tbuckley/cabot-search huggingface dataset:
Phase II single-arm study of irinotecan in combination with temozolomide in children with recurrent or refractory medulloblastoma
Authors: J. Grill, D. Perek, J. Sanchez de Toledo-Codina, L. Madero, E. Estlin, A. Cañete, C. Icher, A. Breazna, B. Geoerger, L. Cisar, D. Hargrave
Journal: Journal of Clinical Oncology (2009)

10018 Background: Irinotecan and temozolomide have demonstrated moderate single agent activity in childhood medulloblastoma (MB). Using the recommended dose established from a prior pediatric phase I study, the combination of irinotecan and temozolomide was investigated in relapsed MB. Methods: Patients aged 6 months to 18 years with radiological measurable relapsed/refractory MB were treated with temozolomide 100–125 mg/m2/day on days 1–5 orally and irinotecan 10 mg/m2/day on days 1–5 and days 8–12 intravenously. After cycle 5, patients who did not progress could receive irinotecan 125 mg/m2 once weekly on days 1 and 8 of the 3-week cycle. The primary objective was confirmed tumor response (partial or complete) after 4 cycles of treatment. According to a two-stage Optimum Simon design, at least 6 of the first 15 evaluable subjects were to have a confirmed objective response, to proceed to stage 2; a total of 19 responses in 46 subjects are required for success. A central radiological review determined tumor response in all patients. Results: Preliminary results are reported on 33 patients entered from May 2007 through to November 2008 in 19 treatment centers. The median age was 9 years (range 2 to 17 years); 23 male and 10 female. The number of relapsed patients with M3:M2:M1:M0 (Chang M stage) were 10:15:2:6, and 17 had more than 1 prior therapy. Previous treatment included chemotherapy, 7 with high-dose regimens, and craniospinal (CSI) (n=30) or posterior fossa irradiation (n=2). Central radiological review is ongoing: 16/26 reviewed patients were evaluable for response. Six patients had confirmed PR, 3 had SD, and 7 had PD. To date, 10 patients have been excluded after central review (8, poor imaging; 2, no measurable disease). Toxicity has been manageable with dose reduction required in 11/33 MB patients, all of these had received prior CSI. The study is ongoing in stage 2 and centrally verified results will be reported at the Meeting. Conclusions: This multi-centre international study is the largest phase II trial of the irinotecan and temozolomide combination in pediatric central nervous system tumors. The activity of the combination in heavily pre-treated recurrent MB patients is promising. [Table: see text]
Potential of activatable FAP-targeting immunoliposomes in intraoperative imaging of spontaneous metastases
Authors: Felista L. Tansi, Ronny Rüger, Claudia Böhm, Roland E. Kontermann, Ulf K. Teichgraeber, Alfred Fahr, Ingrid Hilger
Journal: Biomaterials (2016)

Despite intensive research and medical advances met, metastatic disease remains the most common cause of death in cancer patients. This results from late diagnosis, poor therapeutic response and undetected micrometastases and tumor margins during surgery. One approach to overcome these challenges involves fluorescence imaging, which exploits the properties of fluorescent probes for diagnostic detection of molecular structures at the onset of transformation and for intraoperative detection of metastases and tumor margins in real time. Considering these benefits, many contrast agents suitable for fluorescence imaging have been reported. However, most reports only demonstrate the detection of primary tumors and not the detection of metastases or their application in models of image-guided surgery. In this work, we demonstrate the influence of fibroblast activation protein (FAP) on the metastatic potential of fibrosarcoma cells and elucidate the efficacy of activatable FAP-targeting immunoliposomes (FAP-IL) for image-guided detection of the spontaneous metastases in mice models. Furthermore, we characterized the biodistribution and cellular localization of the liposomal fluorescent components in mice organs and traced their excretion over time in urine and feces. Taken together, activatable FAP-IL enhances intraoperative imaging of metastases. Their high accumulation in metastases, subsequent localization in the bile canaliculi and liver kupffer cells and suitable excretion in feces substantiates their potency as contrast agents for intraoperative imaging.
A phase II study of S-1 for the treatment of cytokine-refractory metastatic renal cell carcinoma
Authors: S. Naito, M. Eto, N. Shinohara, Y. Tomita, M. Fujisawa, M. Namiki, M. Nishikido, M. Usami, T. Tsukamoto, H. Akaza
Journal: Journal of Clinical Oncology (2009)

5100 Background: S-1 is a novel oral anticancer agent, contains tegafur (FT), a prodrug of 5-fluorouracil (5-FU), with 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT: CDHP: Oxo = 1:0.4:1. The purpose of this study was to evaluate the efficacy and safety of S-1 in cytokine-refractory metastatic renal cell carcinoma (mRCC), and to examine the relation between response and mRNA expression levels of 5-FU-related enzymes. Methods: Eligible patients had a histologically confirmed diagnosis of clear cell or papillary type of RCC, measurable lesions, treatment histories with cytokines, an ECOG performance status of 0 or 1 (2 was allowed in patients with bone metastasis), an age of at least 20 years, prior nephrectomy, and adequate organ functions. Any prior treatment for mRCC was discontinued more than 4 weeks before registration. S-1 was administered orally at a dose of 40 mg/m 2 twice daily for 28 days, followed by 14 days of rest. The primary endpoint was the objective response rate (ORR) as confirmed by an independent reviewer. The planned sample size was 44 patients. The threshold response rate was defined as 5%, and the expected rate was set at 17.5%. If the lower limit of the 95% CI exceeded the threshold rate (6 of the 44), S-1 was evaluated to be effective. Formalin fixed paraffin embedded specimens, which had been obtained by radical nephrectomy, were used for mRNA expression assay, performed by RT-PCR method. Results: Between April 2006 and May 2007, 45 patients were enrolled, and 31 assay samples were obtained. ORR was 24.4% (11/45, 95% CI: 12.9 - 39.5%). The median PFS was 9.2 months. The median OS could not be calculated, but the survival rate at 1 year was 87.5%. The most common grade 3–4 adverse events assessed according to the CTCAE v.3.0 included anemia (6.7%), neutropenia (8.9%), anorexia (8.9%), hyperglycemia (6.7%), stomatitis (4.4%), diarrhea (4.4%), and fatigue (4.4%). On mRNA expression analysis, the expression level of 5-FU-related enzyme correlated with ORR and PFS. Conclusions: S-1 is effective and well tolerated in patients with cytokine-refractory mRCC. Measurement of the mRNA level of 5-FU-related enzyme in tumors before treatment may facilitate prediction of the response to S-1. No significant financial relationships to disclose.
Improvement in anemia management with epoietin alfa (EA) in elderly and/or poor performance status (PS) patients (pts) with advanced non-small cell lung cancer (NSCLC) (GFPC 0202)
Authors: H. Lecaer, M. André, P. A. Thomas, J. Crequit, L. Falchero, J. F. Berdah, J. Y. Delhoume, J. M. Chavaillon, H. Lena, M. Perol
Journal: Journal of Clinical Oncology (2006)

18571 Background: EA at a starting dose of 40000 UI sc once weekly (qw) has been show to be effective in the treatment of chemotherapy (CT) induced anemia in cancer pts and early intervention with EA appears important for anemia prevention and reduce CT toxicity in elderly pts. Methods: In this multicenter phase II study, chemonaive pts with stage IIIB (pleural effusion) and IV 50 pts with mild co-morbidity (Charlson score) and good performans status (PS) received docetaxel 30 mg/m 2 weekly (6 wks, 2 wks off) and gemcitabine 900 mg/m 2 (only on day 1, 8, 22, 29) arm A and 50 pts with higher co-morbidity and/or poor performans status (PS) received docetaxel 30 mg/m 2 weekly (6 wks, 2 wks off) arm B. Anemic pts with Hb &lt;11.5 g/dl received EA 40000 UI/qw until a target = 13 g/dl with maintenance phase during CT and 28 days after the end of CT to maintain Hb 11.5 to 12.5 g/dl. Dose could be increased to 60000 UI/qw after 4 wks depending on Hb response. Quality of life (Qol: LCSS, Spitzer score) was assessed at baseline, 8, 16 and 24 wks. This trial assessed the effect of EA on Hb level after 4 and 8 wks, tranfusion requirements and Qol. Results: From Jun 2003 to Dec 2004 100 pts were enrolled, median age was 72,7 (66–82) arm A, 76,6 (70–84) arm B, median co-morbidity 1 (0–4) arm A; 1,9 (0–5) arm B. 59 pts received EA (58% arm A; 60% arm B), mean Hb level was 11.6 at the start of CT, and 10.42 before EA. Mean Hb increase after 4 wks was 0.77 ± 1.11 (p &lt; 0.05), and 1.63 ± 1.36 after 8 wks (p &lt; 0.05). Only 14.1% received transfusions. There was no significant change in global Qol and fatigue (LCSS). The main grade 3/4 CT toxicity was fatigue 25% and neutropenia in arm A and fatigue 50% in arm B. Conclusions: Weekly EA increase Hb level, early EA intervention maintain Qol and decrease red blood transfusions, and mild anemia is probably associated with significant impairment in toxicity in elderly pts with advanced NSCLC. No significant financial relationships to disclose.
Abstract 14988: Involvement of Adventitial Vasa Vasorum and Sympathetic Nerves in Coronary Hyperconstricting Responses After Drug-eluting Stent Implantation in Pigs in vivo
Authors: Hironori Uzuka, Yasuharu Matsumoto, Kensuke Nishimiya, Michinori Hirano, Tsuyoshi Ogata, Tomohiko Shindo, Kenichiro Hanawa, Yuhi Hasebe, Kiyotaka Hao, Ryuji Tsuburaya, Kenta Ito, Jun Takahashi, Hiroaki Shimokawa
Journal: Circulation (2014)

Purpose:  We have previously demonstrated that adventitial inflammation plays an important role in the pathogenesis of coronary vasospasm in porcine models. The adventitia harbors a variety of components with potent modulation of vascular tone, including vasa vasorum (VV) and sympathetic nerve fibers (SNFs). We tested our hypothesis that adventitial VV and SNFs are involved in the pathogenesis of coronary hyperconstricting responses after DES implantation in pigs in vivo.   Methods:  We randomly implanted 3 different types of DES, sirolimus-eluting stents (SES, 1st generation DES), everolimus-eluting stents (EES, 2nd generation DES) and biolimus A9-eluting stents (BES, new generation DES), into the left porcine coronary arteries (n=12 each). After 1 month, coronary responses to intracoronary serotonin (10 and 100 μg/kg) were examined by coronary angiography. After euthanasia, stented vessels and untreated vessels (as controls) were harvested for immunohistochemistry of adventitial VV (von Willebrand factor, vWF) and SNFs (tyrosine hydroxylase, TH).   Results:  Coronary vasoconstricting responses to serotonin were significantly enhanced at the edges of the SES and the EES sites, associated with increased adventitial densities of VV (vWF) and SNFs (TH) as compared with the control sites and the BES edges (all P   Conclusions:  These results indicate that adventitial VV and SNFs may be involved in the pathogenesis of DES-induced coronary hyperconstricting responses, which are less pronounced with new generation BES.
patients with diffuse large B-cell lymphoma (DLBCL): results from the phase II EUR018 trial
Authors: S Luminari, A Montanini, D Caballero, S Bologna, M Notter, Mj Dyer, A Chiappella, J Briones, M Petrini, A Barbato, L Kayitalire, M Federico, Liposomal Doxorubicin Myocettm Combination R-Comp Chemotherapy In Elderly Nonpegylated
Journal: Annals of Oncology (2011)
Bortezomib combined with histone deacetylase inhibitor ITF2357 or arsenic trioxide exerts aynergistic anti-proliferative and pro-apoptotic effect on P39 cells
Authors: H. Savli, S. Galimberti, M. Canestraro, B. Nagy, G. A. Palumbo, M. Petrini
Journal: Journal of Clinical Oncology (2008)

18022 Background: NF-kB is constitutively activated in the P39 cell line and its activity levels are higher in advanced myelodysplastic syndromes (MDS), with a higher risk of transformation into acute leukemia. Bortezomib is able to inactivate NF-kB, exert an anti- proliferative and pro-apoptotic effect, increase release of reactive oxygen species and block cell cycle in the G2 phase. Because others Authors reported a synergistic anti-proliferative effect exerted by the histone deacetylase inhibitor vorinostat plus bortezomib, we co-incubated P39 with bortezomib and ITF2357. Then, because arsenic trioxide (ATO) has been reported to inactivate NF-kB and offer hematological improvement in MDS, we decided to combine bortezomib with ATO. Methods: Samples were hybridized on Whole Human Genome Microarray (Agilent). The genes identified as de-regulated by bortezomib were then analyzed for network and gene ontology by Ingenuity Pathway Analysis software. Results have been confirmed by using the TaqMan® Low Density Array Human Apoptosis Panel. Results: Bortezomib/ITF2357 and bortezomib/ATO exerted synergistic anti-proliferative and pro-apoptotic effects, synergistic increase of ROS production and down-regulation of the WT1. EMSA assays showed that NF-kB, inactivated by each of these drugs, was not inactivated by the association bortezomib/ITF2357. The microarray experiments showed that several NF-kB inhibitors, such as IKB and BCL3, were down- regulated by the combination of bortezomib/ITF2357. When P39 were co-incubated with bortezomib/ATO, PPAR, P53, IL6, IL2, hypoxia, Huntington’s disease, TLR and cell cycle were the pathways more significantly modified. Moreover, bortezomib+ATO down-regulated SHC1, MLL, ITGAV; BCRA2, whereas SPP1 (osteopontin, target for P53, pro-apoptotic) resulted up-regulated. Moreover, only when combined with ATO, bortezomib increased the down-regulation of HMOX1, ICAM1, JUN, and PMAP1. Conclusions: In summary, biological results and gene expression assays suggest the possible use of bortezomib combined with proteasome inhibitors or arsenic trioxide in the treatment of high-risk MDS. No significant financial relationships to disclose.
18F-DOPA Uptake of Developmental Venous Anomalies in Children With Brain Tumors
Authors: Giovanni Morana, Arnoldo Piccardo, Maria Luisa Garrè, Manlio Cabria, Andrea Rossi
Journal: Clinical Nuclear Medicine (2016)

We report the finding of increased F-3,4-dihydroxyphenylalanine uptake of the brain parenchyma adjacent to developmental venous anomalies, incidentally discovered in 3 pediatric patients with diffusely infiltrating gliomas. One patient presented 3 developmental venous anomalies located distant from the tumor, whereas in the remaining 2 patients, the vascular anomalies were inside the tumoral area mimicking a focal area of increased tumor metabolism. In the setting of brain tumor imaging, focal increased F-3,4-dihydroxyphenylalanine uptake should be carefully interpreted in light of MRI findings, and nuclear medicine physicians should be aware of any incidental minor vascular abnormality for proper interpretation of PET data.
The effect of JQ1/SGCBD01 upon c-Myc in human airway smooth muscle in asthma
Authors: Mark Perry, Andrew Durham, Gurpreet Sehra, Ian Adcock, Fan Chung
Journal: European Respiratory Journal (2014)

Rationale 

Increased airway smooth muscle (ASM) mass contributes to chronic airflow obstruction, chronic airway inflammation and airway wall remodelling. The novel chemical probe for BET bromodomians (JQ1/SGCBD01) was more potent at inhibiting TGF-β-induced ASM cell proliferation, IL-6 and CXCL8 release in cells from healthy individuals than in cells from non-severe and severe asthma. JQ1 can affect c-Myc expression or c-Myc association with proliferative gene promoters. Here, we compared the anti-inflammatory effects of JQ1 with that of a specific c-Myc inhibitor in ASM cells from asthmatics.

Methods 

ASM cells were grown from healthy subjects and severe or non-severe asthmatics. Cells were pre-treated with the c-Myc inhibitor 10058-F4 or with JQ1 before being stimulated with FCS±TGF-β. IL-6 and CXCL8 secretion and cell proliferation were measured by ELISAs. mRNA expression was examined by RT-qPCR. Chromatin immunoprecipitation (ChIP) was performed using a specific c-Myc antibody and PCR primers against transcriptional start site of the IL-6 and CXCL8 promoters.

Results 

10058-F4 inhibited ASM proliferation with no effect upon IL-6 or CXCL8 release. JQ1 had no effect on FCS+TGF-β-induced c-Myc expression. ChIP analysis found association of c-Myc with either the IL6 or CXCL8 promoters in ASM cells at baseline or following stimulation with FCS+TGF-β in the presence or absence of JQ1.

Conclusion 

IL-6 and CXCL8 release from ASM cells is not affected by inhibition of c-Myc which corresponded with the failure to show c-Myc association with IL6 and CXCL8 promoters. The effect of JQ1 on c-Myc expression seen in cancerous cells and non-primary cells is different from that seen in primary asthmatic ASM cells.
Response Rate as an Approval End Point in Oncology
Authors: Gideon M. Blumenthal, Richard Pazdur
Journal: JAMA Oncology (2016)

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FANCF promoter hypermethylation as predictor of clinical outcomes in advanced epithelial ovarian cancer
Authors: S. Lim, C. Coens, H. Wong Dr, E. Berns, M. van der Burg, J. Green, T. Crook
Journal: Journal of Clinical Oncology (2008)

5563 Background: Platinum remains the most active drug in the treatment of epithelial ovarian cancer. The Fanconi Anaemia (FA) pathway protects cells against cell death induced by cross-linking agents. Epigenetic silencing of FANCF by promoter hypermethylation has been proposed as a mechanism of sensitization to platinum in vitro (Taniguchi et al., Nature Medicine, 2003). This study aims to profile the methylation of FA genes and to investigate their impact on clinical outcomes in epithelial ovarian cancer treated with cisplatin-based chemotherapy. Methods: Promoter hypermethylation and gene expression of 6 FA genes (FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG) were investigated in 9 ovarian cancer cell lines and in 74 primary ovarian tumors (Stage III/IV) using methylation- specific PCR (MSP) and reverse-transcription PCR (RT-PCR). The clinical samples were retrospectively retrieved from a large Phase III RCT (the EORTC 55931/ NCIC OV10), which randomised patients to cisplatin/ cyclophosphamide or cisplatin/ paclitaxel chemotherapy following surgical debulking. Results: Ovarian cancer cell lines: FANCF hypermethylation was associated with downregulation of mRNA expression. Treatment with demethylating agent, 5'-Azacytidine, resulted in gene reactivation. FANCA, FANCC, FANCD2, FANCE and FANCG were not methylated. Primary tumors: FANCF hypermethylation was detected in 7/74 (10%) of the primary tumors. It predicts for adverse PFS in univariate (median PFS 5.6 vs 18.8 mths, p 0.001) and multivariate analyses (HR 3.70, 95% CI 1.43 - 9.54, p 0.007). 5/7 (71%) of FANCF methylated patients had “clinical platinum resistant / refractory‘ disease compared with 13/67 (20%) of unmethylated (RR 3.68, 95% CI 1.65 - 5.29, p 0.008). HR for OS was 1.16 (95% CI 0.43–3.11, p 0.765). The adverse effects of FANCF methylation on PFS and OS was significant only in patients treated with two cross linking drugs, cisplatin/cyclophosphamide, (p=0.004, and p=0.041, respectively), not one (cisplatin/paclitaxel). Conclusions: Epigenetic silencing of FANCF by promoter hypermethylation is an independent predictor of adverse PFS in advanced epithelial ovarian cancer treated with cisplatin-based chemotherapy, and may also predict for “clinical platinum resistance”. No significant financial relationships to disclose.
Effect of a rituximab-based regimen on the incidence of CNS relapse in patients with diffuse large B-cell lymphoma.
Authors: M. Mahrous, R. Buckstein, E. Piliotis, M. C. Cheung, N. L. Berinstein
Journal: Journal of Clinical Oncology (2010)

8098 Background: CNS relapse following initial treatment of DLBCL is an uncommon but fatal complication. The addition of rituximab improves the clinical outcome dramatically, but its influence on CNS relapse is unproven. This study was conducted to evaluate the impact of adding rituxmab to CHOP regimen on incidence of CNS relapse in patients at risk of CNS relapse. Methods: All patients with DLBCL diagnosed from April 2002 to December 2007 at Odette Cancer Center were retrospectively identified in the Cancer Database. Patients were included if they had advanced stage (stage III /IV, or stage I /II with B symptoms, elevated LDH or bulky disease, were treated with RCHOP regimen only and were free of CNS involvement at diagnosis. Results: A total of 155 patients were newly diagnosed with DLBCL and treated with RCHOP only. 133 pts were eligible (69 male and 64 female). Median age was 64 (Age≤60 was 59.4%). Stage III/IV was 69.9%. LDH was elevated in 59.4%. BM involvement and extra nodal ≥2 were 18.05% and 25.6% respectively. EN sites were: (liver 4.5%, bone 6.8%, pulmonary 4.5%, kidney 3.01%, cardiac 1.5%, intestine 2.3%, testicular 1.5%). IPI was high-intermediate/high in 55.6%. Pathologically transformed was 12.03%. BCL2 was positive in 65.4%, BCL6 was 48.9%, CD10 was positive in 49.6%, Ki-67 was >80% in 25%. All patients received RCHOP (Median 6 cycles). ORR was 88.6%, CR/CRU 72.7% with a median follow up 24.6 months (range 2.6-75.5). 28 patients (21.05%) relapsed systemically. Two patients (1.5%) had a CNS relapse 1 brain parenchyma and 1 leptomeningeal one month after systemic relapse. The median time to CNS relapse was 10.4 mos (6.24-14.5 mos). In univariate analysis (LDH (p=0.8), IPI>3 (p=0.9), No of EN (p=0.9). Actuarial 5 y overall survival was 67.3% (95% CI (57-77%) and progression free survival was 65.7% (95% CI (52.3-78.6%). Conclusions: Our data suggest that the addition of rituximab may reduce the risk of CNS relapse for poor risk patients likely through systemic control. Future prospective studies of rituximab-containing chemotherapies with CNS prophylaxis are warranted. No significant financial relationships to disclose.