tbuckley/cabot-search huggingface dataset:
Which patients with rhabdomyosarcoma (RMS) do need radiotherapy (RTX)? The long-term results of the CWS studies -81, -86, -91, and -96.
Authors: Ewa Koscielniak, Andreas Schuck, Tobias M. Dantonello, Daniel Kosztyla, Thekla von Kalle, Ivo Leuschner, Marc W. Muenter, Heike Scheithauer, Guido Seitz, Bernarda Kazanowska, Gustaf Ljungman, Ruth L Ladenstein, Felix Niggli, Rupert Handgretinger, Stefan S. Bielack, Thomas Klingebiel
Journal: Journal of Clinical Oncology (2014)

10005 Background: RTX is an essential therapy modality in the treatment of RMS. However, RTX is associated with severe late effects, therefore the indication and the optimal dose are still a matter of controversy. The stratification for the RTX indication and cumulative dose has been optimized in the consecutive CWS trials. Here we report the long-term results of four consecutive prospective trials. Methods: A total of 998 patients enrolled in the CWS-81, 86, -91 and -96 met the inclusion criteria for this analysis: 1) RMS histology 2) localized tumor (IRS Group I-III) 3) complete RTX data set and 4) follow up of minimum 10 yrs. 171 patients were classified as IRS Group I, 171 as IRS Group II and 656 as IRS Group III. 200 tumors (20%) had alveolar histology (RMA). The indication for RTX and the doses of 32Gy, 40Gy, 45Gy, 48Gy, 50Gy and 54Gy were stratified according to patient and tumor related factors. Results: The 5yrs event free survival (EFS) and overall survival (OS) did not differ between the trials included in the analysis. 630 pts were irradiated (63%).There was no major difference in proportion of irradiated patients between the trials 81-96 (62%, 59%, 71%, 61%). The 5yrs EFS by IRS Groups and RTX vs. no RTX were as follows: IRS I 60% vs. 84%, IRS II 73% vs. 72%, IRS III 62% vs. 57% (n.s.). The 5yrs EFS by RTX dose (32±2Gy vs. > 34Gy) were: IRS II 80% vs. 69%, IRS III 70% vs. 61%. Restricting the analysis to alveolar type: the 5 yrs EFS of patients irradiated with 32±2Gy vs. > 34Gy were as follows: IRS II 50% vs. 59%(n.s.), IRS III 30% vs. 41% (n.s.). There was no difference in EFS when splitting the RMS patients irradiated with > 34Gy into 40Gy vs. 45Gy, vs. 48Gy vs. 50 vs. 54Gy. Conclusions: The stratification criteria for RTX seem to compensate for different risk factors and allowed for reducing the cumulative dose to 32Gy in the lower risk group. However, the proportion of irradiated patients could not be reduced significantly. Further improvement in identification of patients who do not need RTX is needed.
Quantitative Magnetic Particle Imaging Monitors the Transplantation, Biodistribution, and Clearance of Stem Cells <i>In Vivo</i>
Authors: Bo Zheng, Marc P. von See, Elaine Yu, Beliz Gunel, Kuan Lu, Tandis Vazin, David V. Schaffer, Patrick W. Goodwill, Steven M. Conolly
Journal: Theranostics (2015)

Stem cell therapies have enormous potential for treating many debilitating diseases, including heart failure, stroke and traumatic brain injury. For maximal efficacy, these therapies require targeted cell delivery to specific tissues followed by successful cell engraftment. However, targeted delivery remains an open challenge. As one example, it is common for intravenous deliveries of mesenchymal stem cells (MSCs) to become entrapped in lung microvasculature instead of the target tissue. Hence, a robust, quantitative imaging method would be essential for developing efficacious cell therapies. Here we show that Magnetic Particle Imaging (MPI), a novel technique that directly images iron-oxide nanoparticle-tagged cells, can longitudinally monitor and quantify MSC administration in vivo. MPI offers near-ideal image contrast, depth penetration, and robustness; these properties make MPI both ultra-sensitive and linearly quantitative. Here, we imaged, for the first time, the dynamic trafficking of intravenous MSC administrations using MPI. Our results indicate that labeled MSC injections are immediately entrapped in lung tissue and then clear to the liver within one day, whereas standard iron oxide particle (Resovist) injections are immediately taken up by liver and spleen. Longitudinal MPI-CT imaging also indicated a clearance half-life of MSC iron oxide labels in the liver at 4.6 days. Finally, our ex vivo MPI biodistribution measurements of iron in liver, spleen, heart, and lungs after injection showed excellent agreement (R(2) = 0.943) with measurements from induction coupled plasma spectrometry. These results demonstrate that MPI offers strong utility for noninvasively imaging and quantifying the systemic distribution of cell therapies and other therapeutic agents.
Neonatal thymectomy reveals differentiation and plasticity within human naive T cells
Authors: Theo van den Broek, Eveline M. Delemarre, Willemijn J.M. Janssen, Rutger A.J. Nievelstein, Jasper C. Broen, Kiki Tesselaar, Jose A.M. Borghans, Edward E.S. Nieuwenhuis, Berent J. Prakken, Michal Mokry, Nicolaas J.G. Jansen, Femke van Wijk
Journal: Journal of Clinical Investigation (2016)

The generation of naive T cells is dependent on thymic output, but in adults, the naive T cell pool is primarily maintained by peripheral proliferation. Naive T cells have long been regarded as relatively quiescent cells; however, it was recently shown that IL-8 production is a signatory effector function of naive T cells, at least in newborns. How this functional signature relates to naive T cell dynamics and aging is unknown. Using a cohort of children and adolescents who underwent neonatal thymectomy, we demonstrate that the naive CD4+ T cell compartment in healthy humans is functionally heterogeneous and that this functional diversity is lost after neonatal thymectomy. Thymic tissue regeneration later in life resulted in functional restoration of the naive T cell compartment, implicating the thymus as having functional regenerative capacity. Together, these data shed further light on functional differentiation within the naive T cell compartment and the importance of the thymus in human naive T cell homeostasis and premature aging. In addition, these results affect and alter our current understanding on the identification of truly naive T cells and recent thymic emigrants.
<i>HABP2</i>G534E Mutation in Familial Nonmedullary Thyroid Cancer
Authors: Tao Zhang, Mingzhao Xing
Journal: JNCI Journal of the National Cancer Institute (2016)

Papillary thyroid cancer (PTC) is a common endocrine malignancy, accounting for nearly 90% of all thyroid cancers. About 5% of PTC is hereditary familial nonmedullary thyroid cancer (FNMTC). No general susceptibility gene is known for FNMTC. An oncogenic HABP2 G534E mutation has been recently reported in one FNMTC kindred, suggesting that HABP2 is a susceptibility gene for FNMTC. Because of the limited kindred studied, how commonly this gene is responsible—and hence how important clinically it is—for FNMTC remains to be answered. By investigating a large number of FNMTC kindreds in the present study, we identified HABP2 G534E in several independent kindreds of FNMTC. The overall prevalence of HABP2 G534E was six per 43 (14.0%) PTC patients from the 29 kindreds and four per 29 (13.8%) kindreds. None of the subjects with benign thyroid neoplasm or the normal subjects from these kindreds had this mutation. These results are consistent with HABP2 G534E being a susceptibility gene in a subgroup of FNMTC, providing important diagnostic implications for this hereditary thyroid cancer.
MPTH-10MOLECULAR-GENETIC AND CLINICAL RISK FACTORS FOR PATIENTS WITH GLIOMAS WITH TOTAL 1p19q LOSS
Authors: Saeko Tanaka, Hikaru Sasaki, Yohei Kitamura, Yuichi Hirose, Kazunari Yoshida
Journal: Neuro-Oncology (2015)

Codeleted gliomas are associated with better response to therapy and longer survival. However, early recurrence occurs at times, and there are cases with short survival despite 1p19q loss. Although several unfavorable prognostic factors are known for low grade gliomas, the risk factors for patients with codeleted gliomas has not been elucidated. We studied 57 codeleted tumors of WHO grade II-III for chromosomal copy number abnormality (CNA) by comparative genomic hybridization (metaphase CGH), promoter methylation of the MGMT gene by methylation-specific PCR as well as clinical factors known to be associated with prognosis of glioma patients. Overall survival (OS) curves were estimated using the Kaplan-Meier method, and compared by grade (grade 2 versus grade 3), age (patients from 50 years up versus under 50 years of age, ), extent of surgery (over 95% removal versus partial removal versus biopsy), tumor maximum diameter (larger than 5cm diameter versus less), copy number abberations detected in more than 10% of all cases, status of MGMT methylation and pathological diagnosis by original institutional diagnosis (oligodendroglial versus astrocytic). As a result, there was no significant difference in OS for age, extent of surgery, maximum tumor diameter, histological feature and status of MGMT methylation. On the other hand, the OS was significantly shorter in the patients with gliomas with gain of 19p (p = 0.011), and gain on 17q and histological grade III showed trends towards poor prognosis (p = 0.055, 0.1, respectively).In conclusion, gain of 19p, gain on 17q, and histological grade III might be unfavorable prognostic factors of gliomas with total 1p19q loss.
Prospective surveillance vs clinically driven approach for CMV reactivation after autologous stem cell transplant
Authors: A Mengarelli, O Annibali, F Pimpinelli, E Riva, S Gumenyuk, D Renzi, E Cerchiara, L Piccioni, F Palombi, F Pisani, A Romano, A Spadea, E Papa, I Cordone, M Canfora, W Arcese, F Ensoli, F Marchesi
Journal: Journal of Infection (2015)
Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukemia.
Authors: M L Varterasian, R M Mohammad, D S Eilender, K Hulburd, D H Rodriguez, P A Pemberton, J M Pluda, M D Dan, G R Pettit, B D Chen, A M Al-Katib
Journal: Journal of Clinical Oncology (1998)

PURPOSE To define, in a phase I study in relapsed non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), the maximum-tolerated dose (MTD), major toxicities, and possible antitumor activity of bryostatin 1, a macrocyclic lactone. PATIENTS AND METHODS Bryostatin 1 was delivered by 72-hour continuous infusion every 2 weeks to patients with relapsed NHL or CLL, at doses that ranged from 12 microg/m2 to 180 microg/m2 per course. Correlative investigations included evaluations of total protein kinase C (PKC) in peripheral blood and lymphoid differentiation in patient tumor tissue. RESULTS Twenty-nine patients were treated, including three patients with CLL and 26 with NHL. Generalized myalgia was the dose-limiting toxicity (DLT) and occurred in two of three patients treated with bryostatin 1 at 180 microg/m2 per course. Myalgias were dose-related and cumulative, and often started in the thighs and calves, improved with activity, were somewhat responsive to analgesics, and often took weeks to resolve once taken off study. Six patients were treated at the MTD of 120 microg/m2 per course. Myalgia, headache, and fatigue were common. Hematologic toxicity was uncommon. Total cumulative doses of bryostatin 1 up to 1,134 microg/m2 have been administered without untoward toxicity. Eleven patients achieved stable disease for 2 to 19 months. An in vitro assay for total PKC evaluation in patient peripheral-blood samples demonstrated activation within the first 2 hours with subsequent downregulation by 24 hours, which was maintained throughout the duration of the 72-hour infusion. CONCLUSION This phase I study defined the MTD and recommended phase II dose of bryostatin 1, when administered over 72 hours every 2 weeks, to be 120 microg/m2 (40 microg/m2/d for 3 days). Generalized myalgia was the DLT. Future studies will define the precise activity of bryostatin 1 in subsets of patients with lymphoproliferative malignancies and its efficacy in combination with other agents.
A randomized phase II study comparing capecitabine (C) with C plus oral cyclophosphamide (CCy) in patients (pts) with advanced breast cancer (BC)
Authors: V. J. Harvey, K. Sharples, R. Isaacs, M. B. Jameson, M. Jeffery, B. McLaren, S. Pollard, G. Riley, A. Simpson, M. P. Findlay
Journal: Journal of Clinical Oncology (2008)

1077 Background: C is an active cytotoxic, either alone or in combination, for patients with advanced BC. Cyclophosphamide has nonoverlapping toxicities with C, and shows synergistic activity preclinically. We explored the feasibility, efficacy, and toxicity of an all-oral combination of CCy vs C alone in a multicenter, national, randomized, Phase II study. Methods: Patients with locally advanced or metastatic BC eligible for 1st- or 2nd-line chemotherapy were randomized to treatment with either C alone 666 mg/m2 bid continuously days 1–28, or C plus oral cyclophosphamide 100 mg/m2 days 1–14 on a 28-day cycle for up to 6 cycles. Co-primary endpoints were tumor response and toxicity profile. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). In the 3-region design differences in tumor response were set a priori such that i) >20% would be considered evidence of benefit of CCy over C; ii) between 7.6% and 20% would indicate that CCy should be evaluated further; and iii) <7.6% would suggest no evidence of benefit of CCy over C. Results: 42 pts were randomized to C and 40 to CCy. Groups were well balanced for all baseline prognostic factors. There was no complete response, but partial responses occurred in 31.0% of pts on C and 43.6% on CCy, a difference of 12.6% (95% CI: -8.2% to 33.6%). Significant toxicity was uncommon: grade ≥3 diarrhea in 4 (9.5%) vs 1 (2.5%) pts; grade ≥3 fatigue in 2 (4.8%) vs 5 (12.5%); and hand-foot syndrome at grade ≥2 in 7 (16.7%) vs 11 (27.5%) pts on C vs Ccy, respectively. Conclusions: The 12.6% difference in tumor response was in the middle region of the 3-region design. We conclude that there is a reasonable chance that Ccy is superior to C alone, and given the low toxicity rates in both arms this regimen should be explored in a larger trial. PFS and OS data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche Roche
National survey of oncology fellows on palliative care education
Authors: M. K. Buss, D. S. Lessen, J. Von Roenn, A. M. Sullivan, R. M. Arnold, S. D. Block
Journal: Journal of Clinical Oncology (2009)

9541 Background: Palliative care (PC) is recognized as an integral part of the practice of oncology, yet many oncologists report inadequate training in critical PC domains, such as symptom management, psychosocial care and communication skills. We sought to assess the quantity and quality of PC education within oncology fellowships. Methods: Second year fellows enrolled in US oncology fellowships were invited to complete a 104 item survey that was modified from a national telephone survey of medical students and residents. Topics included: 1) quality and quantity of teaching and education, 2) observation and feedback, 3) knowledge, 4) attitudes and preparation. Items were designed to allow comparison between PC and non-PC topics. To reduce Type I errors from multiple testing, an alpha level of 0.01 was considered statistically significant. Results : Of 402 eligible fellows, 63.5% responded (n=254). Respondents were: 52% male, 62% White, 27% Asian and 64% US medical school graduates. One-quarter (26%) had completed a PC rotation and 68% reported exposure to palliative care during their fellowship. On a 5-point Likert Scale, fellows rated teaching on PC less highly than the overall quality of fellowship teaching (3.0 v 3.7; p&lt;0.001). Fellows rated attending oncologists less favorably in performing PC skills compared to other oncology skills: managing pain in the terminally ill versus managing spinal cord compression (3.9 v. 4.5; p &lt; 0.001); discussing the decision to stop chemotherapy versus discussing chemotherapy side effects (3.8 v. 4.2; p &lt; 0.001). Fellows were less likely to be observed (81% v 93%; p =0.005) or receive feedback (80 v 93%; p= 0.02) on end-of-life (EOL) discussions than bone marrow biopsies. Many fellows reported not receiving explicit education on PC topics: managing depression at the EOL (68%), opioid rotation (67%), telling a patient she is dying (42%) and hospice referral (37%). Fellows who completed a PC rotation were more likely to report explicit teaching on opioid rotation (p =0.005) and hospice referral (p = 0.002). Conclusions: Our study reveals opportunities for improving the PC training of oncology fellows. No significant financial relationships to disclose.
Abstract 10912: Chronic Iron Deposition following Acute Hemorrhagic Myocardial Infarction: A Cardiovascular Magnetic Resonance Study
Authors: Avinash Kali, Andreas Kumar, Ivan Cokic, Richard Tang, Sotirios Tsaftaris, Matthias Friedrich, Rohan Dharmakumar
Journal: Circulation (2012)

Introduction - Intramyocardial hemorrhage frequently occurs in large reperfused myocardial infarctions (MI). However, its long-term fate remains unexplored. Hypothesis - We hypothesize that intramyocardial hemorrhage, secondary to reperfused MI, results in chronic iron deposition within infarcted territories. Methods - We studied 15 patients by Cardiovascular Magnetic Resonance (CMR) T2* mapping (1.5T) on day 3 and 6 months after successful percutaneous coronary intervention for first STEMI. Using the same CMR protocol, we also studied 20 canines, on days 3 and 56 post ischemia-reperfusion injury, of which 3 animals received sham procedures. Subsequently, canine hearts were explanted, imaged ex-vivo, and samples of hemorrhagic infarcts (Hemo+), non-hemorrhagic infarcts (Hemo-), remote and sham myocardium were isolated, sectioned and mass spectrometry was performed. Results - Eleven patients had Hemo+ (verified by T2* CMR on day 3) and their scar tissue T2* values remained significantly lower after 6 month...
Glycolysis and the pentose phosphate pathway are differentially associated with the dichotomous regulation of glioblastoma cell migration versus proliferation
Authors: Annegret Kathagen-Buhmann, Alexander Schulte, Jonathan Weller, Mareike Holz, Christel Herold-Mende, Rainer Glass, Katrin Lamszus
Journal: Neuro-Oncology (2016)

The dichotomy between glioblastoma cell migration and proliferation is regulated by various parameters including oxygen tension. In glioblastoma stem-like cells, hypoxia induces downregulation of pentose phosphate pathway (PPP) enzymes and a flux shift towards glycolysis. We investigated whether the 2 parallel glucose metabolic pathways are intrinsically linked with cell function and whether these pathways are mechanistically involved in regulating functional programs. Enzyme expression, migration, and proliferation under hypoxia were studied in multiple cell types. Rapidly and slowly dividing or migrating glioblastoma cells were separated, and enzyme profiles were compared. Glucose-6-phosphate dehydrogenase (G6PD) and Aldolase C (ALDOC), the most strongly inversely regulated PPP and glycolysis enzymes, were knocked down by short hairpin RNA. Hypoxia caused downregulation of PPP enzymes and upregulation of glycolysis enzymes in a broad spectrum of cancer and nonneoplastic cells and consistently stimulated migration while reducing proliferation. PPP enzyme expression was increased in rapidly dividing glioblastoma cells, whereas glycolysis enzymes were decreased. Conversely, glycolysis enzymes were elevated in migrating cells, whereas PPP enzymes were diminished. Knockdown of G6PD reduced glioblastoma cell proliferation, whereas ALDOC knockdown decreased migration. Enzyme inhibitors had similar effects. G6PD knockdown in a highly proliferative but noninvasive glioblastoma cell line resulted in prolonged survival of mice with intracerebral xenografts, whereas ALDOC knockdown shortened survival. In a highly invasive glioblastoma xenograft model, tumor burden was unchanged by either knockdown. Cell function and metabolic state are coupled independently of hypoxia, and glucose metabolic pathways are causatively involved in regulating “go or grow” cellular programs.
Disorders of Vascular Permeability
Authors: Cindy Park-Windhol, Patricia A. D'Amore
Journal: Annual Review of Pathology Mechanisms of Disease (2016)

The endothelial barrier maintains vascular and tissue homeostasis and modulates many physiological processes, such as angiogenesis. Vascular barrier integrity can be disrupted by a variety of soluble permeability factors, and changes in barrier function can exacerbate tissue damage during disease progression. Understanding endothelial barrier function is critical for vascular homeostasis. Many of the signaling pathways promoting vascular permeability can also be triggered during disease, resulting in prolonged or uncontrolled vascular leak. It is believed that recovery of the normal vasculature requires diminishing this hyperpermeable state. Although the molecular mechanisms governing vascular leak have been studied over the last few decades, recent advances have identified new therapeutic targets that have begun to show preclinical and clinical promise. These approaches have been successfully applied to an increasing number of disease conditions. New perspectives regarding how vascular leak impacts the progression of various diseases are highlighted in this review.
Phase II study of cetuximab in combination with carboplatin and docetaxel for patients with advanced/metastatic non-small cell lung cancer (NSCLC)
Authors: C. P. Belani, S. Ramalingam, M. Schreeder, R. Steis, R. Guidice, T. Marshland, B. Butler
Journal: Journal of Clinical Oncology (2007)

7643 Background: Cetuximab, a chimeric IgG1 monoclonal antibody against the external domain of the epidermal growth factor receptor (EGFR), has demonstrated single-agent activity against NSCLC. When administered in combination with carboplatin and docetaxel, a commonly used regimen for advanced NSCLC, cetuximab exhibits synergistic interaction in preclinical studies. Therefore, we conducted a phase II study to evaluate the efficacy of the combination of cetuximab, carboplatin, and docetaxel for the treatment of advanced NSCLC. Methods: Chemotherapy-naive patients = 18 years with histologically/cytologically confirmed stage IIIB (w/ effusion) or stage IV NSCLC received cetuximab (400 mg/m 2 on day 1 and 250 mg/m 2 on days 8 and 15) plus docetaxel (75 mg/m 2 on day 1) and carboplatin (AUC=6 on day 1) every 21 days for up to 6 cycles. Thereafter, patients without evidence of disease progression (CR/PR/SD) were continued on single-agent cetuximab (250 mg/m 2 /week) for a maximum of 1 year or until disease progression. The primary endpoint was response rate. Results: 81 patients were enrolled and 76 are evaluable for response. Patient characteristics included: gender male/female, 43/38; median age 63 years (range 42–83); ECOG performance status 0/1/, 31/50; and stage IIIB/IV- 5/76. The median number of cycles administered was 4 (range 1–6). The response rate (CR/PR) was 14.5% (95% CI, 7.5 to 24.4), with a median progression-free survival of 4.7 months and a median overall survival of 11 months. With combination therapy, the salient grade 3/4 events were neutropenia (28%), febrile neutropenia (3.8%), hypotension (4%), hypokalemia and hypomagnesemia (5%), hypersensitivity (1%), acne-like rash (3%), peripheral neuropathy (1%), and myalgia (1%). Twenty-five patients received maintenance therapy with single-agent cetuximab (median duration of treatment was 12 weeks) and this was well tolerated. Conclusions: This large multicenter phase II study of the novel combination of cetuximab with docetaxel and carboplatin shows promising efficacy for patients with advanced and metastatic NSCLC and has an acceptable toxicity profile. No significant financial relationships to disclose.