tbuckley/cabot-search huggingface dataset:
Abstract O.26: Angiotensin Receptor Blocker, Losartan suppresses coronary arteritis in a Murine Model of Kawasaki Disease. -Effectiveness of IVIG versus Losartan-
Authors: Eisuke Suganuma
Journal: Circulation (2015)

Background: Although intravenous immunoglobulin (IVIG) is an established treatment for Kawasaki disease (KD), 5 % of KD patients treated with IVIG still have coronary involvement. Angiotensin receptor blockers (ARBs), beside their antihypertensive effects, also suppress cell infiltration in atherosclerosis. However, the efficacy of ARB for KD has not been established. Objective: We aimed to elucidate if ARB ameliorates coronary arteritis (CA) in a murine model of KD, introduced by Lactobacillus casei wall extract (LCWE). We also aimed to verify whether ARB’s effects are different from those of IVIG. Method: 4-week-old male mice were intraperitoneally injected with LCWE (L, n=15) or PBS (P, n=15). 5 days later, those mice were given IVIG (1g/kg, L+IVIG, n=8), or ARB (losartan 100mg/L in drinking water for 2 wks, L+ARB, n=18). 2 weeks after LCWE injection, histological assessment of the heart and measurement of plasma cytokine levels were performed. IL-6 and mannose receptor (MR) mRNA expressions in the aortic root were studied (n=5 each group) in an additional experiment. Results: CA score was significantly increased by LCWE (L: 8.3±0.5 vs. P: 2.9±0.5, p&lt;0.0001). ARB significantly ameliorated CA (L+ARB: 5.1±0.7 vs. L, p=0.008). The effect of IVIG on CA was milder and not significant (L+IVIG: 6.0±0.9 vs. L). Of note, macrophage infiltration was dramatically decreased by ARB but not by IVIG. IVIG treatment ameliorated serum levels of IL-1β, IL-10 and TNF-α in a milder fashion than ARB. Interestingly, serum IL-6 level was suppressed by ARB, but not by IVIG. Locally up-regulated mRNAs of IL-6 and MR were significantly ameliorated by ARB, with milder effects by IVIG. Conclusions: ARB, rather than IVIG, exerts powerful anti-CA effects with suppressing local macrophage infiltration and systemic/local inflammatory cytokines. Thus, ARB potentially exerts additive anti-CA effects in KD under IVIG treatment.
A phase II study of whole brain radiotherapy with simultaneous integrated boost using volumetric modulated arc therapy for 1 to 10 brain metastases.
Authors: Alan Nichol, Michael R. McKenzie, Roy Ma, Fred Hsu, Arthur Cheung, Devin Schellenberg, Lovedeep Gondara, Rosemin Vellani, Hannah Carolan, Robert Anton Olson, Francois Germain
Journal: Journal of Clinical Oncology (2014)

2078 Background: Local control of brain metastases reduces risk of death from intracranial progression and improves survival in selected patients. Volumetric modulated arc therapy can deliver a fraction of whole brain radiotherapy (WBRT) and a simultaneous integrated boost (SIB) to multiple brain metastases in about 5 minutes. This is the first registered clinical trial (NCT01046123) to report WBRT and SIB for up to 10 brain metastases. Methods: Sixty subjects with 1-10 brain metastases were accrued to a single-institution phase II study of a 5-fraction course of 20 Gy WBRT and 50 Gy SIB. Eligible subjects had Karnofsky Performance Status (KPS) 70 - 100, maximum diameter of the largest metastasis ≤ 3 cm, and estimated ≥ 6-month median life expectancy. The phase II primary endpoint was a comparison of 3-month local control with that of the WBRT (37.5 Gy/15) and stereotactic radiosurgery (SRS: 15-24 Gy/1) arm of the RTOG 95-08 study (90%). Overall survival for subgroups with 1-3 and 4-10 metastases were compared. Results: The median number of brain metastases was 3 (range: 1-10). Known prognostic factors for overall survival in the 1-3 subgroup (n = 33) and the 4-10 subgroup (n = 27) were not significantly different. The cancers were: 53% lung, 32% breast and 15% other. The minimum follow-up was 5 months and the median follow-up was 9 months. The 3-month radiographic responses were: 10% complete, 48% partial, 33% stable (90% local control) and 10% progressive disease. Grade 3-4 radionecrosis occurred in 7% (4/60) of subjects at a median of 9 months. The median survival was 10 months in the 1-3 subgroup and 12 months in the 4-10 subgroup (p = 0.8). Multivariable analysis of overall survival showed that KPS 70-80 (HR = 3.2, p < 0.004), extracranial disease (HR = 2.9, p = 0.04) and no use of targeted systemic therapy (HR = 7.5, p = 0.0003) were associated with worse survival, but age (HR = 0.98, p = 0.1) and number of metastases 1-3 vs. 4-10 (HR = 1.1, P = 0.8) were not. Conclusions: WBRT and SIB had similar 3-month local control to the WBRT and SRS arm of RTOG 95-08. Equivalent survival of the 1-3 and 4-10 subgroups justifies including selected patients with 4-10 brain metastases in phase III trials for brain metastases. Clinical trial information: NCT01046123.
Effect of sulfasalazine (SSZ) on cancer stem-like cells (CSCs) via inhibiting xCT signal pathway: Phase 1 study in patients with gastric cancer (EPOC 1205).
Authors: Kohei Shitara, Shunji Takahashi, Takako Eguchi Nakajima, Shuichi Hironaka, Osamu Nagano, Chiyo K. Imamura, Miki Fukunani, Hiromi Hasegawa, Akihiro Sato, Atsushi Ohtsu, Hideyuki Saya, Toshihiko Doi
Journal: Journal of Clinical Oncology (2014)

2545 Background: CD44 is an adhesion molecule expressed in cancer stem-like cells (CSCs). Our group recently reported that CD44 splice variant (CD44v) is expressed in CSCs and interacts with xCT, a glutamate-cystine transporter, keeping high levels of the intracellular reduced glutathione (GSH). Thus, CSCs with a high expression of CD44v have an enhanced capacity for GSH synthesis and defense against reactive oxygen species (ROS), resulting in resistance to various therapeutic stresses. Sulfasalazine (SSZ) as an xCT inhibitor suppressed CD44v-dependent tumor growth and increased sensitivity to cytotoxic drugs in vivo study. Methods: A phase 1 dose escalation study in patients with advanced gastric cancer was conducted to determine the optimal dose. SSZ was given fourth-daily oral administration with 2 weeks as one cycle. A 3+3 escalation was used to evaluate a MTD. Tumor tissues were obtained pre- and post SSZ administration to evaluate expression of CD44v and intra-tumor level of GSH by immunohistochemistry and boron doped diamond microelectrode, respectively. Results: Eleven patients were dosed from 8 g to 12 g/day; median age: 71 years (61-78); median number of prior chemotherapies: 3 (1-4). There was two DLT of grade 3 anorexia and nausea among patients who were treated with 12 g/day. One additional patients required frequent dose interruption with grade 2 anorexia and nausea. Therefore 12g/day was judged as MTD. No DLT was observed among patients with 8g/day. Patients with high CD44v expression patientss achieved reduced expression of CD44v after the administration of SSZ for 2 weeks as well as decreased level of GSH. The individual variability of SSZ exposure was explainable in terms of the genotypes of ABCG2 and NAT2 which influence SSZ pharmacokinetics. Conclusions: Optimal dose of SSZ was considered as 8g/day. Down regulation of CD44v expression and decreased level of GSH migh be a pharmacodynamic marker of drug-on-target effect and mode of action of SSZ for CSCs, which warrants further investigation for combination with chemotherapy or other targeting agents. Clinical trial information: UMIN000010254.
Effect of toxicity-adjusted dose (TAD) of sunitinib on intra-patient variation of trough levels: A longitudinal study in metastatic renal cell cancer (mRCC).
Authors: Alison Yan Zhang, Peter Fox, Sally Coulter, Bavanthi Balakrishnar, Christopher Liddle, Howard Gurney
Journal: Journal of Clinical Oncology (2014)

2597 Background: It has been proposed that trough levels of sunitinib (S) + metabolite of >50ng/mL may be associated with better anti-cancer effect. Large inter-patient variations of trough S have been reported in patients (pts) with mRCC at standard doses. However, little is known about the intra-patient variation of S levels over time. Methods: Dose and schedule of S was adjusted to ensure grade 1 or 2 toxicity on >10 days (d) of each 42 d cycle. Trough levels of S and its active metabolite, N-desethyl-sunitinib (NdS) were determined by HPLC-mass spectrometry every 6 weeks. Total trough level (TTL) was defined as the sum of S + NdS. Pts achieving a TTL target of >50ng/mL at stable dose were determined. Results: 27 pts with mRCC received S for a median of 7 months (range 0.5 to 11 months) with doses ranging from 25 to 87.5mg/day in the dose adjustment period. There was no correlation between dose and S trough level (r=0.14; P=NS). However there was a positive correlation between dose and NdS level (r=0.54; P<0.01), and dose and TTL (r= 0.34; P<0.01). The mean stable dose was 41.8mg (range 25-75mg) usually on a 14/7 schedule. Dose was significantly lower for females (32.5 vs 42.5 mg; P=0.05). Between pts, TTL ranged from 3.61 to 190.8 ng/mL (mean 68.0 ng/mL, coefficient of variation 42.3%). In contrast, mean intra-patient variability of TTL in pts at stable dose was 16.2% (range 0.4% to 32.2%). 24/27 patients (88.9%) reached the target TTL >50 ng/mL using the TAD protocol. Conclusions: Using a novel TAD protocol almost 90% of pts achieved the target TTL. This study demonstrates that individuals on stable dose had negligible variation in trough level over time and has implication for therapeutic drug monitoring. The study is ongoing to correlate TTL at stable dose with outcome. Clinical trial information: NCT01711268.
Frequency of MYC Overexpression and MYC-BCL2 Double Expression (DEL) in Localized Diffuse Large B-Cell Lymphoma (DLBCL) at a Large Academic Cancer Center
Authors: Stephanie Ryanne Corder, Ankit Agarwal, Jonathan Galeotti, Xianming Tan, Natalie S Grover, Christopher Dittus
Journal: Blood (2018)
Fetal Valproate Exposure and Attention-Deficit/Hyperactivity Disorder
Authors: Kimford J. Meador
Journal: JAMA Network Open (2019)

Jakob Christensen, MD, PhD, DrMedSci; Lars Pedersen, PhD; Yuelian Sun, PhD; Julie Werenberg Dreier, PhD; Isabell Brikell, PhD; Søren Dalsgaard, MD, PhD
Genetic features of pulmonary adenocarcinoma presenting with ground-glass nodules (GGN): Differences between those with growth potential and those without.
Authors: Yoshihisa Kobayashi, Yasushi Yatabe, Tetsuya Mizuno, Hiroaki Kuroda, Noriaki Sakakura, Tetsuya Mitsudomi, Yukinori Sakao
Journal: Journal of Clinical Oncology (2014)

7546 Background: Some pulmonary GGNs become larger or increase solid component, whereas others, mainly pure GGNs, remain unchanged for years. We have previously reported that 3-year follow-up is a reasonable benchmark to distinguish GGNs with growth from those without growth, and that smoking history and larger diameter were associated with growth (Lung Cancer 83:61-66, 2014). However, genetic differences between them remain unclear. This study aimed to evaluate the genetic features of resected GGNs and clarify the differences. Methods: We examined 97 pulmonary nodules with ground-glass component ≥50% on CT in 90 patients that had been resected in 2012 and 2013. The tumors were evaluated for clinicopathologic features including lesion diameter, presence of invasion, and presence of EGFR/KRAS/ALK/HER2 mutations. Results: There were three atypical adenomatous hyperplasia (AAH), 17 adenocarcinoma in situ (AIS), 25 minimally invasive adenocarcinoma (MIA), and 52 invasive adenocarcinoma (IA). We identified mutations or rearrangements in 75 % (73/97): EGFR in 65% (63/97), KRAS in 4% (4/97), ALK in 5% (3/66), and HER2 in 7% (3/41). Smoking history, lesion diameter, solid component (mixed versus pure), tendency to grow, and pathological diagnoses (MIA/IA versus AAH/AIS) were significantly different (P <0.2) in tumors with any of driver oncogene mutation (mut+) as compared with those with no mutation (mut-), whereas age and gender were not (Table). In multivariate analyses, tendency to grow [Odds ratio (OR) 8.34, P <0.01], MIA/IA [OR 6.74, P = 0.01], and non-smoking history [OR 3.63, P = 0.02] were independent factors for mut+. Conclusions: Mut+ GGNs were associated with tendency to grow, MIA/IA, and non-smoking history. These results may suggest that mut- GGNs could remain unchanged and thus could be candidates for observation alone without surgical intervention. Variables Mut+ (N=73) Mut- (N=24) p Age (mean) 62 62 0.95 Male 30 10 0.96 Nonsmoking 46 10 0.07 Lesion diameter ≥15mm 55 13 0.05 Mixed GGN 61 17 0.17 Tendency to grow 32 2 <0.01 MIA/IA 64 13 <0.01
Results of stage 1 of the oparatic trial: A phase I study of olaparib in combination with temozolomide in patients with relapsed glioblastoma.
Authors: Anthony J. Chalmers, Alan Jackson, Helen Swaisland, William Stewart, Sarah E. R. Halford, L Rhoda Molife, Darren R Hargrave, Alex McCormick
Journal: Journal of Clinical Oncology (2014)

2025 Background: Drug delivery is a major problem in the treatment of glioblastoma (GBM). Tumour pharmacokinetics (PK) of small molecule targeted agents in GBM are not well understood, and poor activity may result from lack of biological efficacy or adverse PK. Olaparib, a small molecule inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), has potential to overcome treatment resistance of GBM. Despite radiological responses in brain metastases, GBM penetration by olaparib has not been studied. Methods: Preclinically, blood-brain barrier penetration was assessed by directional transport of [14C]-olaparib across MDCKII cells expressing MDR1 and autoradiography of rats and mice treated with [14C]-olaparib. Clinically, 8 patients with recurrent GBM underwent dynamic contrast enhanced (DCE) MRI at baseline followed by tumour resection after 4 days of oral olaparib (tablet: 100 mg QD, n=5; 200 mg BID, n=3). Olaparib levels were measured in tumour and plasma by LC-MS. Results: Olaparib was a substrate for MDR1 and efflux was blocked by the MDR1 inhibitor ketoconazole. Radioactivity was not detected in the central nervous systems (CNS) of rats or mice after single dose [14C]-olaparib, but significant levels were measured in subcutaneous HCT-116 tumour xenografts up to 96 hrs. Olaparib was detected in 24/24 resected GBM specimens from 8 patients (Table) at concentrations similar to those in previous breast cancer studies in which PARP inhibition and tumour responses were observed. Pre-treatment DCE-MRI showed increased vascular permeability in tumours, and tumour cellularity parameters correlated with olaparib levels. Conclusions: Olaparib is excluded from the CNS under normal conditions but reliably penetrates recurrent GBM at therapeutic levels. Small molecule PK in GBM are poorly predicted by standard pre-clinical models. Clinical trial information: NCT01390571. Subject Daily olaparib dose (mg) Olaparib concentration (day 4) Tumor section (ng/g) Mean tumor (ng/g) Plasma (ng/ml) 1 400 137 238 5290 210 367 2 400 71.2 94.7 3840 72.9 140 3 400 431 282 1330 133 281 4 100 177 112 876 105 55.0 5 100 324 364 773 354 413 6 100 494 413 617 345 401 7 100 53.1 59.8 1290 65.8 60.6 8 100 203 175 1460 156 166
Characteristics and Outcome of Older Patients with Acute Promyelocytic Leukemia Front-Line Treated with or without Arsenic Trioxide — an International Collaborative Study
Authors: Sabine Kayser, Ramy Rahmé, David Martínez-Cuadron, Gabriel Ghiaur, Xavier Thomas, Marta Sobas, Agnes Guerci Bresler, Salut Brunet, Arnaud Pigneux, Cristina Gil, Emmanuel Raffoux, Mar Tormo, Norbert Vey, Javier de la Serna, Olga Salamero, Eva Lengfelder, Mark J. Levis, Pierre Fenaux, Miguel A. Sanz, Richard F. Schlenk, Uwe Platzbecker, Lionel Ades, Pau Montesinos
Journal: Blood (2018)
Abstract 14829: Semi-quantitative Assessment of OCT-macrophage Predicts Future Development of Thin-cap Fibroatheroma in Non-culprit Lipid Plaques: A Serial Optical Coherence Tomography Study
Authors: Yoshiyasu Minami, Daniel S. Ong, Shiro Uemura, Zhao Wang, Aaron D. Aguirre, Tsunenari Soeda, Rocco Vergallo, Lei Gao, Lei Xing, Hang Lee, Bo Yu, Ik-Kyung Jang
Journal: Circulation (2015)

Introduction: Previous pathological studies have demonstrated that macrophages play an important role for the deterioration of fibrous cap and the onset of acute coronary syndrome. However, the significance of macrophage on the development of thin-cap fibroatheroma (TCFA) had not been fully evaluated in vivo. Aim: To explore the impact of OCT detected macrophage on the development of TCFA in patients with coronary artery disease using serial OCT images. Methods: A total of 152 non-culprit plaques from 90 patients who had serial OCT imaging at baseline and follow-up (median 6.38 [6.07-12.5] months) were included. TCFA was defined as the plaque with the fibrous cap thickness &lt;65μm.OCT detected macrophage was semi-quantitatively assessed in every 1mm along the entire target plaque using a previously introduced grading system; Grade 0: no macrophage, Grade 1: localized macrophage accumulation, Grade 2: clustered accumulation&lt;1 quadrant, Grade 3: clustered accumulation≥1 quadrant but &lt;3 quadrants, Grade 4: clustered accumulation≥3 quadrants. The summation of 0 to 4 grades was evaluated. Results: Among 45 TCFA at baseline, 19 remain as TCFA [persistent TCFA] and 26 changed to non-TCFA [resolved TCFA] at follow-up (Figure). The macrophage grade in persistent TCFA was significantly greater than that in resolved TCFA (13.0 [8.00-17.0] vs. 4.00 [2.00-8.25] (P&lt;0.001)) at baseline. On the other hand, 11 among 107 non-TCFA at baseline changed to TCFA [acquired TCFA] at follow-up. The macrophage grade in acquired TCFA was significantly greater than that in non-TCFA (14.0 [11.0-19.0] vs. 2.0 [0.00-6.75] (P&lt;0.001)) at baseline. The macrophage grade&gt;7.5 at baseline had good performance in discriminating TCFA from non-TCFA at follow-up (area under the curve [AUC] = 0.884, P&lt;0.001) (Figure). Conclusions: The semi-quantitative evaluation of OCT detected macrophage at baseline had the potential to predict the future development of TCFA in patients with coronary artery disease.
Effect of the BRAF inhibitor LGX818 on endoplasmic reticulum stress and sensitivity of NRAS-mutant melanoma cells to the MEK inhibitor binimetinib.
Authors: Friedegund Elke Meier, Claus Garbe, Keiran Smalley, Keith Flaherty, Dirk Schadendorf, Stefan Beissert, Dagmar Kulms, Heike Niessner
Journal: Journal of Clinical Oncology (2014)

9062 Background: The BRAF inhibitors vemurafenib and dabrafenib have demonstrated antitumor activity in patients with metastatic BRAFV600-mutant melanoma. However, patients with BRAF wild-type, in particular patients with aggressive NRAS-mutant melanoma, do not benefit. In a phase 2 trial, the MEK inhibitor binimetinib showed activity in patients with NRAS-mutant melanoma with overall response rates of >20%. In a previous study, we showed that the BRAF inhibitor vemurafenib induces apoptosis in BRAFV600-mutant melanoma cells through a mechanism involving induction of endoplasmic reticulum (ER) stress. ER stress induction appeared to be an off-target effect of vemurafenib that remarkably enhances its pro-apoptotic activity in BRAFV600-mutant melanoma. Methods: In this study, we investigated whether it is possible to take advantage of ER stress induction to establish effective combination therapies for patients with NRAS-mutant melanoma. Results: BRAF-mutant and NRAS-mutant metastatic melanoma cell lines were treated with the BRAF inhibitors vemurafenib, dabrafenib and LGX818, and the classical ER stress inducer thapsigargin, and were subjected to electron microscopy. Of note, LGX818 induced morphological features of ER stress, including a significant dilation of the ER in both BRAF-mutant and NRAS-mutant melanoma cell lines. As expected, LGX818 inhibited phosphorylation of ERK and growth and induced apoptosis in BRAF-mutant but not in NRAS-mutant melanoma cells. However, LGX818 significantly enhanced growth inhibition and apoptosis induced by the MEK inhibitor binimetinib in NRAS-mutant melanoma cells. Moreover, LGX818 in combination with binimetinib induced the expression of the ER stress-related factors p8, ATF4, ATF3, CHOP and TRB3 in NRAS-mutant melanoma cells. siRNA inhibition of ATF4 reduced melanoma cell apoptosis induced by LGX818 combined with binimetinib. Conclusions: These data suggest that the BRAF inhibitor LGX818 induces endoplasmic reticulum stress and potentiates the antitumor activity of MEK inhibitors in NRAS-mutant melanoma.
Circulating cell-free total and Epstein–Barr virus DNA in pediatric lymphomas.
Authors: Tezer Kutluk, Bilgehan Yalcin, Serpil Kahraman Agbaba, Cetin Demir, Munevver Buyukpamukcu
Journal: Journal of Clinical Oncology (2014)

e21004 Background: Quantification of serum EBV DNA and/or cell-free total DNA (cf-DNA) may become valuable sources for diagnosis and prognosis evaluation in pediatric lymphomas, and also for disease monitoring. In order to investigate serum cf-DNA and EBV DNA as potential markers, we serially quantified cell-free and EBV serum DNA in pediatric Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) cases by real-time PCR. Methods: Between June 2005–November 2008, 37 HL and 51 NHL patients were prospectively included in the study. Serum samples were collected upon diagnosis, after 1-3 months and 4-6 months and at end of treatment, or at disease recurrence. DNA was extracted from serum using standard techniques. Quantitative real-time PCR determination of cf-DNA and EBV DNA were performed using amplification of BAMH1W region of EBV genome and of β-globin gene. Results were analyzed for correlation with clinical and pathological characteristics. Results: Median ages were 9 years for HL and 8 years for NHL cases. At initial diagnosis, serum EBV copies were elevated in 20/34 HL and 8/45 NHL cases [p<0.001]. Median serum EBV copy numbers were 15988/mL (125-6032075) for HL and 25163 (1475-1214550) for NHL cases [p=0.9]. Serum EBV levels decreased significantly after induction treatment and in the follow-up. Median serum cf-DNA levels were 435 ng/mL (2.3-17306) in HL and 700 ng/mL (4.9-14009) in NHLs [p=0.12]. Initial serum LDH levels were significantly correlated with cf-DNA levels. No significant differences were detected between median cf-DNA levels of cases according to disease stages, response to induction chemotherapy or presence of recurrent disease. Serum cf-DNA levels decreased significantly in the follow-up, and elevated again when recurrences were diagnosed. Conclusions: Serum EBV DNA levels are elevated especially in HL, decreased significantly following induction therapies, but were not elevated when recurrences occurred. Serum cf-DNA levels were elevated significantly at initial diagnosis in both HL and NHL cases. Significant decreases were observed in cf-DNA levels when the cases entered remission. Elevation of levels at recurrences indicated that serum cf-DNA levels can have importance in the follow-up of pediatric lymphomas.