by any of the other modalities. In the remaining 11 patients, 6 had multiple sites of metastasis, 3 had liver and 2 had pulmonary metastasis. Among patients in whom PET/CT was negative for metastasis, CECT had suggested metastasis in 4 and bone scan in 3. Of the 11 patients where PET/CT detected metastasis, the CECT was reported normal in 5 patients and bone scan in 10 patients. Further only 2 patients with CECT suggestive of pulmonary metastasis had positive PET/CT along with other site of metastasis. Conclusions: The whole body PET/CT can detect site of metastasis in more number of patients than the other conventional methods. The PET/CT can also detect multiple sites of metastasis with greater accuracy.
A Detailed Alternate Splicing Landscape in Multiple Myeloma with Significant Potential Biological and Clinical Implications
Authors: Anil Aktas Samur, Mehmet Kemal Samur, Stephane Minvielle, Florence Magrangeas, Mariateresa Fulciniti, Raphael Szalat, Paul G. Richardson, Kenneth C. Anderson, Michel Attal, Philippe Moreau, Giovanni Parmigiani, Herve Avet-Loiseau, Nikhil C Munshi
Journal: Blood (2016)