tbuckley/cabot-search huggingface dataset:
Preclinical evidence of positive effect of l-MTP-PE alone or combined with zoledronic acid in osteosarcoma.
Authors: Francoise Redini, Kevin Biteau, Julien Taurelle, Romain Guiho, Julie Chesneau, Jerome Amiaud, Nadege Corradini, Dominique Heymann
Journal: Journal of Clinical Oncology (2014)

10048 Background: Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III clinical trials in Europe for the treatment of malignant primary bone tumors. The beneficial effect of the liposomal form of MuramylTriPeptide-Phosphatidyl Ethanolamine (MTP-PE, mifamurtide), activating the macrophage population in tumors, has also proved its efficacy in osteosarcoma. The objective of our study was to evaluate the safety of the combination of zoledronic acid and liposomal mifamurtide in pre-clinical models of osteosarcoma before transfer to patients. Methods: Two protocols were developed in mouse syngenic models of osteosarcoma: (1) 1 or 2.5 mg/kg mifamurtide alone in primary tumor progression and pulmonary metastasis dissemination (experimental model induced by paratibial injection of murine osteosrcoma cells), (2) the potential interference of mifamurtide on ZA induced effect on osteosarcoma. These effects were evaluated at clinical, radiological (bone microarchitecture by microCT analysis), biological and histological levels. Results: Mifamurtide alone induced slight but not significant inhibitory effect on primary osteosarcoma growth. However, it significantly inhibits spontaneous (lung metastasis dissemination from primary bone tumor) and experimental (lung colonization after intraveinous injection of osteosarcoma cells) metastases at pulmonary site. Combinatory studies of mifamurtide associated with zoledronic acid showed no significant interference on specific effect on primary bone tumor growth, but rather synergism. Conclusions: In mouse, mifamurtide alone has a potent inhibitory effect on lung metastasis development, probably due to high macrophage infiltration in the lung parenchyma. Preliminary data did not evidence any interference of mifamurtide with ZA potential therapeutic activity in preclinical models of osteosarcoma.
PROBAST: A Tool to Assess the Risk of Bias and Applicability of Prediction Model Studies
Authors: Robert F. Wolff, Karel G.M. Moons, Richard D. Riley, Penny F. Whiting, Marie Westwood, Gary S. Collins, Johannes B. Reitsma, Jos Kleijnen, Sue Mallett
Journal: Annals of Internal Medicine (2018)

Clinical prediction models combine multiple predictors to estimate risk for the presence of a particular condition (diagnostic models) or the occurrence of a certain event in the future (prognostic models). PROBAST (Prediction model Risk Of Bias ASsessment Tool), a tool for assessing the risk of bias (ROB) and applicability of diagnostic and prognostic prediction model studies, was developed by a steering group that considered existing ROB tools and reporting guidelines. The tool was informed by a Delphi procedure involving 38 experts and was refined through piloting. PROBAST is organized into the following 4 domains: participants, predictors, outcome, and analysis. These domains contain a total of 20 signaling questions to facilitate structured judgment of ROB, which was defined to occur when shortcomings in study design, conduct, or analysis lead to systematically distorted estimates of model predictive performance. PROBAST enables a focused and transparent approach to assessing the ROB and applicability of studies that develop, validate, or update prediction models for individualized predictions. Although PROBAST was designed for systematic reviews, it can be used more generally in critical appraisal of prediction model studies. Potential users include organizations supporting decision making, researchers and clinicians who are interested in evidence-based medicine or involved in guideline development, journal editors, and manuscript reviewers.
Actionable information generated by a multiplatform approach to molecular profiling on 12,265 patients.
Authors: David Spetzler, Sting Chen, Todd Maney, Zoran Gatalica, Joachim Schorr, David D Halbert
Journal: Journal of Clinical Oncology (2014)

e22052 Background: Molecular profiling-guided treatment strategies are frequently being used when other options do not exist. The availability of data generated by next-generation sequencing (NGS) has ushered in a new era of molecular profiling and needs to be evaluated for use in making clinical treatment decisions. As such, we propose a definition for actionable molecular data and show the frequency of actionable alterations across a variety of platforms including immunohistochemistry (IHC), in situhybridization (ISH), and NGS. Methods: We evaluated 12,265 patients using 34 actionable biomarkers to make associations with 43 FDA-approved drugs. We define a biomarker alteration as actionable when the association between the alteration and the drug is supported by clinical evidence. In this analysis, clinical evidence was demonstrated by a randomized prospective study, a nonrandomized cohort/case-controlled retrospective or an observational study with statistically significant associations showing predictive utility. We did not deem biomarkers and drugs connected only by mechanistic associations (e.g., a common cellular pathway) as actionable, as treating patients with compounds not demonstrated to be effective by clinical evidence may not be optimal. Results: Using the above definition of actionable, we found that recommendations could be made for drugs with a potential beneficial response for 94% of patients and a recommendation against drugs with a potential lack of benefit could be made for 97% of patients. Of the beneficial compounds identified, 87% were driven by IHC and ISH results, 13% by IHC, ISH, and NGS results, and 0.2% by NGS results alone. Of the lack of benefit compounds identified, 74% were driven by IHC and ISH, 20% by IHC, ISH, and NGS, and 6% by NGS alone. Conclusions: These results show that a multiplatform approach to molecular profiling is essential to provide patients with the clinically supported information needed to help treat their disease with broadly available therapies. Using NGS alone misses the majority of actionable alterations, but may prove more beneficial when the next generation of targeted therapies is available.
Therapy-Related Myeloid Neoplasms Following Autologous Stem Cell Transplantation: The Prevalence of Chip Mutations at Time of Transplantation — a Single Center Experience
Authors: Johannes Frasez Soerensen, Anni Aggerholm, Gitte Birk Kerndrup, Marcus C Hansen, Ina Kathrine Lykke Ewald, Lene Hyldahl Ebbesen, Carina A Rosenberg, Peter Hokland, Anne Stidsholt Roug, Maja Ludvigsen
Journal: Blood (2018)
Activity of TGR-1202, a novel once-daily PI3Kδ inhibitor, in patients with relapsed or refractory hematologic malignancies.
Authors: Howard A. Burris, Manish R. Patel, Mark C. Lanasa, Danielle Brander, Owen A. O'Connor, Changchun Deng, Martin Gutierrez, Suzanne Fields Jones, John G. Kuhn, Hari P. Miskin, Peter Sportelli, Swaroop Vakkalanka, Ian Flinn
Journal: Journal of Clinical Oncology (2014)

2513 Background: TGR-1202 is a novel, next generation PI3Kδ inhibitor. Preliminary data from an ongoing Ph I study of TGR-1202 demonstrated clinical activity in patients (pts) with advanced hematologic malignancies. Herein we present updated results from this Phase I, first in human study of TGR-1202. Methods: TGR-1202 is administered orally daily following a 3+3 dose escalation design. Previously treated pts with an ECOG PS < 2 and confirmed diagnosis of B-cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other lymphoproliferative disorders are eligible. Endpoints include safety, PK/PD, and efficacy. Results: 27 pts have been enrolled to date across 7 dose levels: 50, 100, 200, 400, 800, 1200, and 1800 mg QD. 74% male, ECOG 0/1: 33%/67%, median age of 59 yrs (range: 28-82), median 3 (range: 1-14) prior treatment regimens, and 40% were refractory to prior treatment. Evaluable pts include 7 indolent NHL (iNHL), 11 CLL/SLL, 4 Hodgkin's lymphoma (HL), 2 mantle cell lymphoma (MCL), 1 each of lymphoplasmacytic lymphoma, DLBCL, and atypical hairy cell leukemia. TGR-1202 was well tolerated. Gr≥3 AE's in >5% of patients were limited to: dyspnea (7%), neutropenia (15%), rash (7%), and thrombocytopenia (7%). Two DLTs were observed: 1 Gr. 3 rash at 800 mg (pt rechallenged with no recurrence), and 1 Gr. 3 hypokalemia at 1800 mg (pt discontinued due to non-compliance). Notably, no hepatotoxicity has been observed to date. Of the 27 enrolled, 23 were evaluable for efficacy. A significant dose-response relationship was observed. Of the 13 pts treated at < 800 mg QD who completed 2 cycles of treatment, 7 achieved SD. Of 10 pts treated at ≥ 800 mg QD: 4/6 CLL pts (67%) achieved a nodal PR, 1/3 Hodgkin's pts (33%) achieved a PR. Nodal reductions occurred rapidly in patients with CLL and were accompanied by marked lymphocytosis. Conclusions: TGR-1202 is well tolerated in pts with rel/ref hematologic malignancies with no reported hepatic toxicity and signs of clinical activity at doses ≥ 800 mg QD. Enrollment continues in expansion cohorts and at higher dose cohorts. Updated safety, efficacy, PK, and PD data will be presented. Clinical trial information: NCT01767766.
Evaluation of CT changes in the neck after cancer treatment: Development of a measuring tool.
Authors: Barbara A. Murphy, Joseph M. Aulino, Sheila H. Ridner, Kenneth J. Niermann, Jie Deng, Mary S. Dietrich
Journal: Journal of Clinical Oncology (2014)

e17052 Background: The late effect continuum of soft tissue lymphedema and fibrosis (LEF) affects more than 70% of head and neck cancer (HNC) patients resulting in increased symptom burden and decreased function/quality of life. We undertook the development of a tool that may allow post treatment surveillance imaging to objectively assess soft tissues changes of LEF. Methods: The tool was initially constructed to incorporate assessment of known sites of soft tissue damage secondary to surgery and/or radiation. It was applied to the baseline and post-treatment CT scans for 10 patients with HNC. Review of data by an expert panel resulted in tool modification. The process was reiterated until a final draft was formulated. The final draft was then used to score 176 CT exams from 20 patients (range 4-14 exams/patient). Results: The draft tool evaluates fat stranding using an ordinal grading scale of 0-2. To accommodate for considerable differences in patient positioning over time, 2 mm thick oblique axial reformatted images are generated parallel to the C4-5 disc space. These images are used to measure skin thickness, prevertebral soft tissue swelling, platysma thickness, and fat stranding in 5 locations. Sagittal reformatted images are used to assess epiglottis thickness, skin thickness, and midline submandibular fat stranding. Neck circumference cannot be measured reliably because of the variability of patient positioning, and the anteroposterior dimension is used as a surrogate. CT Exams that did not include thin-section ‘source’ images could not be used to generate additional reformatted images, and evaluation of these studies was incomplete. Surgical violation of neck fat results in partial or total obliteration on CT images, and prevents reliable evaluation of neck fat focally. Conclusions: We have developed a tool to measure CT changes in soft tissue in HNC patients treated with chemotherapy, surgery, and/or radiation. The tool provides a standardized method for assessing critical sites that are involved by LEF. Studies correlating the CT appearance with clinical findings on physical exam and endoscopy are underway. This tool may provide a clinically important method for using CT to objectively evaluate LEF.
Genomic characterization of metastatic cisplatin-resistant samples from urothelial cancer patients.
Authors: Yohann Loriot, Christophe Massard, Celine Lefebvre, Semih Dogan, Elena Ileanaecaterina, Ludovic Lacroix, Bastien Job, Maud Ngo-camus, Karim Fizazi, Nathalie Auger, Catherine Richon, Valerie Koubi-Pick, Antoine Hollebecque, Thierry De Baere, Philippe Vielh, Marie-cecile Ledeley, Gilles Vassal, Alexander M. Eggermont, Fabrice Andre, Jean-Charles Soria
Journal: Journal of Clinical Oncology (2014)

11057 Background: Although several studies have reported genomic characterisation of primary urothelial carcinoma (UC), little is known about the genomic alterations of the metastatic cisplatin-resistant tissues. We sought to define the prevalence and co-occurrence of actionable genomic alterations in patients with metastatic cisplatin-resistant lethal UC. Methods: Patients with metastatic UC, who progressed after at least one line of standard therapy, were enrolled in a prospective molecular screening trial (MOSCATO 01) at Gustave Roussy. CT-Scan or ultrasound-guided biopsies were performed in metastases to carry out a comprehensive molecular characterization. DNA was extracted from fresh tumor samples and analyzed by comparative genomic hybridization (CGH) (≥ 30% tumor cells required) and by Next Generation Sequencing (NGS) for up to 74 target genes (≥ 10% tumor cells required). Whole-exome sequencing (WES) was performed retrospectively in selected cases. Results: From December 2011 to December 2013, 30 heavily pretreated patients with metastatic UC were included in the MOSCATO 01 trial. Median age was 61 (37-73); All patients had been treated with platin-based chemotherapy with a median number of lines of 2.5 (1-5). Out of them, a tumor biopsy could be performed in 26 patients (87%). CGH and targeted exome sequencing profiles were assessed in 19 (73%) and 23 (88%) of them, respectively. A total of 19 patients (73% of biopsied patients) were profiled for both sequencing and CGH. WES was performed in 16 (62%) pairs of metastatic tissue and normal DNA (Integragen Inc, Hiseq platform). Our analyses identified potential therapeutic targets in 61 % of the tumours, including 31% with targets in the PI3K/AKT/mTOR pathway, 31% with targets in the FGF/FGFR pathway and 15% with targets in the RTK/MAPK pathway (including ERBB2). Others frequent aberrations were found in the chromatin regulatory genes (MLL gene family) and cell-cycle regulatory genes (E2F3, CDKN2A/B genes). Conclusions: Lethal platin-resistant UC exhibit high-level of genomic heterogeneity. The majority of these tumors harbour actionable genomic alterations that can be targeted with selective agents currently in clinical development or registered.
Survival outcomes of metastatic/unresectable hepatocellular carcinoma patients treated with sorafenib.
Authors: Jomjit Chantharasamee
Journal: Journal of Clinical Oncology (2014)

e15109 Background: Hepatocellular carcinoma is a common cancer in Asia-Pacific region due to high incidence of chronic viral hepatitis B infection. There are several studies showed the lower survival rate among the patients in the Asian-Pacific region compared with patients in north america possibly due to Sorafenib has been less efficious in HBV population. No survival data available among patients in Thailand. Methods: From January 2008 to September 2013, we had retrospectively reviewed the clinical outcomes of 83 metastatic/unresectable hepatocellular carcinoma patients treated with Sorafenib and compared the survival with different prognostic factors. Results: There were 83 patients start treating metastatic/unresectable hepatocellular carcinoma with Sorafenib. A median age of 56 years old. 85% were male. 51%of patients had extra-hepatic disease at the time of Sorafenib was indicated. Chronic viral hepatitis B were found in 68% of patients. The median duration of full dose administration was 1.35 months.(95%CI 0.03-50.23). The median duration of treatment was 2.33 months(95%CI 0.33-50.23). The most common reason for discontinuation of treatment was progressive disease. Among 80 available reports, the most frequently grade3 toxicities were HFS (9.6%) and diarrhea (7.2%). A grade3 diarrhea and grade3 HFS, respectively, occurred in two patients who had treatment-related toxicities lead to discontinuation. Median overall survival was 5.2 months (95%CI 0.77-9.63). 1-year overall survival was 29%. Median progression-free survival was 2.88 months (95%CI 2.20-3.45). We found similar survival outcomes between different prognostic factors. Conclusions: The Clinical outcome and toxicities profiles of Sorafenib among the patients in Thailand consistent with the previous large randomised controlled studies. Sorafenib is appropriate for treatment with well tolerated.
Top health official resigns over Italy’s “antiscientific” stance
Authors: Michael Day
Journal: BMJ (2019)

The head of Italy’s national health technology body has resigned, accusing the government of ignoring scientific evidence on vaccines and sinking to the type of populist policy that has marked the government of Donald Trump in the US.

Walter Ricciardi, president of the National Institute of Health (Istituto Superiore di Sanita), said that the antivaccine stance of the League and Five Star Movement coalition and its “unfounded” claims that immigrants spread diseases had made his position at the institute untenable.

In an interview with the national daily newspaper Corriere della Sera Ricciardi said that “representatives of the government have endorsed unscientific or frankly antiscientific positions on many issues.” His …
Mapping HRQoL questionnaires into utilities for prostate cancer patients: Epic, UCLA-PCI, SHIM, IPSS, SF36 to PORPUS.
Authors: Renske MT ten Ham, Jeanette M Broering, Matthew R. Cooperberg, John Kornak, Leslie S Wilson, Peter Carroll
Journal: Journal of Clinical Oncology (2014)

e16012 Background: Patients diagnosed with prostate cancer (PCa) have similar survival rates across treatments, making treatments choices based on health related quality of life (HRQoL) more important. It is unknown how the general and disease specific HRQoL measures relate to one other. We developed functions (mapped) to predict Patient Oriented Prostate Utility Scale (Porpus) utilities from 5 different HRQoL questionnaires: Expanded Prostate Cancer Index 26 (EPIC), UCLA Prostate Cancer Index (PCI), Sexual Health Inventory for Men (SHIM), International Prostate Symptom Score (IPSS) and Short Form 36v2 (SF36). Methods: 1,720 CaPSURE patients completed the six questionnaires, at the same time. The full cohort was randomly split into a model and validation cohort. Each utility was mapped using individual questions (IPSS, SHIM) or total scores (EPIC, PCI, SF36). We performed identity, log, square and logit-transformations of the dependent variable (Porpus utility). Linear and Lowess regression models were fitted to the model dataset for each dependent variable and compared. The predicted and actual scores were compared with t-tests. R2and root mean square errors (RMSE) were computed and models further examined within specific disease severity level subsets. Results: For EPIC and SHIM, a logit transformed model fit best as: log(PorpusU/(1-PorpusU))= 0.53 + 0.00080 * EPIC(Urinary Incontinence)score + 0.00045* EPIC(Urinary Irritation)score + 0.0011 * EPIC(Bowel)score + 0.0015 * EPIC(Sexual)score + 0.0014 * EPIC(Hormonal)score). A linear model was preferred for IPSS and a log transformed linear model for PCI and SF36. The difference between Porpus predicted and observed utilities mapped from EPIC, PCI, SHIM, IPSS and SF36 were respectively 0.007, -0.004, 0.012, 0.001 and -0.004 (all p<0.01). IPSS and SF36 had the lowest R2(0.22 and 0.25) and others ranged from 0.41-0.66. Conclusions: We were able to adequately predict utility scores using different general and disease specific questionnaires. These mapping equations are useful for determining the relationship of HRQoL measures commonly used in prostate cancer. Mapping to utility scores also allows use of HRQoL in cost-effectiveness analyses.
Abstract 15372: The Right Ventricular Infundibular Sparing Approach for the Repair of Tetralogy of Fallot Results in Better Intermediate-Term Right Ventricular and Left Ventricular Systolic Function as Assessed by Cardiac MRI
Authors: Mary K Olive, Shelby Kutty, Charles D Fraser, Emmett D McKenzie, James M Hammel, Rajesh Krishnamurthy, Shiraz A Maskatia
Journal: Circulation (2014)

Introduction: The right ventricular infundibular sparing approach (RVIS) to repair Tetralogy of Fallot (TOF) avoids the ventricular incision used in the transventricular (TV) approach. Hypothesis: ...
INNOVA: A phase II randomized study comparing INterval versus NeOadjuVAnt chemotherapy in magnetic resonance imaging-defined high risk rectal cancer.
Authors: Ramakrishnan Ayloor Seshadri, Trivadi S. Ganesan, Arunkumar M N, Shirley Sundersingh
Journal: Journal of Clinical Oncology (2018)

TPS879 Background: Patients with rectal cancers treated with neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy are not exposed to systemic doses of chemotherapy until very late in the treatment schedule. Preoperative chemotherapy, either in the neoadjuvant or interval setting can lead to early treatment of micrometastasis, improve the tumor response and possibly the overall survival. Phase II studies of neoadjuvant chemotherapy in rectal cancer have shown good response to chemotherapy with no tumor progression and good compliance. A phase II study evaluating the effect of giving chemotherapy in the interval waiting period between chemoradiation and surgery has shown acceptable toxicity and high pathological complete response rates. Methods: This single centre, randomized, open label, phase II trial compares the safety and efficacy of two pre-operative regimens in locally advanced MRI defined high-risk rectal cancers. Based on the Simon optimal two-stage design, 94 patients will be randomised to either Arm A [3 cycles of neoadjuvant chemotherapy (capecitabine and oxaliplatin) followed by chemoradiation (50.4 Gy with capecitabine) and then surgery] or Arm B [neoadjuvant chemoradiation followed by 3 cycles of interval chemotherapy and then surgery]. Patients in both arms receive 3 cycles of adjuvant chemotherapy. The primary end-point is the pathological complete response rate. Secondary end-points include frequency and severity of adverse events, RO resection rates, tumor regression grading and compliance to treatment. The inclusion criteria: age 18 to 70 years; ECOG performance status 0-2; non-metastatic, locally advanced rectal cancer with any one of the following features on high-resolution thin slice MRI: any T3/T4 tumor in the lower rectum, T3c/T3d/T4 tumor in the mid rectum, N2 disease, threatened mesorectal fascia, or extramural vascular invasion. Patients are randomly assigned to one of the two intervention arms in a 1:1 ratio. Prespecified activity goal for the first stage of accrual was met; second stage accrual began in July 2017. Clinical trial information: CTRI/2015/01/005385.
Comparing the Liver Function of Children with Acute Lymphoblastic Leukemia (ALL) Receiving Standard or High Intensity Treatment during the Interim Maintenance I Phase of Therapy: A Study of 658 Patients
Authors: Joanna S. Yi, Tiffany Simone Chambers, Kelly D Getz, Michael Scheurer, Philip J Lupo, Evanette Burrows, Marla Daves, Richard Aplenc, Karen R. Rabin, M. Monica Gramatges
Journal: Blood (2018)