tbuckley/cabot-search huggingface dataset:
Oral lenalidomide plus melphalan and prednisone (R-MP) for newly diagnosed multiple myeloma
Authors: A. Palumbo, P. Falco, G. Benevolo, L. Canepa, S. D’Ardia, A. Gozzetti, A. Nozza, J. Zeldis, M. Boccadoro, M. T. Petrucci
Journal: Journal of Clinical Oncology (2006)

7518 Background: Lenalidomide (Revlimid) is a novel oral immunomodulatory drug active in refractory multiple myeloma (MM). In this multicenter trial, we evaluate the effect of the combination lenalidomide, melphalan and prednisone (R-MP). Methods: Patients (pts) with newly diagnosed symptomatic MM ≥ 65 years received 9 courses of lenalidomide (21 days every 4–6 weeks) plus MP (4 days every 4–6 weeks). The trial was designed to asses toxicity and efficacy of R-MP combination. Four dose levels were tested (table 1). Each cohort included 6 pts, with additional 15 pts in level 3 and 4. Dose limiting toxicity (DLT) was defined as: grade ≥ 3 non-hematologic toxicity; grade 4 hematologic toxicity (with neutropenia lasting &gt;7 days); treatment delay due to toxicity during the first cycle. All pts received ciprofloxacin and aspirin as prophylaxis. Results: At present, 50 pts (median age 71) received at least one R-MP course. No DLTs were observed in levels 1 and 2. In level 3, 1 pt experienced DLT (grade 4 neutropenia &gt; 7 days). In level 4, 3 pts showed DLTs (neutropenic fever, grade 3 cutaneous toxicity, pulmonary embolism and cycle 2 delay due to neutropenia). After 1 cycle, no one was in complete remission (CR) (according to the EBMT/IBMTR criteria), 51% of pts showed a response of 50–99% (PR) and 49% a response &lt;50%, no progressive disease (PD) occurred. After 3 cycles, CR was observed in 10% of pts, PR in 60% and response &lt;50% in 30%, no PD occured. Major grade 3–4 adverse events were hematological toxicities: neutropenia (58%) and thrombocytopenia (21%). Major grade 3–4 non-hematological toxicities were cutaneous eruption (11%), infections (5%) and febrile neutropenia (3%). Neuropathy was not observed and only one thromboembolism was recorded. Conclusions: R-MP was well tolerated with a manageable toxicity. Significant response rate was observed. It represents a feasible and promising approach for elderly newly diagnosed pts. An update of these data will be presented. [Table: see text] [Table: see text]
Pilot Trial of the Safety, Tolerability, and Retinoid Levels of N-(4-hydroxyphenyl) Retinamide in Combination With Tamoxifen in Patients at High Risk for Developing Invasive Breast Cancer
Authors: Barbara Conley, Joyce O’Shaughnessy, Sheila Prindiville, Julia Lawrence, Catherine Chow, Elizabeth Jones, Maria J. Merino, Muriel I. Kaiser-Kupfer, Rafael C. Caruso, Marvin Podgor, Barry Goldspiel, David Venzon, David Danforth, Suhlan Wu, Marianne Noone, Jennifer Goldstein, Kenneth H. Cowan, JoAnne Zujewski
Journal: Journal of Clinical Oncology (2000)

PURPOSE: N-(4-hydroxyphenyl) retinamide ([4-HPR], Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) have synergistic antitumor and chemopreventive activity against mammary cancer in preclinical studies. We performed a pilot study of this combination in women at high risk for developing breast cancer. PATIENTS AND METHODS: Thirty-two women were treated with four cycles of 4-HPR, 200 mg orally (PO) for 25 days of each 28-day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone. Tolerability, dark adaptometry, tissue biopsies, and retinoid plasma concentrations (Cp) were evaluated. RESULTS: Symptomatic reversible nyctalopia developed in two patients (6%) on 4-HPR, but 16 (73%) of 22 patients had reversible changes in dark adaptation, which correlated with relative decrease in Cp retinol (P ≤ .01). Four patients stopped treatment for side effects, and 84% of patients had hot flashes. Other commonly reported (grade ≤ 2) reversible toxicities included skin and ocular dryness, fatigue, and mood changes. Serum high-density lipoprotein increased and cholesterol decreased from baseline to month 4. Baseline mean ± SD Cp retinol was 708 ± 280 ng/mL. Mean ± SD Cp of 4-HPR, N-(4-methoxyphenyl) retinamide (4-MPR), and retinol after 1 month of 4-HPR were 0.34 ± 0.21 μmol/L, 0.28 ± 0.21 μmol/L, and 282 ± 127 ng/mL, respectively. Mean retinoid Cps did not change after 3 months of 4-HPR + TAM. CONCLUSIONS: TAM administration did not affect Cp 4-HPR or 4-MPR. Reversible nyctalopia correlated with relative decrease in Cp retinol but was not symptomatic for most patients. TAM + 4-HPR has acceptable tolerability for this high-risk cohort.
Abstract 18998: Macrophage-Specific Mineralocorticoid Receptor Antagonists for Cardiovascular Disease
Authors: Sascha N Goonewardena, Ryan E Tsuchida, Bertram Pitt, Hong Zong
Journal: Circulation (2013)

Background: Mineralocorticoid receptor antagonists (MRA) have consistently led to improved clinical outcomes in patients with cardiovascular disease. Despite these benefits, off-target effects have limited the use of MRAs. Studies have begun to define the molecular mechanisms underlying cell-specific MR signaling, with several groups demonstrating a pathologic role for macrophage-MR activation in animal models of heart failure. Objective: We sought to engineer and evaluate a macrophage-specific MRA (Mf-MRA) composed of three elements: a nanoparticle delivery platform, the MRA eplerenone, and a fluorogenic biomarker for therapeutic monitoring. Methods and Results: The individual elements of the Mf-MRA were assembled using click chemistry. Bone marrow-derived macrophages (BMDM) and control cell models were used to evaluate the cell-specificity and therapeutic efficacy of the Mf-MRA. Using flow cytometry, we found that the Mf-MRA internalizes and is activated specifically in macrophages and not other cells. To confirm the functionality of the Mf-MRA, we evaluated oxidative stress induction and inflammatory gene expression in BMDM in response to aldosterone (Aldo). Equivalent concentrations (1 μM) of spironolactone and the Mf-MRA blocked Aldo induced superoxide production (Figure 1). Additionally, the Mf-MRA blocked Aldo induction of TNFα gene transcription (p&lt;0.005). Finally, preliminary studies in a murine heart failure model confirmed the macrophage-specific delivery and activation of the Mf-MRA. Conclusions: We have developed a novel, macrophage-specific MRA using a synthetic nanoparticle, a fluorogenic biomarker, and an established MRA. This cell-specific MRA combines targeted-delivery with therapeutic monitoring. We believe that this innovative platform will have unique diagnostic and therapeutic applications for a broad spectrum of cardiovascular diseases.
Assessment of diffusion parameters in scans prior to progression in GBM patients following antiangiogenic therapy.
Authors: L. Jalilian, E. Essock-Burns, S. Cha, S. M. Chang, N. A. Butowski, S. J. Nelson
Journal: Journal of Clinical Oncology (2010)

2090 Background: The apparent diffusion coefficient (ADC) obtained from diffusion-weighted imaging (DWI) has been reported as providing early biomarkers of response to conventional therapy, but its role in GBM patients receiving antiangiogenic therapy is unknown. The objective of this study was twofold: (a) to investigate if diffusion parameters on scans prior to progression act as early biomarkers to predict contrast-enhancing areas at presumed tumor progression, (b) to investigate if diffusion parameters can be used to differentiate true tumor progression and pseudo-progression following antiangiogenic treatment. Methods: 13 newly diagnosed GBM patients treated with surgical resection, radio-, chemo- and antiangiogenic therapy were examined. ADC values were obtained from DWI for the following parameters at one scan and two scans prior to progression: normal appearing white matter (NAWM), contrast-enhancing lesion (CEL), T2 hyperintense lesion (T2L), new areas of contrast-enhancement at progression not seen on two prior scans, and areas of T2L that did not include enhancement (NEL). Signrank tests compared ADC values of these parameters between scans and at individual scans. Results: Increasing ADC values in scans prior to progression correlated with areas of new contrast- enhancement at progression. There was no significant difference in median normalized ADC (nADC) between the CEL and area of new enhancement at one scan prior to progression (p < 0.1465), but the difference was significant at two scans prior to progression (p < 0.0002). There was a significant difference in median nADC between the CEL and T2L of the first and second scans prior to progression (p < 0.0171 and p < 0.0479). There was no significant difference between the median nADC for the NEL at one and two scans prior to progression (p < 0.3054). Conclusions: ADC data from this study demonstrate that DWI parameter values may aid in assessing treatment effect and predicting pseudo-progression by providing cellular changes that predate emergence of contrast enhancement and nonenhancing FLAIR abnormality in GBM patients receiving anti- angiogenic therapies. The mechanism responsible for these changes remains unknown. No significant financial relationships to disclose.
Reduction in vertebral fracture rates by a combination of monofluorophosphate and raloxifene in postmenopausal osteoporosis
Authors: P. Durez, D. Felsenberg, J. Stepan, J. Payer, H. Resch, D. Quail, L. Pavo, Jean-Yves Reginster
Journal: Annals of the Rheumatic Diseases (2002)
Stem cell transplantation for acute myeloid leukemia (AML): The Brazilian experience
Authors: D. Barton, N. Hamerschlak, R. Pasquini, F. L. Dulley, V. A. R. Colturato, S. R. Brandalise, C. A. de Souza, J. Voltarelli, M. A. Ruiz, M. Rotolo, V. C. Ginani
Journal: Journal of Clinical Oncology (2005)

6725 Background: Data from the International Bone Marrow Transplant Registry (IBMTR) contribute for improvement of Bone Marrow Transplant (BMT) worldwide. We studied the Brazilian experience in BMT for AML to compare with international data. Methods: We performed a retrospective study by sending questionnaires to 14 BMT centers regarding clinical and treatment variables. Statistical analyses concerning autollogous BMT (autoBMT) and allogeneic BMT (alloBMT) were performed using the Kaplan-Meier method and the log-rank test. All p values were two-tailed. Results: We collected data from 726 pts (205 autoBMT and 521 alloBMT). Median overall survival (OS) for autoBMT pts was longer than alloBMT pts (1035 vs 466 days, p=0,0012). AlloBMT stem cell source (SCS): 73% bone marrow stem cell (BMSC), 23% peripheral blood stem cells (PBSC) and 4% umbilical cord blood. Among the autoBMT pts, the SCS was 63% PBSC, 22% BMSC and 15% both. The SCS did not impact on OS. There was no difference in OS between different FAB classification in the alloBMT group, but in the autoBMT the M3 pts had longer survival. As expected, the main cause of mortality among autoBMT pts was related to disease relapse (60%), while in the alloBMT, to infection (38%). In both groups we found longer OS in first complete remission (1CR) compared to second (2CR) and other (p<0,0001), and longer OS in de novo AML than in secondary. Table1. Number of pts (n) and OS (days). Conclusions: In the alloBMT group we have found more pts with advanced disease (60%), while in the autoBMT group, we have found more M3 pts (24%), what could explain the difference in OS. Most of our results are in accordance with IBMTR data. One should consider the fact that this is a retrospective study and our findings should be analysed with caution. No significant financial relationships to disclose.
Anaesthesia for Minor Procedures in Children with Malignant Disease
Authors: W R Hain, J H Tomlinson, P R H Barbor
Journal: Journal of the Royal Society of Medicine (1985)

Minor invasive procedures in children with leukaemia can be very distressing for patients, parents and staff. In Nottingham a combined clinic has been established with an anaesthetist as an integral member of the team. General anaesthesia, usually by inhalation, is frequently employed. From May 1980 to September 1984, 515 anaesthetics were given to 97 patients. Records are kept to allow analysis of the clinic's function. With close personal contact, induction of anaesthesia becomes increasingly a matter of cooperation between patient and anaesthetist, removing much of the fear of these procedures. The development of this service is described and the reasons for its success are discussed.
A metamodule for conceptual integration: Language or theory of mind?
Authors: Scott Atran
Journal: Behavioral and Brain Sciences (2002)

Those who assume domain specificity or conceptual modularity face Fodor’ Paradox (the problem of “combinatorial explosion”). One strategy involves postulating a metamodule that evolved to take as input the output of all other specialized conceptual modules, then integrates these outputs into cross-domain thoughts. It’ difficult to see whether this proposed metamodular capacity stems from language or theory of mind.
Efficacy and safety of bendamustine and rituximab in the treatment of indolent and mantle cell lymphomas in older patients
Authors: M. J. Rummel, K. Heine, H. Bodenstein, M. Baldus, M. Stauch, U. von Gruenhagen, A. Banat, U. Kaiser
Journal: Journal of Clinical Oncology (2008)

8572 Background: Promising results have been observed in both our previous phase-II and phase-III studies evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory and previously untreated indolent or mantle cell lymphomas. An overall response rate of at least 90%, including a high rate of complete remissions (CR) was documented. Objective: In August 2005 we initiated a multicenter phase-II study to evaluate efficacy and toxicity of the combination B-R in the treatment of patients older than 75 years of age with follicular, indolent and mantle cell lymphomas. Here we report first data from this phase II trial for an elderly patient population. Patients and Methods: 41 pts with indolent and mantle cell lymphomas were enrolled into this trial so far. Median age of the patients was 79 years. Bendamustine was given at a dose of 90 mg/m² on day 1 and 2, combined with Rituximab at a dose of 375 mg/m² on day 1. BR treatment was administered every 28 days, up to a maximum of 4 cycles Bendamustine and 6 cycles Rituximab. Results: So far data of 26 pts are evaluable for response: The overall response rate was 88% (23 pts) with a CR rate of 35% (9 pts). Major treatment toxicities were myelosuppression and infections. Conclusion: Bendamustine plus rituximab is an effective and safe regimen in elderly patients with indolent or mantle cell lymphomas. Updated data with respect to toxicity and efficacy based on the entire study population will be available for the Meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ribosepharm, Roche Ribosepharm, Roche
A hypothesis-generating exploratory analysis of efficacy and safety of abiraterone acetate (AA) in African American (Af Am) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Eleni Efstathiou, Vasily J. Assikis, Scott A. North, John Showel, Thomas E. Hutson, Stephen Boyd Riggs, Jonathan Waxman, Youn Choi Park, Thian San Kheoh, Christopher M. Haqq, Christopher Logothetis, Arturo Molina
Journal: Journal of Clinical Oncology (2012)

55 Background: The reported increased prostate cancer lethality in Af Ams has been attributed by some to altered androgen receptor (AR) signaling. We compared toxicity, PSA response, time-to-PSA progression (TTPP), and radiographic progression-free survival (rPFS) in Af Am vs non Af Am pts with CRPC treated with AA + prednisone (P) vs placebo + P. We hypothesized that differences in response to AA may be observed if differences in AR signaling exist in Af Ams. Methods: COU-AA-301 is a randomized double blind study of AA (1000 mg + P 5 mg po BID) vs placebo + P post-docetaxel. Results: TTPP, rPFS, and PSA response rate were higher with AA vs placebo. In Af Am pts, treatment emergent AEs (TEAEs) for AA vs placebo occurred in 96.4% vs 100.0% of pts (50.0% and 66.7%, respectively, grade 3/4); serious TEAEs occurred in 42.9% and 33.3% of pts (28.6% and 26.7%, respectively, grade 3/4). The safety profile of AA appears comparable between the Af Am and overall study populations. Conclusions: Although the small number of Af Am pts in this study precludes formal conclusions regarding efficacy and safety of AA in this pt population, the overall trend suggests these pts experienced clinical benefit from AA with a safety profile comparable to the overall study population. These findings do not appear to support the hypothesis that AR signaling accounts for the increased lethality of prostate cancer seen in Af Ams. Further studies of AA in Af Am pts are planned to understand the potential benefit in this population. Additional efforts are needed to increase participation of Af Am pts in clinical trials. [Table: see text]
Oxaliplatin/Capecitabine combination (Xelox) with or without targeted therapies in advanced colorectal cancer (ACRC) and pharmacokinetic analysis
Authors: M. Gil-Delgado, G. Bastian, J. Spano, B. Paule, G. Des-Guetz, A. Bardier-Dupas, D. Khayat
Journal: Journal of Clinical Oncology (2009)

e15068 From 04/2002 to 12/2004, and 03/2006 to 08/2008, two consecutive steps were conducted in ACRC patients with chemotherapy alone for the step 1 and with Cetuximab and Bevacizumab for the step 2. Treatment schedule: oxaliplatin (0) 130 mg/m2 D1 over 4 to 6 hours, capecitabine (X) 1000 mg/m2 bi daily D2 to 15, 1 week rest. Cetuximab D1 at cyle 1 and at D2 at cycle 2(400 mg/m2 loading dose, then 250 mg/m2 every week), bevacizumab 7.5 mg/Kg D2 at cycle 1 and at D1 for the cycle 2. At cycle 3 cetuximab and bevacizumab were given at D1. PK analysis were performed at cycles 1 and 2, days 1,2,15,22 and 23. In the step 1, 23 pts were included, M/F = 9/14, M. age 57, PS 0–1-2 = 14/6/3, 1st line /2/3 = 18/4/1. Eleven responses were obtained (4 CR and 7 PR) 2 pts were in CR after hepatectomy, ORR = 48 %( intent to treat). In the step 2, 18 pts were included, M/F = 11/7, M. age = 55, PS 0–1-2 = 8/7/3, 1st line/2 = 17/1.Status K-RAS mutated/wild = 2/13.Seven pts responded to therapy: 1 CR, 6 PR and 1MR for an ORR of 38 %(intent to treat) 3 pts were in CR after hepatectomy and 6 pts were in SD, tumor control in 16/18 pts=88 %.Toxicity was mild, only 1 pt had G3 diarrhoea, 1pt G3 acne, 1pt had G3 neurotoxicity with need oxaliplatin discontinuation after 14 cycles. One pt had fatal pulmonary embolism at first cycle. PK results in plasma ( 14 pts in step 1 and 12 pts in step 2):no statistical differences between X and its metabolites on D2 and 15. Urinary elimination is about 2 % of total dose administered over 4 hours for 5- FU and 8 to 22% for Fluoro β Alanine (FBAL). Plasma clearance of 1.73±1.22ml/h/m 2 for 5FU, 53.76±25.36ml/h/m 2 for FBAL. For O, residual level at D15 higher in erythrocytes than in plasma suggest an important irreversible binding with red cells without blood toxicity. Conclusions: Xelox with and without targeted therapies is an active and safe combination in ACRC. When O is administered over a long period of time and X is given at least 12 h later, neurotoxicity was mild and no hand-foot syndrome was observed. Important PK parameters variability mainly for 5FU and FBAL suggest posology adaptation on the basis of concentration ratio 5FU/FBAL in blood. No PK interaction between monoclonal antibodies and X or O were observed whatever the schedule of drug administration. No significant financial relationships to disclose.
Consistent response to treatment with cetuximab monotherapy in patients with metastatic colorectal cancer
Authors: H. J. Lenz, R. J. Mayer, B. Mirtsching, A. L. Cohn, A. Pippas, P. Windt, E. van Cutsem
Journal: Journal of Clinical Oncology (2005)

3536 Background: Erbitux (Cetuximab), an IgG1 monoclonal antibody, is active in patients with metastatic colorectal cancer (CRC). A phase II study explored the activity of cetuximab in patients with heavily pretreated CRC. Methods: Patients with metastatic CRC were eligible if they had failed at least two prior chemotherapy regimens, containing irinotecan, oxaliplatin, and a fluoropyrimidine. There was no limit in the number of lines of prior treatment. Patients received cetuximab at an initial dose of 400 mg/m2, followed by weekly doses of 250 mg/m2, until disease progression or unacceptable toxicity. Response was assessed by an independent review committee, using a modified version of WHO criteria. Results: 346 patients treated had a median age of 59 years; 54% were male, and an ECOG performance status of 0 (42%) or 1 (58%). Patients received a median of 4 regimens of prior CRC therapy (range 2–9). Median cetuximab therapy was 9 doses (range 1–56+). Patients achieved a 12% PR rate (95% CI 8%–15%) and a median survival time of 6.6 months (95% CI 5.6–7.6 months). 259 patients received oxaliplatin after irinotecan. The other 87 patients received irinotecan after or with oxaliplatin. The response rate was 12% in both groups. 282 patients (81%) progressed on, or within 30 days of the last dose of the latest prior regimen with a response rate of 11%. 64 patients (19%) either progressed after 30 days of the last dose or were intolerant of the latest prior regimen, with a response rate of 14%. Conclusion: Cetuximab is active in patients with heavily pre-treated metastatic colorectal cancer with a consistent response rate regardless of the number of the lines of prior therapy, or sequence of prior agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ImClone Systems Bristol-Myers Squibb, Chiron, Response Genetics, Genentech Bristol-Myers Squibb, Roche, Pfizer, Lilly Oncology, Sanofi Bristol-Myers Squibb, National Cancer Institute, National Institutes of Health