tbuckley/cabot-search huggingface dataset:
A phase I trial of intravenous liposomal irinotecan in patients with recurrent high-grade gliomas.
Authors: Jennifer Leigh Clarke, Annette M Molinaro, Ashley A DeSilva, Jane E Rabbitt, Daryl C. Drummond, Susan Marina Chang, Nicholas A. Butowski, Michael Prados
Journal: Journal of Clinical Oncology (2015)

2029 Background: Treatment options for recurrent malignant glioma are limited. Preclinical activity of irinotecan has been seen in glioma models but only modest efficacy has been noted in clinical studies, perhaps related to drug distribution and/or pharmacokinetic limitations. In preclinical testing, liposomal irinotecan (nal-IRI, also MM-398, PEP02) demonstrates prolongation of drug exposure and higher tissue levels of drug due to slower metabolism. A Phase I study was undertaken in advanced solid tumor patients in Taiwan, and the MTD was 120 mg/m2; UGT1A1 genotyping was not prospectively undertaken in that solid tumor study. Objectives: To assess the safety and pharmacokinetics (PK) of nal-IRI and to determine the maximum tolerated dose (MTD) in patients with recurrent malignant glioma stratified based on UGT1A1 genotyping. Methods: This Phase I study in recurrent malignant glioma stratified patients by UGT1A1 status, to homozygous WT ("WT") vs heterozygous WT/*28 ("HT"). Patients who were homozygous *28 were ineligible. Eligibility criteria included age > = 18, KPS > = 60, not on enzyme-inducing drugs (including enzyme-inducing seizure medications), and no prior treatment with irinotecan. The design was a standard 3+3 Phase I design. Patients who were WT were started at 120 mg/m2 (the MTD from the Taiwanese study) with dose increases in 60 mg/m2 increments. Patients who were HT were started at 60 mg/m2, with dose increases in 30 mg/m2increments. Dosing was given IV every 3 weeks. The DLT assessment period was 1 cycle (21 days). Results: In the WT cohort, the MTD was 120 mg/m2. In the HT cohort, the MTD was 150 mg/m2. DLTs in both cohorts included diarrhea, some with associated dehydration and/or fatigue. Analysis of PK data is in process, and will be presented at the meeting. Conclusions: Nal-IRI had no unexpected toxicities when given via IV. The toxicity profile of the drug was felt acceptable to move forward with additional testing using convection-enhanced delivery into intracranial tumors, and such a Phase I study is currently enrolling at our institution. Clinical trial information: NCT00734682.
Multispectral Optoacoustic Tomography for Assessment of Crohn’s Disease Activity
Authors: Ferdinand Knieling, Clemens Neufert, Arndt Hartmann, Jing Claussen, Alexander Urich, Cornelia Egger, Marcel Vetter, Sarah Fischer, Lukas Pfeifer, Alexander Hagel, Christian Kielisch, Rüdiger S Görtz, Dane Wildner, Matthias Engel, Jens Röther, Wolfgang Uter, Jürgen Siebler, Raja Atreya, Wolfgang Rascher, Deike Strobel, Markus F Neurath, Maximilian J Waldner
Journal: New England Journal of Medicine (2017)

A preliminary study suggests that intestinal-wall assessment by means of noninvasive multispectral optoacoustic tomography may distinguish remission from active disease in patients with Crohn’s disease.
Fusion transcript discovery in formalin-fixed paraffin-embedded human breast cancer tissues and its relation to tumor progression.
Authors: Yan Ma, Ranjana Ambannavar, James Stephans, Jennie Jeong, Andrew Dei Rossi, John Morlan, Mei-Lan Liu, Samuel Levy, Joffre Baker, Dominick Sinicropi, Kunbin Qu
Journal: Journal of Clinical Oncology (2013)

11018 Background: While several recently discovered gene fusions already play an important role in personalized cancer treatment, many cancer gene fusions remain to be discovered. Next generation sequencing has enabled identification of many rare gene fusion events in fresh or frozen solid tumors. There is a need to detect gene fusions in transcriptomes of formalin-fixed paraffin-embedded (FFPE) tumor tissue, for which there is long-term clinical outcome data. We therefore sought to develop bioinformatics methods to detect fusion transcripts in FFPE tissue and to characterize their association with clinical outcomes. Methods: RNA sequencing libraries were created and sequenced from tumor biopsy tissues (Plos One 2012 7(7): e40092) of two ER+ breast cancer cohorts consisting of 136 and 77 patients, for which clinical outcomes were available. The fusion junctions were nominated by the RNA-seq aligner GSNAP and further filtered to consider discontinuous expression patterns at exon/intron levels. Results: A total of 108 candidate fusion transcripts were detected and RT-PCR assays confirmed 89% of the top ranking fusion transcript candidates. The majority (82%) of identified fusion gene partners are listed in the COSMIC database of known cancer sequence variations. Of note, several patients expressed multiple fusion transcripts that are significantly associated with tumor progression (P&lt;0.001), including genes associated with cell proliferation and cellular metabolism. Furthermore, these patients also harbored inter-chromosomal gene fusions. It is noteworthy that several gene fusions were present in multiple patients. In one of these recurrent fusions the estrogen receptor gene acts as the fusion pair donor. Conclusions: Novel bioinformatics approaches developed here demonstrate the ability to detect fusion transcripts as biomarkers from archival FFPE tissues that associate with breast cancer progression. Some gene fusions were common in multiple patients and deserved further study.
Identification of circulating microRNAs for the diagnosis of early-stage gastric cancer.
Authors: Anna Brunet-Vega, María José Ramírez-Lázaro, Juan José Lozano, María Elisa Quílez, Lorena Garcia-Martinez, Félix Junquera, Carles Pericay, Xavier Calvet, Sergio Lario
Journal: Journal of Clinical Oncology (2017)

33 Background: The development of gastric cancer (GC) is a stepwise progression from non-active gastritis (NAG), chronic active gastritis (CAG) and precursor lesions of GC (PLGC: atrophy, metaplasia). Early detection of GC improves survival rates. Recent evidence has proposed circulating microRNAs (c-miRNAs) as biomarkers. The aim was to explore the c-miRNA profile of a cohort of non-GC and GC patients in order to identify early biomarkers of GC. Methods: Thirty-eight patients were enrolled: ten with NAG, nine with H. pylori infected with CAG, eight with PLGC, and ten with GC. GC patients were at TNM stages I and II. As quality controls, synthetic RNA was added during the isolation, cDNA synthesis, and PCR steps. MiRNA profiling was performed using Exiqon Human Panel I. Exploratory significance was set at P&lt;0.05 with fold change (FC)≥1.6. Results: Of the total of 372 miRNAs analyzed, 154 miRNAs were detected in all samples. miR-185-5p was used to normalize. Compared to NAG individuals, GC patients showed downregulation of three miRNAs. GC patients also showed reduced expression of miR-205 compared to H.pylori-infected patients with CAG. Five miRNAs were upregulated in GC patients compared to PLGC patients (miR-134, miR-204, miR-224, miR-409, miR-877). Finally, in comparison with non-GC, seven miRNAs were found to be deregulated in GC patients (miR-130b, miR-144, miR-205, miR-219a, miR-224, miR-451a, miR-501). Specificities calculated at 90% sensitivity were low and significant FC ranged from -3.2 to 2.8. Conclusions: Using miRNA qPCR quantification, we found a deregulation of c-miRNAs in early GC. However, our results also show low diagnostic accuracy for early GC due to the small FC observed and the overlap in the miRNA levels between non-GC and GC patients. Further validation in a larger cohort and a prospective study is needed to determine conclusively whether these miRNAs serve as biomarkers. In our opinion, new methods need to be developed in order to quantify c-miRNAs and improve their diagnostic accuracy. [Table: see text]
Impact of adjuvant chemotherapy on recurrence risk in stage II colon cancer.
Authors: Taiwo Adesoye, Chung-Yuan Hu, Amanda Cuddy, Amanda B. Francescatti, Jessica R. Schumacher, Y. Nancy You, Katherine Van Loon, Deborah Schrag, Daniel P. McKellar, David Porter Winchester, George J. Chang
Journal: Journal of Clinical Oncology (2017)

533 Background: Although clinical guidelines recommend consideration of adjuvant chemotherapy in high-risk stage II colon cancer, the impact on recurrence risk and cancer related survival is unclear. Furthermore, among Medicare patients, adjuvant chemotherapy was not associated with improved survival. We examine the effect of adjuvant chemotherapy on recurrence risk and overall survival in a diverse cohort. Methods: 6,095 patients who underwent surgery for stage II-III colon cancer (2006-2007) were randomly selected from facilities reporting to the National Cancer Data Base for additional abstraction of tumor information, 5 year recurrence and survival. Death or second cancer within 6 months were excluded. Patients were classified as high or low risk using standard pathologic factors. Multivariate Cox regression with propensity score weighting was performed to compare recurrence risk and overall survival. Results: Of 3,423 patients with stage II colon cancer, 26.9% (n = 883) received chemotherapy compared to 76.2% (n = 1,839) of stage III patients. Among stage II patients, 47.8% (n = 1,636) had at least one high risk feature and 30.8% (n = 481) of these received chemotherapy. Five year recurrence rate in stage II patients was 13% (n = 392), greater in high risk compared to non-high risk patients (13.3% vs 9.3% p &lt; 0.0001) and 24.4% (n = 874) in stage III patients. Chemotherapy did not improve recurrence risk in stage II patients regardless of risk status (High risk: hazard ratio [HR] 1.37; 95% CI 0.96 - 1.97; Non-high risk: HR 1.39; 95% CI 0.91 - 2.11). Chemotherapy was associated with a significant improvement in recurrence risk in stage III patients (HR 0.79; 95% CI 0.63 - 0.96). However, chemotherapy was associated with improved overall survival in both high (HR 0.69; 95% CI 0.51 - 0.92) and non-high risk stage II patients (HR 0.76; 95% CI 0.55 - 1.04), and also in stage III patients (HR 0.47; 95% CI 0.41 - 0.54). Conclusions: Adjuvant chemotherapy was not associated with a lower recurrence rate among stage II colon cancer patients. The observed survival benefit associated with chemotherapy is likely attributable to non-oncologic factors such as patient selection. Decision-making regarding chemotherapy use in this cohort should be carefully approached.
Significantly Elevated Vitamin B12 Levels in Autoimmune Lymphoproliferative Syndrome (ALPS), a Rare Lymphoproliferative Disorder with Apoptosis Defect
Authors: Raffick AR Bowen, Janet K Dale, Margaret Brown, Steven K Drake, Tarsilla Moura, Kennichi Dowdell, Alan T Remaley, Thomas A Fleisher, Glen L Hortin, Ebba Nexo, Stephen E Straus, V. Koneti Rao
Journal: Blood (2008)
Targeting IRE1α-XBP1 Pathway Is a Novel Therapeutic Strategy In Multiple Myeloma
Authors: Naoya Mimura, Teru Hideshima, Gullu Gorgun, Diana Cirstea, Loredana Santo, Yiguo Hu, Claire Fabre, Martina Blumenthal, Victor Tam, Nathalie L. Kertesz, Qingping Zeng, John B. Patterson, Nikhil C. Munshi, Paul Richardson, Kenneth C. Anderson
Journal: Blood (2010)
Distinct MET alterations to induce a common phenotype and to define a MET-driven subset of papillary RCC: Results from the Cancer Genome Atlas (TCGA) Kidney Renal Papillary (KIRP) Working Group.
Authors: Laurence Albiges, Bradley Murray, Angela Brooks, Andrew Cherniack, Alice Berger, Chad J. Creighton, Christopher Ricketts, Donald P. Bottaro, Ramaprasad Srinivasan, Laura S. Schmidt, Matthew Meyerson, Paul Spellman, W. Marston Linehan, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2015)

4521 Background: Papillary Renal Cell carcinomas (pRCC) are the most frequent non-clear cell RCC, commonly classified as type I and type II. MET oncogene mutations have been reported predominantly in type I. MET overexpression is a common feature in pRCC and correlates with copy number alteration (CNA). We aim to report the distinct molecular alterations of MET and their impact within the TCGA KIRP dataset. Methods: KIRP TCGA provides a comprehensive molecular evaluation of pRCC tumors. Results: Genomic analysis of 161 TCGA pRCC tumors revealed recurrent mutations in MET in 18 cases (11.2%): 3 germline and 15 somatic, and 72 cases (46%) with gain of chromosome 7. Analysis of RNA-Seq identified a new recurrent splicing isoform of MET in 8 cases (5%) skipping exons 1-2 (encoding the ligand binding domain) with inclusion of a new transcription start site prior to exon 3. Two new fusions (1.2%) involving the MET kinase domain and predicted to be constitutively activated were also identified. We further defined MET alterations as either a MET mutation, a splice variant or a MET-fusion. These alterations were mutually exclusive but tended to co-occur with CNA (p < 0.001). MET expression by RNA-seq was significantly elevated compared to the rest of the cohort (p < 0.001) when the alteration co-occurred with chromosome 7 gain. The MET-altered tumors exhibited a common phenotype associated with lower grade (p < 0.001), lower stage (p < 0.001), and better overall survival (log-rank p < 0.001) relative to all other pRCC. MET alterations were mostly observed in type I pRCC (p < 0.001). Conclusions: Overall, at least 17% of pRCC tumors included in the TCGA KIRP dataset present a MET alteration and display a common phenotype. A new splice variant is identified and may constitute a mechanism of ligand-independent MET activation. This report provides a survey of the diverse mechanisms of activation of the MET oncogene. Ongoing clinical trials of MET inhibitors in pRCC will hopefully help characterize the functional relevance of each proposed mechanism of activation involving MET in pRCC. Funded in part by FNLCR Contract HHSN261200800001E.
포스터발표 : 그랜드볼룸 ; 유리지방산을 이용한 in vitro 비알콜성 지방간 모델 확립 (초)
Authors: 박정화, 허원희, 최정은, 홍성우, 류광수, 김성우, 김송아, 송명준, 배시현, 최종영, 윤승규
Journal: Clinical and Molecular Hepatology (2010)
An updated systematic review and meta-analysis of randomized controlled trials on duration of chemotherapy for advanced non-small cell lung cancer.
Authors: Yu Yang Soon, Martin R. Stockler, Lisa Askie, Michael J. Boyer
Journal: Journal of Clinical Oncology (2014)

8104 Background: We previously published a meta-analysis which identified a survival benefit with extended duration of chemotherapy in patients with advanced non-small cell lung cancer. We have updated our meta-analysis with results from new or updated randomized trials presented in June 2008 to Oct 2013. Methods: Biomedical literature databases and conference proceedings were searched for randomized controlled trials (RCTs) comparing: (i) a defined number of cycles versus continuation of the same chemotherapy until disease progression; (ii) a defined number of cycles versus a larger defined number of cycles of identical chemotherapy, and (iii) a defined number of cycles of identical initial chemotherapy versus the addition of cycles of alternative chemotherapy. Meta-analysis was performed using the fixed effect model. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival (PFS), adverse events (AE), and health-related quality of life (HRQL). Results: We identified updated results of two trials from the previous meta-analysis and found four new trials, resulting in a total of 17 trials including 5069 patients. Extending chemotherapy improved PFS substantially (hazard ratio [HR], 0.70; 95% CI 0.66 to 0.75; P < 0.00001, I2 = 72%, Chi2 P < 0.0001) and OS modestly (HR, 0.91, 95% CI 0.85 to 0.96, P = 0.001, I2=14%, Chi2 P = 0.29). Subgroup analysis revealed that the effects on PFS were greater for trials extending chemotherapy with third generation chemotherapy regimens, non-platinum regimens and maintenance therapy trial design. There was no evidence of difference in the effects on overall survival between subgroups defined by use of third generation chemotherapy regimens or platinum regimens and trial design. Extending chemotherapy was associated with more frequent AE in all trials where it was reported and impaired HRQL in two of 12 trials. Conclusions: This updated meta-analysis continues to demonstrate improvement in both progression- free and overall survival benefit with extended duration of chemotherapy in patients with advanced non-small cell lung carcinoma.
A phase I study of hepatic arterial infusion (HAI) of irinotecan in patients with inoperable liver metastases of colorectal cancer
Authors: T. J. Vogl, K. Eichler, M. G. Mack, J. O. Balzer, C. Herzog, O. Söllner, S. Zangos, A. Thalhammer
Journal: Journal of Clinical Oncology (2004)

3714 Background: Hepatic intraarterial (IA) chemotherapy with agents such as FUDR has been shown to reduce local recurrence rates in patients with liver metastases of colorectal origin. Irinotecan is active in metastatic colorectal cancer. This phase I study was conducted to determine the maximum tolerated dose (MTD) of IA irinotecan in patients with inoperable liver metastases. Methods: Patients were required to have histologically confirmed disease, adequate hematologic, liver and renal function, no symptomatic CNS metastasis, a Karnofsky performance status of at least 70% and a life expectancy of at least 12 weeks. Patients received HAI irinotecan on days 1, 15, 29 and 43. Starting from an initial dose of 140 mg/m2, irinotecan was escalated in 20-mg/m2 steps up to a maximum dose of 200 mg/m2. Three patients were treated per dose level. Dose-limiting toxicity (DLT) was defined as WHO grade >= 3 myelosuppression or grade >= 3 non-hematologic toxicity. The MTD was reached when 2 of 3 patients experienced DLT during the first cycle. Tumor response was assessed after each cycle by CT and MRI. Clinical response benefit was evaluated using a standardized questionnaire (EORTC QLQ-C30). Results: So far, 9 patients have been enrolled (5 male, 4 female, median age 65.8 yrs). All patients tolerated the treatment well, and no DLT was observed. Overall, 3 patients (33%) achieved a partial response (PR), 3 patients (33%) stable disease, and 3 (33%) had progressive disease. Patients with PR subsequently received laser-induced thermotherapy (LITT). Conclusions: Preliminary results from this ongoing study indicate that HAI irinotecan is well tolerated and can produce encouraging response rates in patients with liver metastases of colorectal origin. No significant financial relationships to disclose.
Alcohol consumption and prognosis in patients with stage III colon cancer: A correlative analysis of phase III trial NCCTG N0147 (Alliance).
Authors: Amanda I. Phipps, Qian Shi, Paul J. Limburg, Garth D. Nelson, Daniel J. Sargent, Frank A. Sinicrope, Emily Chan, Sharlene Gill, Richard M. Goldberg, Morton S. Kahlenberg, Suresh Nair, Anthony Frank Shields, Polly A. Newcomb, Steven R. Alberts
Journal: Journal of Clinical Oncology (2015)

1508 Background: Alcohol consumption is associated with a modest increased risk of colon cancer (CC). The relationship between alcohol and survival after CC, however, has not been well elucidated. Using data from N0147, a phase III randomized adjuvant trial in stage III CC, we assessed the association of alcohol consumption with CC outcomes. Methods: Patients completed a risk factor questionnaire before randomization to FOLFOX or FOLFOX + cetuximab (N = 1984). Information was collected on lifestyle factors, including smoking, physical activity, and the frequency and extent of alcohol consumption. Separate information was collected for different alcohol types. Multivariate Cox models assessed the association between alcohol consumption and outcomes of disease-free survival (DFS), time-to-recurrence (TTR) and overall survival (OS), adjusting for age, sex, study arm, body mass index, smoking, physical activity, and performance status. Results: Overall, 70% of patients had ever consumed alcohol regularly. There was no statistically significant difference in outcomes between ever and never drinkers in multivariate analyses [hazard ratio (HR)DFS= 0.86, p = 0.11, HRTTR= 0.87, p = 0.18, HROS= 0.86, p = 0.14]. However, when considering alcohol type, ever consumers of red wine (n = 639) had significantly better outcomes than never consumers (HRDFS= 0.81, p = 0.01; HRTTR= 0.81, p = 0.02; HROS= 0.78, p = 0.01). Favorable outcomes were confirmed in patients who consumed 1-30 glasses of red wine per month (n = 612, HR = 0.81 to 0.83, p = 0.03 to 0.048); there was a suggestion of more favorable (but not statistically significant) outcomes in patients who consumed > 30 glasses of red wine per month (n = 27, HR = 0.30 to 0.38, p = 0.05 to 0.06). For white wine, better OS was observed for patients who consumed 1-30 glasses/month (n = 538) compared to never consumers (HR = 0.75, p = 0.007), but no association was noted for other outcomes. Beer and liquor consumption were not associated with improved outcomes. Conclusions: Although alcohol consumption was not associated with CC outcomes overall, mild to moderate red wine consumption was suggestively associated with longer OS, DFS, and TTR in stage III CC patients.
Phase II trial of RAD001 in renal cell carcinoma patients with non-clear cell histology.
Authors: Youngil Koh, Ji Yeon Kim, Ho Yeong Lim, Jin-Hee Ahn, Jae-Lyun Lee, Sun Young Rha, YuJung Kim, Tae Min Kim, Se-Hoon Lee
Journal: Journal of Clinical Oncology (2012)

4544^ Background: In non-clear cell renal cell carcinoma (ncRCC), the efficacy of VEGF tyrosine kinase inhibitor (TKI) is controversial. In the while, a mTOR inhibitor, temsirolimus showed a promising efficacy in ncRCC patients in ARCC trial. Hence, we investigated the role of everolimus in ncRCC with this phase II trial. Methods: ncRCC patients received everolimus 10 mg once daily until disease progression or unacceptable toxicity. We included patients who had received VEGF TKI previously, while excluded patients who received previous mTOR inhibitor. The primary end point was progression free survival (PFS). Results: A total of 49 patients were enrolled from 5 centers. Their median age was 57 years (range 24-75 years) and male to female ratio was 37:12. Histology of the patients included papillary (n=29), chromophobe (n=8), collecting duct (n=2), sarcomatoid (n=4), and unclassifiable (n=6) RCC. Twenty-three patients had been treated with VEGF-TKI prior to the study enrollment. Among 49 patients, 46 patients underwent radiologic response assessment after everolimus treatment. Partial response was observed in 5 patients (10.2%) and stable disease in 25 patients (51.0%). Diseases of 16 patients (32.7%) progressed despite of everolimus administration. Histology of 5 patients who showed objective response to everolimus included chromophobe carcinoma (n=2), papillary carcinoma (n=2) and unclassifiable carcinoma (n=1). During the study period, 34 patients experienced PFS events and median PFS was 5.2 months. Patients with chromophobe histology showed longer PFS than patients with the other histologies (median PFS 18.8 months vs. 3.5 months, p=0.027). Estimated median PFS were not significantly different between patients VEGF-TKI treatment and patients without previous VEGF-TKI treatment (median PFS 7.1 vs. 3.7 months, p=0.110). Toxicity profiles were commensurable with previous reports. Conclusions: Everolimus shows considerable efficacy in ncRCC. Patients with chromophobe histology might earn benefit from everolimus treatment especially. Previous treatment with VEGF-TKI seems not to significantly influence outcome of everolimus therapy in these patients. (ClinicalTrials.gov number, NCT00830895)