tbuckley/cabot-search huggingface dataset:
Sequential Treatment with Rituximab and CHOP Chemotherapy in B-Cell PTLD - Moving Forward to a First Standard of Care: Results From a Prospective International Multicenter Trial.
Authors: Ralf Trappe, Sylvain Choquet, Stephan H.K. Oertel, Veronique Leblond, Daan Dierickx, Peter Mollee, Monica Sender, Tor Ekman, Jan Maciej Zaucha, Petra Reinke, Ruth Neuhaus, Hans Lehmkuhl, Martin H. Dreyling, Ulrich Dührsen, Gilles Salles, Franck Morschhauser, Arnaud Jaccard, Thierry Lamy, Ioannis Anagnostopoulos, Martine Raphael, Bernd Dörken, Hanno Riess
Journal: Blood (2009)
Is opioid-induced hyperalgesia a genuine issue for palliative care patients and clinicans?
Authors: Peter Eastman, Brian H. Le, Ian Grant, Sue Berry
Journal: Journal of Clinical Oncology (2014)

197 Background: Opioid-Induced Hyperalgesia (OIH) has been described as a paradoxical response whereby opioid administration induces an increase in pain sensitivity rather than an analgesic effect. It is proposed this results from increased pro-nociceptive sensitivity following changes in central and peripheral neural pathways. While there is basic science and pre-clinical evidence supporting OIH, debate remains about its clinical relevance or even existence. The existence or otherwise of OIH has relevance for palliative care as many patients are prescribed opioids and the standard management of unstable pain in palliative care may worsen symptoms in OIH. Therefore recognition of the concept would seem important for palliative care clinicians. Methods: An electronic survey of Australian and New Zealand palliative care clinicians was undertaken addressing awareness of OIH as well as approaches to recognising and managing it. The survey which contained single response, multiple-choice and open-ended questions was distributed through the Australian New Zealand Society of Palliative Medicine. Mixed-methods analysis was performed. Results: One hundred and twenty-three surveys were returned (response rate = 31%). The majority of respondents identified as palliative care specialists. More than 75% of respondents reported observing OIH in their clinical practice, often with malignant disease and with morphine, oxycodone and fentanyl identified as the commonest causal agents. The three features felt to be most suggestive of OIH were; escalating pain despite increasing opioids, demonstrable hyperalgesia or allodynia and a more diffuse pain distribution away from pre-existing pain sites. Most clinicians utilized more than one approach when OIH was encountered. The commonest of these were opioid reduction, opioid rotation and optimization of adjuvant analgesia. Conclusions: Our survey found a higher rate of reported observation of OIH amongst clinicians than might have been anticipated given debate about the existence of OIH in humans outside of a research environment. These results suggest that many palliative care clinicians perceive OIH to be a genuine issue for their patients.
Investigation of ethnic differences in the prevalence of chromosomal number aberrations of luminal and triple-negative breast cancers associated with risk of recurrence.
Authors: A. M. Brewster, P. Thompson, K. Do, A. Sahin, L. Zhang, J. L. Murray, S. Tsachavidis, G. B. Mills, M. Bondy
Journal: Journal of Clinical Oncology (2010)

1526 Background: Distinct subtypes of breast cancer have been identified (luminal, HER2-positive, and triple- negative) that exhibit different clinical behaviors. Epidemiological studies have demonstrated that African American women are more likely to develop triple-negative tumors, a particularly aggressive form of breast cancer, than white women. Ethnic differences in the prevalence of chromosomal number aberrations (CNAs) that are associated with breast tumor subtype (luminal, triple-negative) and predict for risk of recurrence have not previously been described. Methods: The molecular inversion probe (MIP) based high density single nucleotide polymorphism array from Affymetrix was used to identify genome-wide DNA CNAs in formalin-fixed, paraffin-embedded tumors from 971 stage I and II breast cancer patients treated at the M. D. Anderson Cancer Center between 1985 and 2000. Cox-Boost was applied to identify CNAs associated with risk of recurrence. Multivariable Cox proportional hazards regression models for risk of recurrence were built for the identified CNA markers and age at diagnosis, stage and systemic treatment separately for luminal and triple-negative tumors. Results: Overall, African American (n = 123) and Hispanic (n = 122) patients were more likely to have triple-negative breast cancers than white patients (n = 707) (p < 0.05). Among the triple-negative breast cancers, higher copy number loss was observed in the Xp11.22-11.23 region among African American and Hispanic patients compared to white patients (p = 0.009). Among the luminal breast cancers, CNAs in chromosomes 8q (p = 0.026), 8p (p = 0.079), 20q (p = 0.079), 14q (p = 0.085) and 11q (p = 0.06) were associated with ethnicity. There was higher copy number variation in the narrow region of 7q36.1 which contains only the GALNTL5, GALNT11 and MLL3 genes in the luminal tumors of African American compared to Hispanic and white patients (p = 0.01). Conclusions: Ethnic differences in the prevalence of specific CNAs that are associated with risk of recurrence may explain disparities in breast cancer outcome and can be targeted for the development of novel therapies. No significant financial relationships to disclose.
Biomarker correlates of survival in NSCLC: Role of RXRβ and PPARγ in mediating bexarotene impact on patient survival
Authors: A. Negro-Vilar, U. Gatzemeier, R. Ramlau, S. L. Sun, R. Negro-Vilar, T. Hermann, J. K. Zhang, Z. Dziewanowska
Journal: Journal of Clinical Oncology (2006)

7227 Background: Bexarotene is a selective modulator of retinoid X nuclear receptors (RXRs), which form heterodimers with many other nuclear receptors playing a critical role in cell growth, differentiation, and apoptosis. Loss of RXRs is seen in many advanced tumors, including NSCLC and higher RXR levels in NSCLC lung biopsies (stages I-III) have been correlated with longer overall survival. Two large first line NSCLC Phase III trials reported at ASCO 2005 (SPIRIT I and II) showed that while no benefit in overall survival was seen adding bexarotene to two chemo regimens, a large (36%) subpopulation of patients in both trials that had high grade hypertriglyceridemia in response to bexarotene had significantly longer survival. A retrospective analysis was conducted to evaluate the baseline characteristics of these patients and to examine the level of expression of RXR and one of its partners (PPARγ) in lung tumor tissue biopsies obtained from a subgroup of patients in both studies. Methods: RXRs (α,β,γ) and PPARγ expression levels in lung tumor tissue from patients in SPIRIT I and II trials (stage IIIB/IV) taken prior to study entry were assessed by Q-PCR analysis of RNA isolated from microdissected lung tumor tissue biopsies. Cox regression and Kaplan-Meier survival estimation were used for statistical evaluations. Results: In an initial subset of 41 patients, RXRβ expression in lung tumor showed positive correlation with survival. High RXRβ = longer survival (median survival 438 days), low RXR shorter (MS = 317). Treatment with bexarotene increased the differences (RXRβ Hi, MS = 627 days; RXRβ low = 211 days). PPARγ showed a negative correlation with survival and those patients with RXRβ Hi/PPARγ low ratios had the longest MS (627 days vs. 226 days for the RXRβ low/PPARγ high group), a difference that was magnified by bexarotene treatment. Conclusions: RXRβ expression level correlates with a positive survival in late stage NSCLC while PPARγ shows negative correlation. Bexarotene treatment enhances the survival differences, supporting an involvement of triglyceride and lipid metabolism as regulated by these two key nuclear receptors in the longer survival seen in the 215 patients in the high triglyceride subgroup. [Table: see text]
Ethnic difference in toxicity in non-small cell lung cancer patients treated with chemotherapy: A systematic review on phase II and III clinical trials.
Authors: Y. Hasegawa, T. Kawaguchi, A. Kubo, M. Ando, J. Shiraishi, S. Isa, T. Tsuji, K. Tsujino, K. Nakagawa, M. Takada
Journal: Journal of Clinical Oncology (2010)

7638 Background: There are a large number of global clinical trials ongoing for patients with non-small cell lung cancer (NSCLC). Ethnic difference in toxicity has not been fully studied. Methods: We performed a systematic search of PubMed for phase II (PII) and phase III (PIII) trials of NSCLC from January 2000 to December 2009 to examine ethnic difference in hematological toxicity due to cytotoxic chemotherapy. Ethnicity was classified into Asian and non-Asian (mostly Caucasian). We chose the treatment regimens that were commonly used globally including carboplatin (CBDCA) plus paclitaxel (PTX), cisplatin (CDDP) plus gemcitabine (GEM), and CDDP plus vinorelbine (VNR) for NSCLC. Because ethnicity origins were not fully reported in the entire trials, we applied sensitivity analysis by changing the percentage of Asian patients from 5 to 15% in the trials reported from the United States and Europe. In these analysis, the percentage of toxicity in the Asian patients was settled as the mildest toxicity in the trials collected. Results: We identified 12 PII and 38 P III trials (11,271 patients), and the 14 trials had reported ethnicity origins. Grade 3-4 toxicities were more frequently observed in the Asian studies. Based on sensitivity analysis, odds ratio for the risk of grade 3 or greater toxicities (neutropenia and anemia) was higher in Asian. Although there was no significant association between median survival time (MST) and degree of neutropenia, MST was better in the Asian study (12.2 month vs. 9.6 months, p=0.012). Conclusions: Severe hematological toxicity was frequently observed in Asian patients compared with non-Asian (mostly Caucasian) in treatment of chemotherapy for NSCLC. Neutropenia Anemia Thrombocytopenia CBDCA + PTX,* odds ratio** 70.9% vs. 33.7%(p < 0.0001), 2.1-3.2 10.8% vs. 7.4%(p < 0.0001),1.2-1.4 8.8% vs. 6.5%(p = 0.11),1.1-1.2 CDDP + GEM,* odds ratio** 53.9% vs. 25.3%(p < 0.0001),1.1-1.7 24.7% vs. 9.2%(p < 0.0001),1.6-2.1 28.0% vs. 16.0%(p < 0.001),0.8-1.2 CDDP + VNR,* odds ratio** 77.2% vs. 36.7%(p = 0.02),1.9-3.0 23.9% vs. 10.0%(p < 0.0001),2.0-2.4 1.9% vs. 4.5%(p = 0.20),0.3-0.4 * Asian trials vs. non-Asian trials. ** Asian against non-Asian in sensitivity analysis. No significant financial relationships to disclose.
Abstract 20280: Suppression of Post-Ischemic Arrhythmias by a Selective Small Molecule Inhibitor of Dynamin and Dynamin Related Protein 1
Authors: Jun Hu, Alejandro Chavez, Chaoqin Xie, Fadi G Akar
Journal: Circulation (2014)

Introduction:  Dynamins (Dnm) and Dnm related protein 1 (DRP1) play central roles in cell biology by regulating pathways involved in endocytosis and mitochondrial fission, respectively. Disruption of both processes has been implicated in cardiac dysfunction associated with ischemia reperfusion (IR) injury. Recently, the small noncompetitive Dnm GTPase inhibitor, Dynasore (Dyn) was shown to improve cardiac lusitropy in response to IR injury. Here, we investigated the electrophysiological (EP) consequences of Dyn under conditions of acute oxidative stress (OS) caused by H2O2 challenge or IR injury.   Methods:  Rat hearts (N=39) were treated with a low (1uM) or high (5uM) concentration of Dyn for 35 or 120 min before challenge with H2O2 (200uM) or no flow ischemia for 12 min followed by reperfusion. High resolution optical mapping was used to measure spatio-temporal changes in the action potential and mitochondrial membrane potential (MMP) across the heart.   Results:  Pretreatment of hearts with 1um Dyn for 120 min but not 35 min suppressed the incidence of reperfusion arrhythmias compared to untreated hearts (5/12 vs 6/7). Investigation of the EP substrate revealed marked attenuation of conduction slowing with no change in APD in response to ischemia in Dyn treated hearts. These beneficial effects were abrogated by selective PKC inhibition in an additional subset of experiments (n=3). Similar to IR injury, challenge of hearts with H2O2 for 30 min was associated with a significantly (p=0.0019) lower arrhythmia score in Dyn-treated compared to untreated hearts. Underlying this reduction in arrhythmic vulnerability was the prevention of H2O2 induced MMP depolarization and attenuation of MMP heterogeneity. Importantly, treatment of hearts with a higher (5uM) concentration of Dyn that is more consistent with inhibition of clatherin mediated endocytosis resulted in the rapid elevation of coronary perfusion pressure, MMP depolarization, and early onset of arrhythmias.   Conclusions:  At low but not high concentrations, Dyn exerts potent anti-arrhythmic activity likely by preventing OS-induced mitochondrial fission and associated dysfunction. Selective DRP1 inhibition may be a novel strategy for arrhythmia suppression in ischemic heart disease.
Phase II study of UFT, vinorelbine and gemcitabine as first-line treatment in advanced non-small-cell lung cancer
Authors: S. Atagi, M. Kawahara, M. Takada, M. Kawasaki, A. Tamura, R. Saitou, S. Fukai, H. Komatsu
Journal: Journal of Clinical Oncology (2006)

17100 Background: Vinorelbine (VNR)/gemcitabine (GEM) is active and well tolerated chemotherapy regimens for the treatment of patients (pts) with advanced non-small-cell lung cancer (NSCLC). UFT is composed of uracil and tegafur in a molar ratio of 4:1, and tegafur is a prodrug of 5-FU. Sequential exposure to 5-FU followed by GEM has been reported to give additive effects in vitro. For these reasons, we conducted a phase II study of triple treatment with these 3 drugs for advanced NSCLC. The objectives were to determine the tumor response rate, survival, safety and toxicity of this combination chemotherapy. Methods: Eligible pts were required to have histologically or cytologically comfirmed measurable or evaluable stage IIIB or IV NSCLC, age &lt;75 years, no previous chemotherapy, a Karnofsky performance status (PS) 0–1, and adequate organ function and bone marrow reserve. In this study, pts received UFT (300 mg/m 2 orally on days 1-5, 8–12) plus VNR (25 mg/m 2 IV on days 6 and 13) and GEM (1000 mg/m 2 IV on days 6 and 13). Treatment was repeated every 3 weeks. Results: Between September 2002 and November 2004, 32 pts were enrolled on this study. Characteristics of this study were as follows: male/female = 20/12; median age = 65 years (range 46–74); PS 0/1 = 11/21; stage IIIB/IV = 5/27. Median # of cycles = 2 (range 1–10). Response: PR = 7 (21.9%), SD = 14, PD = 10, NE = 1. Median survival time was 13.9 mos. 1-year survival rate was 56.7% (95% confidence interval, 38.9–74.4%). Gr 3/4 toxicity (% of pts) was as follows: leukocytes 40.6%, neutrophils 56.3%, platelets 3.1%, infection 9.4%, hypoxia 6.3%, dyspnea 3.1% and ALT/AST 3.1%. There were no treatment-related deaths. Conclusions: The combination of UFT, VNR and GEM appears effective with acceptable toxicity. No significant financial relationships to disclose.
Combination of antagonists of growth hormone-releasing hormone antagonist (GHRH) with rapamycin as a potential therapy in human breast cancers.
Authors: S. Buchholz, F. Weber, A. Schally, O. Ortmann, S. Seitz
Journal: Journal of Clinical Oncology (2010)

e13627 Background: Antagonists of growth hormone releasing hormone (GHRH) are being developed fort he treatment of various cancers. In this study we investigated the effectiveness of treatment with GHRH Antagonist JMR 132 alone and in combination with rapamycin in hormonereceptor negative breast cancers in vitro and in vivo. Rapamycin represents an mTor Inhibitor. Methods: In the cell lines MDA MB 231 and SKBR 3 we evaluated the receptor status by Western Blot (GHRH-R, EGFR/Her1, Her2/neu) and immunohistochemistry (GHRH-R, ER, PgR). In our on vitro trials we investigated effect of JMR 132 and/or rapamycin on the cell cycle (G0, G1, S-Phase) by Flowcytometry. For animal experiments nude mice bearing MDA MB 231 human breast cancer xenografts subcutaneously where randomized to 4 treatment groups receiving 1. solvent (Control) 2. JMR-132 10 μg/d s.c 3. rapamycin 0,75 mg 2qw ip, 4 combination. Results: In the animal trials a significant inhibition of tumor growth was seen in the JMR 132 and rapamycin group compared to control. This effect was enhanced by the combination compared to all other treatment groups. A dose dependent inhibition of growth of the single agents and an additive effect of the combination was seen in the in vitro experiments. Conclusions: Our results show that JMR 132 is a potential partner for combined treatment strategies in breast cancer patients. No significant financial relationships to disclose.
Effective management of patients receiving XELOX: Evaluation of impact of dose modifications on outcome in patients from the NO16966, NO16967, and NO16968 trials.
Authors: J. Cassidy, J. V. Cox, N. Scotto, H. Schmoll
Journal: Journal of Clinical Oncology (2011)

497 Background: In patients (pts) with metastatic colorectal cancer (MCRC), XELOX is non-inferior to FOLFOX4 in terms of PFS and OS as either first-line (NO16966, Cassidy et al. JCO 2008) or second-line therapy (NO16967, Rothenberg et al. Ann Oncol 2008). In pts with stage III colon cancer (NO16968, Haller et al. ECCO-ESMO 2009), adjuvant XELOX is superior to 5-FU/LV in terms of DFS. While XELOX is generally well tolerated, regional differences in fluoropyrimidine tolerability were noted in a pooled analysis [Rothenberg et al. ASCO GI 2008], leading to use of lower than recommended doses of capecitabine (i.e. 1,000mg/m 2 bid d1–15 with oxaliplatin 130mg/m 2 d1 q3w) in some countries. Methods: NO16966, NO16967 and NO16968 protocols included standard dose/schedule modifications for capecitabine, 5-FU and oxaliplatin for treatment-related adverse events (AEs). Safety parameters included AEs, deaths, laboratory parameters, exposure to trial medication, and withdrawals. In NO16966 and NO16967, Kaplan-Meier curves for PFS were developed for pts with no treatment modifications, and pts with dose reductions, treatment interruptions or cycle delays to assess the effect of treatment modifications on efficacy. NO16968 also included a planned analysis of the effect of dose modifications on DFS. Results: NO16966 included 1335 pts with previously untreated MCRC receiving XELOX or FOLFOX4. NO16967 included 627 pts with previously treated MCRC receiving XELOX or FOLFOX4. NO16968 included 1886 pts with resected stage III disease receiving XELOX or 5-FU/LV; dose modifications were required for capecitabine in 65% and oxaliplatin in 62% of pts in NO16968. Kaplan-Meier curves of PFS (NO16966/NO16967) or DFS (NO16968) for pts who did and did not require dose modifications indicated that the efficacy of XELOX did not appear to be compromised by dose modifications. Indeed, pts who required dose modifications seemed to have a favourable outcome compared with those who did not. Conclusions: From these data we cannot make a recommendation that initial dosing should be lower than the labeled dose. However, it is clear that dose modification does not seem to impact patient outcome. [Table: see text]
False positivity of rheumatoid factor and different assays for anti-citrullinated peptide antibodies detection in patients with systemic lupus erythematosus
Authors: Iea Hoffman, I Peene, A Union, L Meheus, WJ Huizinga, L Cebecauer, D. Isenberg, K De Bosschere, F. Hulstaert, Emilie Veys, DK Filip
Journal: Annals of the Rheumatic Diseases (2004)
Abstract 18555: Pre-operative Three-Dimensional Echocardiography Predicts Repair Failure in Ischemic Mitral Regurgitation
Authors: Melissa M Levack, Fenton H McCarthy, Manabu Takebe, Albert T Cheung, Y. J Woo, Michael A Acker, Joseph H Gorman, Robert C Gorman, Benjamin M Jackson
Journal: Circulation (2012)

Objective: Early recurrence (≤ 6 months) of mitral regurgitation after ring annuloplasty for ischemic mitral regurgitation (IMR) is common. We hypothesized that the degree of pre-repair leaflet tethering as assessed by a novel three-dimensional (3D) echocardiographic based algorithm would be a sensitive predictor of repair failure within 6 months of surgery. Methods: Real-time 3D full volume transesophegeal echocardiography loops were acquired on patients (N=12) undergoing mitral valve repair for IMR. Images were segmented using previously described methodology. Using custom algorithms, leaflets were divided into six regions for calculation of the respective degree of tethering in each leaflet region. Patients received 2D echocardiography follow-up six months after surgery to assess for recurrence of MR. Pre-operative tethering of patients who recurred were compared to those who did not recur to identify predictors of repair failure. Students’ t-tests were used to compare groups; to account for multiple dependent variables, P&lt;.026 was considered statistically significant (Bonferroni correction). Results: 33% of patients had moderate to severe MR at the six month follow-up. The degree of horizontal tethering for the P3 leaflet region was 13.77 ± 4.29º compared to 36.71 ± 8.04º (P&lt;0.001) in the group which recurred. Repair failure at six months was predicted by A3 and P3 horizontal tethering angles. (Table 1) Tenting index and 2D echocardiography measurements of left ventricular size and ejection fraction were not predictive of failure. Conclusions: Pre-operative 3D posterior leaflet tethering is predictive of mitral valve repair failure. Three-dimensional modeling may aid in determining which patients should undergo replacement rather than repair in IMR.
A phase II study of irinotecan and cisplatin for metastatic or unresectable high grade neuroendocrine carcinoma
Authors: M. A. Mani, R. T. Shroff, C. Jacobs, R. A. Wolff, J. A. Ajani, J. C. Yao, A. T. Phan
Journal: Journal of Clinical Oncology (2008)

15550 Background: High-grade neuroendocrine carcinoma (HGNEC) are rare but aggressive characterized by high mitotic rate. Metastatic disease is incurable. Systemic treatments for HGNEC have been extrapolated from those for small cell lung carcinoma. Effective regimens for HGNEC alone have not been established. The combination of Irinotecan (I), and Cisplatin (P) was evaluated among patients with metastatic or unresectable HGNEC. Methods: Eligible patients were histologically confirmed HGNEC, previously untreated with unresectable or metastatic, measurable disease, adequate bone marrow, renal function, hepatic function and Zubrod performance status < 2. Patients were treated with IP (I 65mg/m2 IV D1+8 and P 25mg/m2 D1+8, every 21 days cycle). Primary endpoints were objective responses and toxicity profile. Response assessed by RECIST every 3 cycles. Dose modification of both drugs was allowed for grade 3/4 toxicities. Results: 20 patients were enrolled from 2003 until 2007, with 19 were evaluable for response and all were evaluable for toxicities. Patients received median of 5 cycles (2–14). 2 (11%) achieved complete response (CR), and 9 (47%) with partial response (PR), with overall objective response in 11 (58%). 3 (16%) attained stable disease (SD) and 5 (26%) with progressive disease (PD). Overall median time to progression (TTP) is 16 weeks (5–43), and among responders TTP 26 weeks (12 weeks for non-responders, p < 0.001). 25 grade 3 toxicities without any patients experiencing grade 4. Specifically, there were 32% leucopenia, 8% anemia, 20% fatigue, 12% nausea, 8% diarrhea, 8% hyponatremia, 4% hypokemia, 4% myalgia, and 4% dyspnea. Total accrual was expected to be 36, but the study was ended early because of slow accrual. Conclusions: The combination of irinotecan and cisplatin is feasible and a well-tolerated option for patients with advanced HGNEC. Responders specifically show a better time to progression. No significant financial relationships to disclose.