tbuckley/cabot-search huggingface dataset:
Retrospective analysis of 561 breast magnetic resonance imaging (MRI). The largest study to dat
Authors: X. Tchiknavorian, S. Perruchio, P. Agin, A. Lachard, B. Beedassy, J. M. Blanc, L. Cals
Journal: Journal of Clinical Oncology (2004)

712 Background: More than 40,000 new breast cancer are discovered in France each year. Diagnosis is based on clinical examination, mammography and sonography, after histological control 70 to 85% of breast lesions are benign. There is no clearly defined indications for the use of MRI for detection, diagnosis and staging of breast cancer. Does MRI could reduce this percentage in good condition of safety? Methods: Our study is a retrospective study, including 561 patients with suspect mammography and/or echography. 318 have an histopathologically verified breast lesion, and 243 have been under medical supervision for at least 24 month after multidisciplinary board decision. Results: 158 cancers were found. For the combinated method (clinical examination, mammography, sonography and MRI) the sensibility was 93%, specificity 58% and negative predictive value (NPV) 95%, all of these have small confidence intervalle because of the important number of patients, and respectively 80%, 77% and 91% if we consider only breast MRI. The false positive were mainly benin proliferative lesions (fibroadenoma), false negative mainly intraductal carcinoma associated with micro-calcifications. Conclusions: MRI of the breast is useful as a further exam after usual investigations, especially in doubtful cases. The combined method increases sensibility and it keeps very good NPV. On the other hand, we must exclude from the indication of breast MRI all patients with micro-calcifications, which too often correspond to false negative. In some cases surgery could be avoid with a close follow-up. No significant financial relationships to disclose.
NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity
Authors: Takaya Moriyama, Rina Nishii, Virginia Perez-Andreu, Wenjian Yang, Federico Antillon Klussmann, Xujie Zhao, Ting-Nien Lin, Keito Hoshitsuki, Jacob Nersting, Kentaro Kihira, Ute Hofmann, Yoshihiro Komada, Motohiro Kato, Robert McCorkle, Lie Li, Katsuyoshi Koh, Cesar Rolando Najera, Shirley Kow-Yin Kham, Tomoya Isobe, Zhiwei Chen, Edwynn Kean-Hui Chiew, Deepa Bhojwani, Cynthia Jeffries, Yan Lu, Matthias Schwab, Hiroto Inaba, Ching-Hon Pui, Mary V Relling, Atsushi Manabe, Hiroki Hori, Kjeld Schmiegelow, Allen E J Yeoh, William E Evans, Jun J Yang
Journal: Nature Genetics (2016)
A dose and schedule optimizing evaluation of MG98 given as either a 2 hour IV infusion twice weekly or as a 7 day continuous infusion in combination with interferon alpha (INF) in nephrectomized patients (pts) with advanced renal cell carcinoma (RCC)
Authors: J. Stephenson, R. J. Amato, S. Hotte, J. Nemunaitis, B. Berman, K. Bélanger, T. A. Patterson, A. R. Macleod, G. K. Reid, R. E. Martell
Journal: Journal of Clinical Oncology (2006)

14557 Background: RCC is often associated with hypermethylated and silenced tumour suppressor genes. The enzyme DNMT1 is responsible for the majority of cellular DNA methylating capacity. MG98 is a second generation antisense inhibitor of DNMT1 which has been shown to reduce DNMT1 mRNA and protein. Methods: A trial of MG98 given as a 2 hour IV infusion twice weekly (Intermittent Schedule, IS) or as a 7 day continuous infusion (CI) in combination with INF has been conducted with nephrectomized pts with advanced RCC. Main endpoints: identification of the optimum regimen, safety, tolerability, pharmacokinetics (PK) and the degree of PBL DNMT1 mRNA suppression. Results: CI schedule: dose levels of 125mg of MG98 combined with 12 MIU of INF (125/12) and 125/9 have been evaluated (9 pts). The MTD has been reached; thrombocytopenia is dose limiting at 125/12. Pt demographics: M:F= 6:3, mean age of 63.2y (52–71). Most common Adverse Events (AEs): fever and chills (gr.1), fatigue (gr.1–2; 100% of pts), nausea and anorexia (gr.1–2), vomiting (gr.2; 66%). Best response: Stable Disease (SD) =3; Partial Response (PR) =1. Currently within the IS schedule, 3 dose levels (9 pts) have been evaluated: 160/12, 200/12 and 200/9, totaling 26 cycles. The MTD has been reached, with GI/constitutional symptoms being dose limiting at 200/12. Demographics: M:F= 7:2 median age 59.8y (40–76). Most common AEs in the first 3 pts are nausea and chills (100% of patients); fatigue (gr.1–2) and fever (66%; gr. 1–3). Best responses: 3 SD, 1 PR. PK evaluation on both schedules revealed no interaction between INF and MG98. DNMT1 inhibition data will be presented. Conclusions: Combination of INF and MG98 exhibits clinical activity and acceptable safety. [Table: see text]
Optimizing clinical use of biomarkers in high-risk acute heart failure patients
Authors: Biniyam G. Demissei, Mattia A.E. Valente, John G. Cleland, Christopher M. O'Connor, Marco Metra, Piotr Ponikowski, John R. Teerlink, Gad Cotter, Beth Davison, Michael M. Givertz, Daniel M. Bloomfield, Howard Dittrich, Peter van der Meer, Dirk J. van Veldhuisen, Hans L. Hillege, Adriaan A. Voors
Journal: European Journal of Heart Failure (2015)
CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation
Authors: Vinit Kumar, Pingyan Cheng, Thomas Condamine, Sridevi Mony, Lucia R. Languino, Judith C. McCaffrey, Neil Hockstein, Michael Guarino, Gregory Masters, Emily Penman, Fred Denstman, Xiaowei Xu, Dario C. Altieri, Hong Du, Cong Yan, Dmitry I. Gabrilovich
Journal: Immunity (2016)
A phase III trial of biologically-based therapy reduction for intermediate risk neuroblastoma
Authors: D. L. Baker, M. Schmidt, S. Cohn, W. B. London, A. Buxten, A. Sandler, H. Shimada, K. Matthay
Journal: Journal of Clinical Oncology (2007)

9504 Background: Infants with advanced neuroblastoma (stage 3 and 4) and children &gt;1 year with favorable biology stage 3 disease have had a survival exceeding 80% with aggressive chemotherapy. The primary objective of Childrens Oncology Group A3961 was to maintain a 3-year event-free and overall survival rate above 90% for intermediate risk (IR) neuroblastoma with a reduction in therapy compared to historical trials for similarly defined risk patients. Methods: IR patients were defined by selected clinical (age, INSS stage, histopathology) and biologic (MYCN status and DNA index) factors. All eligible IR patients were MYCN non-amplified and were divided into subcategories defined as favorable or unfavorable biology. Therapy consisted of 2 to 3 agent combinations of carboplatin, etoposide, cyclophosphamide and doxorubicin given every 3 weeks for a total of 4 cycles (favorable biology) or 8 cycles (unfavorable biology). Patients with favorable biology failing to achieve CR/VGPR after 4 cycles and surgery, received 8 cycles. All patients were required to enter a companion neuroblastoma biology study and to enroll on A3961 within 28 days of diagnosis. Results: Between March 1997 and May 2005, 467 eligible patients were enrolled on study. These included 261 stage 3 (105 children; 156 infants), 174 stage 4 infants, and 32 stage 4s infants. 362 (78%) were less than 12 months of age at diagnosis. 330 (71%) patients had favorable and 137 (29%) unfavorable biology. There were 40 (12.1%) of 330 favorable biology patients who went onto cycles 5–8. There were 52 events in 467 cases including 15 deaths and two secondary AML. Conclusions: The primary hypothesis of this study was confirmed and survival rates greater than 90% were maintained for IR neuroblastoma with reduced therapy compared to historical trials. The successor trial will prescribe duration of therapy based, in part, on loss of heterozygosity states at 1p36 and 11q23 as well as initial response to treatment in an endeavor to further reduce therapy for this group of patients. [Table: see text] No significant financial relationships to disclose.
Comparison of patients with early-, typical-, and late-onset affective psychosis
Authors: K W Sax, S M Strakowski, P E Keck, S L McElroy, S A West, M L Bourne, E R Larson
Journal: American Journal of Psychiatry (1997)

Objective: The authors compared the clinical characteristics and family history of patients with early-onset (before age 18), typical-onset (at 20-25 years), and late-onset (after age 35) affective psychosis at the time of first hospitalization.Method: Diagnostic, symptom, and family history information was obtained from 88 consecutively hospitalized patients.Results: Major depression was more common in the late-onset group, and a family history of affective and substance abuse disorders was more common among the early-onset patients.Affective symptoms differed significantly among groups; specifically, early-onset patients had more energy, minimal sleep disruption, and greater suicidality, while typical-onset patients had more severe abnormal thought content.Conclusions: Among patients with affective psychosis, there may be heterogeneity of symptoms and family history associated with age at first hospitalization.
Sector analysis to provide additional spatial information on the permanent prostate brachytherapy learning curve.
Authors: Ahamed Badusha Mohamed Yoosuf, Sai Jonnada, Eoin Napier, Monica M. Byrne, Margaret A. Flynn, Geraldine Workman, Darren M. Mitchell, Suneil Jain
Journal: Journal of Clinical Oncology (2015)

93 Background: To evaluate the spatial pattern of permanent prostate brachytherapy (PBT) learning curve using post-implant multi-sector dosimetric analysis. Methods: Two hundred patients treated with I-125 PBT at a single institution were assessed. A 12 sector analysis of post-implant CT was created for each case by dividing the prostate base, mid gland and apex into 4 sectors each. Dosimetric analysis was evaluated for whole prostate and individual sectors assessing: minimum dose to 90% of prostate (D 90 ) and dose to 0.1 cm 3 of the rectum (D 0.1cc ). Linear regression analysis and Pearson’s correlation co-efficient were used to investigate changes in D 90 with case number. Results: Global prostate analysis demonstrated a post-implant learning curve with significant improvement in D 90 (p&lt;0.01) in the last 50 cases (157.0 Gy ± 9.7) when compared to the initial 50 (141.6 Gy ± 14.5). Linear regression confirmed a significant improvement in global D 90 with case number (r 2 =0.19, p=0.0001) at a rate of 0.11 Gy/case. Sector analysis demonstrated greatest improvement in base sectors with increasing case number with an improvement of 0.16 Gy/case (Table; p=0.049 when compared to global D 90 ). Further, D 90 in posterior mid-gland reduced with case number and correlated with reduced rectal D 0.1cc . Conclusions: Sector analysis demonstrated increased spatial information on the PBT learning curve which may enable on-going improvements in implant quality. [Table: see text]
Initial results from a phase II study of increased-dose abiraterone acetate in patients with castration resistant prostate cancer (CRPC).
Authors: Terence W. Friedlander, Julie Nicole Graff, Li Zhang, Rosa Paz, Gayatri Premasekharan, Archana Dilip, Andrew Caleb Hsieh, Rahul Raj Aggarwal, Won Kim, Amy M. Lin, Lawrence Fong, Eric Jay Small, Pamela Paris, Charles J. Ryan
Journal: Journal of Clinical Oncology (2015)

188 Background: Resistance to abiraterone is hypothesized to result from increased systemic or tumor androgen production, mutations in the androgen receptor (AR) signaling pathway leading to ligand-independent, autonomous AR activity, and/or AR-independent pathways. This study investigated the clinical benefit of maximization of androgen suppression by increasing the abiraterone acetate dose at the time of initial resistance to standard-dose therapy. Methods: Eligible patients had progressive metastatic CRPC per consensus criteria. No prior abiraterone, enzalutamide, or chemotherapy was allowed. All patients started therapy with abiraterone acetate 1,000 mg daily and prednisone 5mg BID. Patients achieving any PSA decline after 3 cycles continued abiraterone until PSA or radiographic progression. At progression the abiraterone acetate dose was increased to 1,000 mg BID, prednisone was maintained at 5mg BID, and patients were monitored for response for a minimum of 12 weeks or until a second PSA or radiographic progression. Results: 41 patients were accrued from 3/2013 through 3/2014, and 13 patients currently remain on therapy. Median age was 68 (range 55-79), median ECOG PS was 0 (range 0-2), and median baseline PSA was 27.4 (range 3.9-1763). Thirteen men (31%) underwent a pre-treatment metastatic biopsy. To date 13 men who experienced progressive disease on standard-dose therapy were treated with 1,000 mg BID therapy, and are evaluable for response. No PSA declines ≥30% nor radiographic responses have been observed at the elevated-dose. Grade 3 transaminitis was observed in 1 patient on the elevated dose and resolved with dose decrease. Conclusions: Pharmacokinetic failure alone is unlikely to explain resistance to standard-dose abiraterone acetate and increasing the dose at the time of resistance may be of limited clinical utility. Analysis of serial androgen levels, abiraterone pK, and molecular and genomic analysis of circulating tumor cells and metastatic biopsies is underway, with a specific focus on the contributions of AR amplification, AR splice variation, and mesenchymal and neuroendocrine differentiation to the development of abiraterone resistance. Clinical trial information: NCT01637402.
Evaluation of pemetrexed (PEM) dosing paradigms using exposure-response relationships (ERRs)
Authors: J. Latz, L. Claret, J. Symanowski, C. Falcoz, R. Bruno, I. Smith, H. Calvert
Journal: Journal of Clinical Oncology (2007)

2530 Background: PEM is primarily renally eliminated and dosed based on body surface area (BSA). A direct relationship exists between creatinine clearance (CrCL) and PEM clearance (CL [and therefore exposure, AUC]). BSA-dosing has been increasingly challenged, especially for renally cleared drugs. ERRs and dosing paradigms (BSA, fixed, renal-based) were evaluated in silico for PEM. A superior dosing strategy is dependent on the strength of the ERR and results in decreased between-patient variability in both AUC and clinical outcome. Methods: An established pharmacokinetic model was used to estimate AUCs from CrCL for patients in malignant pleural mesothelioma (MPM) and NSCLC studies where patients with CrCL =45 mL/min received PEM 500 mg/m 2 q3w. AUC was evaluated as a predictor of clinical outcome (survival, TTPD, toxicities) to identify ERRs. Efficacy models included previously identified prognostic factors and inverse of mean AUC over the treatment period as covariates. Probability of toxicity was modeled as a function of AUC at each cycle. Simulations were performed for statistically and clinically significant ERRs to compare distributions of outcome for the 3 dosing paradigms. Results: AUC was individually significant (or borderline) in the survival and TTPD ERRs for MPM (PEM + cisplatin; N=226) and NSCLC (PEM; N=258). AUC was independently significant only for the NSCLC TTPD ERR. The distribution of simulated TTPDs for the 3 dosing paradigms were similar (see table ). Model-predicted increase in incidence of Grade 3–4 hematologic toxicities with increasing AUC was statistically but not clinically significant. Graphical review of nonhematologic toxicities showed trends by AUC. The incidence of death due to drug-related toxicities was too sparse for modeling. Conclusion: Neither renal-based nor fixed dosing provides a clinical benefit over BSA-based dosing for patients with CrCL =45 mL/min based on ERRs and simulations using AUCs estimated from CrCL. [Table: see text] No significant financial relationships to disclose.
Immune (idiopathic) thrombocytopenic purpura (ITP) treatment pattern and clinical efficacy
Authors: N. M. Chowhan, R. L. Robles, B. Kamenova, C. Ze, B. Deeter, J. J. Isitt
Journal: Journal of Clinical Oncology (2008)

17529 Background: Immune (Idiopathic) Thrombocytopenic Purpura (ITP) is an autoimmune disorder characterized by persistent thrombocytopenia (peripheral blood platelet count <150 × 109/L). Few studies report efficacy of current therapies for ITP or resulting health-related quality of life (HRQoL). We present interim results of an international multi-center prospective observational study describing clinical efficacy of ITP treatments (trts). Methods: Patients (pts) with a diagnosis (dx) of ITP from community and academic centers were enrolled. Pts retrospective chart data provided date of 1st ITP dx, trts received and medical history. ITP trts, dose, response, and duration of response were collected prospectively for 12 months (mo). HRQoL was assessed with an ITP questionnaire (ITP-PAQ) where higher scores relate to better patient-reported outcomes. Results: Of the first 100 pts (43% male and mean age 70 years), 24 received a splenectomy and 74 received ITP-related trts. Among the 74 pts, corticosteroids (N=61), intravenous immunoglobulins (IVIG) (N=36), rituximab (N=27), and anti-D antibody (N=22) were the most frequently used. On average, pts received 2 to 3 types of ITP trts during the study period (median person years=2.97) with corticosteroids usually as 1st line of treatment. Median duration of response was 8 mo for rituximab, 10 mo for corticosteroids, 15 mo for IVIG and 17 mo for anti-D antibody. Hospitalizations per person year ranged from 0 (rituximab) to 0.8 (IVIG). ITP-PAQ scores significantly decreased in pts on corticosteroids (p<0.05), compared to other trt groups where ITP-PAQ scores increased. Conclusions: Efficacy of all ITP trts was limited in duration and pts receiving corticosteroids had significantly decreased HRQoL. Further studies are needed to assess the long-term impact of ITP trts on patient outcomes, health resource utilization, and downstream costs. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Inc. Amgen, Inc. Amgen, Inc.
First-in-human clinical, pharmacokinetic (PK), and pharmacodynamic (PD) phase I study of the first-in-class spliceosome inhibitor E7107 administered IV (bolus) on days 1, 8, and 15 every 28 days to patients with solid tumors
Authors: F. A. Eskens, F. J. Ramos, H. Burger, M. J. de Jonge, J. Wanders, A. Lopez-Anaya, J. Baselga, J. Tabernero
Journal: Journal of Clinical Oncology (2009)

3508 Background: E7107 is a potent first-in-class inhibitor of the spliceosome, most likely by interacting with spliceosome-associated protein-130 (SAP 130). Splicing removes intron sequences from pre-mRNA and exons are fused resulting in the formation of mature mRNA. Alternative splicing frequently encodes oncoproteins. E7107 interferes the maturation process of pre-mRNA to mRNA, with consequent changes in protein expression profiles. Methods: Objectives of this study were to explore (1) tolerability and safety profile, (2) PK, (3) PD effects on pre-mRNA splicing, and (4) anti tumor activity of E7107 administered as bolus infusion on days 1, 8, 15 of a 28-day schedule Results: 36 patients (21M/15F, median age 61yrs (45–79)) received E7107 doses of 0.6 mg/m 2 (n=4), 0.9 mg/m 2 (n=3), 1.3 mg/m 2 (n=3), 2.0 mg/m 2 (n=3), 3.0 mg/m 2 (n=4), 4.5 mg/m 2 (n=3) and 4.0 mg/m 2 (n=16). At 4.5 mg/m 2 two episodes of DLT (grade 3 and 4 diarrhea) and at 4.0 mg/m 2 one episode of DLT (a combination of grade 3 nausea, vomiting and abdominal cramps) were observed. Other frequently occurring side effects were mainly gastrointestinal. The maximum tolerable dose (MTD) is 4.0 mg/m 2 . No complete or partial responses were observed. Pharmacokinetic analysis revealed large volume of distribution (Vss: 279 to 1369 L), high systemic clearance (CL: 111 to 253 L/hr), and moderate elimination half-life (t 1/2 : 5.3 to 15.1 hr). Systemic exposure on Days 1 and 15 (Cmax, AUC0-∞) increased in a dose-dependent manner. At the MTD, mRNA levels of selected target genes (TRAPPC4, SLC25A19, GTF2H1), monitored in PBMC's, showed a 15–25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a 10–25-fold increase. Notably, at days 1 and 15, modulations generally peaked at 2–6 hr after end of the infusion and almost completely recovered to base-line levels at 24–48 hr. Conclusions: The MTD for E7107 using this schedule is 4.0 mg/m 2 . PK is dose-dependent and reproducible within subjects. PD analysis revealed dose-dependent reversible inhibition of pre-mRNA processing of target genes, confirming proof-of-principle activity of E7107. [Table: see text]
Selective Photodepletion of Recipient-Alloreactive T-Cells Enables Safe and Efficacious Haploidentical HSCT: Initial Results from a Phase 2 Trial in Patients with AML, ALL, and MDS
Authors: Denis-Claude Roy, Johan Maertens, Irwin Walker, Silvy Lachance, Jean Roy, Stephen Ronan Foley, Philippe Lewalle, Dominik L.D. Selleslag, Liesbeth De Jong, Jurjen H.L. Velthuis, Lisya Gerez, Karen Reitsma, Edwin Wagena, Stephan Mielke
Journal: Blood (2014)
Phase II study of irinotecan plus cisplatin followed by amrubicin in patients with extensive-stage small-cell lung cancer (WJTOG 0301)
Authors: Y. Iwamoto, M. Kobayashi, K. Matsui, H. Yamamoto, K. Yamazaki, H. Saka, T. Sawa, K. Shibata, K. Takeda, K. Nakagawa
Journal: Journal of Clinical Oncology (2008)

19039 Background: The combination chemotherapy of irinotecan (CPT-11), that is a topoisomerase (topo) I inhibitor, and cisplatin (CDDP) is one of the standard treatments in patients with extensive-stage small-cell lung cancer (SCLC). Amrubicin (AMR), that is a novel 9-aminoanthracycline, inhibits topo II. Some preclinical studies reported that a combination of topo I and II inhibitors shows a synergistic cytotoxicity. We investigated the sequential chemotherapy that consisted of CPT-11 plus CDDP followed by AMR in patients with extensive- stage SCLC. Methods: Eligible patients had an ECOG performance status of 0 or 1, an age of ≤ 70 years, measurable lesions, and adequate organ functions. Treatment consisted of CPT-11 60 mg/m2 on days 1 and 8 plus CDDP 60 mg/m2 on day 1 every three weeks for three cycles, and then AMR 40 mg/m2 on days 1 to 3 every three weeks for three cycles. We evaluated the efficacy and toxicity of this treatment. Results: From Sep. 2004 to Sep. 2006, 45 patients were enrolled, of whom, 43 patients were assessable for response and survival, and 44 patients were assessable for toxicity. Twenty-eight (64%) patients received full planned chemotherapy. One patient achieved a CR and 33 patients had a PR, with a response rate of 79% (95% CI, 64% to 90%). The median overall survival time was 15.4 months and the median progression-free survival was 6.5 months. The major toxicity was myelosuppression. Grade 3 or 4 neutropenia, neutropenic fever, and anemia occurred in 57%, 7%, and 7% of patients during the CPT-11 plus CDDP phase, and 91%, 15%, and 27% of patients during the AMR phase, respectively. No treatment-related death was observed. Conclusions: CPT-11 plus CDDP followed by AMR is an effective and well-tolerated treatment in patients with extensive-stage SCLC. It is likely that the sequential AMR prolongs the survival. No significant financial relationships to disclose.
A randomised trial investigating the dose intensity of primary chemotherapy in patients with ovarian carcinoma: A comparison of alternating combination chemotherapy given every four weeks for six cycles with the same dose of chemotherapy given at three week intervals
Authors: Wrigley E, Weaver A, Jayson G, Ranson M, Renninson J, Prendiville J, Dobson M, Collins Cd, Swindell R, Buckley Ch, Radford J, Crowther D
Journal: Annals of Oncology (1996)
Magnetic Resonance Imaging/Angiography Findings in Adult Patients with Sickle Cell Disease: Correlation with Transcranial Color Doppler Sonography
Authors: Giovanna Graziadei, Francesca Marta Casoni, Antonella Costa, Alessia Marcon, Fabio Triulzi, Maria Domenica Cappellini, Federico Annoni
Journal: Blood (2014)