tbuckley/cabot-search huggingface dataset:
Outcomes and health status of patients undergoing usual care for highly emetogenic chemotherapy
Authors: C. R. Lewis, I. N. Olver, E. Walpole, C. Shannon, N. Pavlakis, D. Dalley, G. Van Hazel, S. Lybrand
Journal: Journal of Clinical Oncology (2006)

18591 Background: Chemotherapy-induced nausea and vomiting (CINV) remains a significant issue for patients, especially management of delayed symptoms. The Perugia 2004 antiemetic guidelines recommended that anthracycline/cyclophosphamide (A/C) combination regimens be considered as high risk emetogenic potential. The aim of our study was to determine the extent of CINV, and effect on quality of life for chemotherapy-naïve patients in a practice-based environment. Methods: Eligible patients were receiving their 1st cycle of high risk emetogenic or carboplatin chemotherapy, administered with “standard care” (5HT 3 antagonist + dexamethasone) antiemetics (use of NK 1 antagonists excluded). Patients completed a daily diary for 5 days post chemotherapy, capturing data on CINV activity and rescue medications usage. Emesis and nausea-specific health status was measured by the Functional Living Index - Emesis (FLIE); general health status was assessed using a 100mm VAS (EQVAS). Results: Of 74 patients, 42 received an A/C regimen, 16 cisplatin and 16 carboplatin. Overall complete response (no vomiting, no use of rescue antiemetics during the study period) was 60% in patients receiving carboplatin, 24% A/C and 21% cisplatin. During the delayed phase, mean total emesis episodes for carboplatin was 0.6, A/C 2.21 and cisplatin 4.08. Patients receiving carboplatin reported less delayed nausea, and better outcomes for FLIE and EQVAS scores. Treatment with either A/C or cisplatin was associated with similar deterioration in nausea control across the study period, and similar impact on FLIE scores (see table ). Conclusions: Our results are consistent with the recommendation that A/C regimens be considered highly emetogenic, with similar impact on patient symptoms and quality of life compared with cisplatin. Delayed CINV remains a target for antiemetic intervention. Similar studies need to be repeated in patients receiving additional NK 1 antagonists to assess their impact on CINV outside clinical trials. [Table: see text] [Table: see text]
The association of relative survival benefit and approval of oncological drugs: An analysis of oncology drug advisory committee reviews.
Authors: Idoroenyi Usua Amanam, Austin Blake Gardner, Spencer L. James, Daniel Stuart Kapp, John K. Chan
Journal: Journal of Clinical Oncology (2015)

2582 Background: To evaluate the association of relative survival benefit (additional benefit / historic control) as a modality to predict for oncology drug approval. Methods: Data was extracted from transcripts of drug license application sessions of the FDA’s Oncology Drug Advisory Committee (ODAC). Relative survival benefit (RB) is defined as the percent survival improvement associated with new therapy over standard therapy. SAS was used to conduct statistical analysis. Results: The FDA approved 13 of 29 oncological drug license applications from 2001 to 2014. 5 breast, 3 pancreatic, 3 renal, 3 ovarian, 2 hematologic, 2 prostate, 2 soft tissue sarcoma, 2 lung, 2 bone metastasis, 2 brain, and 2 skin drug applications were reviewed by the FDA. 11 (38%) drug license applications used overall survival (OS) as an endpoint, 8 (28%) used PFS, and 10 (34%) used both OS and PFS as endpoints. The median relative benefit (RB) of all reviewed end points (n = 39) was 15.1% (range: 0% to 190%). Of the studies that used PFS (n = 18) vs. OS (n = 21) as an endpoint, the average relative benefit was 70% (range: 7% to 190%) and 11% (range: 0% to 50%) (p < 0.01), respectively. Using the median RB of 15%, drugs with a greater RB had an approval rate of 68%, while drugs with a lower RB had an approval rate of 6% (p = 0.24). Subset analyses of studies using OS or PFS as the primary endpoint showed no difference in approval of drugs with RBs higher or lower than the median (p = 0.47, p = 0.066, respectively). Analysis of the years 2001-6, 2007-10, and 2011-14 showed significant increases in RB (p < 0.01) and drug approval (p = 0.032) as well as greater use of PFS rather than OS as an endpoint in studies (p = 0.017). Conclusions: The use of relative survival benefit may assist as a predictive indicator for prediction of FDA approval of novel anti-cancer agents. Researchers may need to consider using relative survival benefit to improve the success of FDA approval of novel drug agents.
Clinical and safety data of a phase I/II trial with imatinib and vinorelbine for patients with metastatic breast cancer (MBC).
Authors: Christoph Mundhenke, Christian Schem, Dirk Olaf Bauerschlag, Marion T. Weigel, Antonia Sophie Wenners, Fritz Werner Schaefer, Katharina Tiemann, Sven Hanson, Mathias Muth, Christoph May, Walter Jonat, Nicolai Maass
Journal: Journal of Clinical Oncology (2012)

e13503 Background: Imatinib is a tyrosine kinase inhibitor of bcr-abl, PDGF-R, SCF, c-Kit and abl. In solid tumors it inhibits proliferation and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in MBC. This study evaluates the combination of imatinib and vinorelbine. Methods: In aprospective open-label, phase I/II trial 400 mg imatinib p.o. daily (amended from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels with 10, 15, 20, 25 mg/m² (each n ≥ 5) for pats. with MBC (which express PDGF-R-α and/or -β and/or c-kit). The last pat. of a level was treated &gt; 28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and non-hematological toxicity and clinical efficacy (data cut: 18/11/2011). A translational subprotocol is ongoing. 33 pats. have been enrolled; all dose levels have been fully recruited. 1 patient is still on study medication. Results: 32 pats. are evaluable (ITT population). 11 pats. went off study early (progressive disease, toxicity and withdrawal of consent). 22 pats. were on study &gt;28 days (“ITT&gt;28”). Within the ITT population the response rate (complete (CR) and partial response (PR)) was 9.4% (n=3), the clinical benefit rate CBR (CR+PR+stable disease) 50% (n=16), median time to progression (TTP) 155 days. 21.3% were on study medication &gt;6 months, 15.2% &gt; 12 months (mean 133 days, 15-617 days). Within “ITT&gt;28,” the response rate was 13.6%, CBR 72.7% and median TTP 176 days. Toxicities (ITT population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% periph. neuropathy (severe 9.1%) and 36.4% dyspnea (3% severe). 1 patient on study medication died (non drug related). Conclusions: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pre-treated pats. proves the efficacy of this combination. Although toxicities were frequent, they appeared to be manageable.
Comprehensive genomic profiling of solid tumors from 677 adolescents and young adults for revealing a distinct spectrum of targetable genomic alterations.
Authors: Deborah Morosini, Kai Wang, Klaus Wolfgang Wagner, Roman Yelensky, Doron Lipson, Juliann Chmielecki, Siraj M. Ali, Jeffrey S. Ross, Phil Stephens, Vincent A. Miller
Journal: Journal of Clinical Oncology (2014)

11008 Background: Adolescent and young adult (AYA, age 15-39) cancers (CA) pose unique clincial challenges, yet genomic alterations (GA) in AYA CA have not been widely profiled. To identify potential therapeutic targets, we profiled a consecutive series of 677 AYA solid tumors, and describe a case of matching GA to targeted therapy. Methods: Tumor DNA extracted from FFPE tissue underwent library construction and hybrid capture for all exons of 236 cancer-related genes and 47 introns of 19 genes frequently rearranged in cancers and was sequenced to an average depth of >700x. Sequence data were assessed for base substitutions, in/dels, copy number alterations, and rearrangements. Actionable alterations were defined as those for which approved or experimental targeted therapies could be identified. Results: Across 30 AYA tumor types profiled, the most common were breast (BC) (15%), sarcoma (14%), brain (13%), colorectal (CRC)(9%), unknown primary (9%) and lung (LC)(6%). An average of 3.4 GAs per sample was found (range 0-22). Potentially actionable GAs were found in 71% of cases, including 93% of brain, 87% of BC, 85% of CRC and 75% of LC. Initial comparison reveals that in 44 AYA LCs, 20% had ALK fusions vs. 4% in older adults (age >39). Of 23 GBM cases, 48% had loss of function of ATRX and 39% had IDH1 mutations, whereas ATRX/IDH1 mutations were each present in 2-3% of our older GBM cohort. In one case, a 19 yr old female with LC was admitted to hospice having failed standard of care chemotherapy. Prior testing was negative for EGFR, ALK and ROS1. Genomic profiling revealed a novel ALK rearrangement and she began crizotinib therapy. Within 5 days she was discharged and continues to improve after 2 mos of therapy. Conclusions: Comprehensive genomic profiling can be optimized to accurately detect all classes of genomic alteration across AYA CA. These data highlight differences in this population and demonstrate the feasibility of identifying clinically meaningful alterations that can potentially guide targeted treatment decisions.
Aspirin use in robot-assisted radical prostatectomy? Systematic review and metanalysis.
Authors: Arie Carneiro, Jonathan Doyun Cha, Marcelo Langer Wroclawski, Paulo Priante Kayano, Oliver Rojas Claros, Natasha Kouvaleski Saviano Moran, Ary Serpa, Gustavo Caserta Lemos
Journal: Journal of Clinical Oncology (2017)

e553 Background: Low dose aspirin (81-100mg) used as secondary prevention in cardiovascular diseases is correlated with increased bleeding and overall complications in surgical procedures. However, the suspension of this medication can increase the risk of cerebrovascular accident and myocardial infarction. Robot-assisted radical prostatectomy (RARP) has significantly decreased the surgical morbidity and the peri-operative bleeding. Our aim was to analyze whether RARP is feasible and safe in patients with low dose aspirin intake. Methods: Systematic review of the literature using MEDLINE, ESCOPUS, Lilacs, Scielo and Cohcrane articles published until June 2016. We included prospective trials and large cohorts that evaluated patients with (Group A) or without the maintenance of aspirin (Group B). Results: 5 trials (n = 1481 men) were included. One thousand and thirteen men stopped the use of the medication and 168 kept it during the peri-operatory setting, including the procedure. For the analyses of overall complications 3 articles with 458 men were included. The overall complication rate was 19%, without statistically significant difference between groups (Group A: 10.5%; Group B: 21.8% - OR: 0.70 IC:0.31- 1.56; I 2 = 0%). In a sub analysis evaluating major complications (Clavien &gt; 2), cardiovascular events were similar between groups (Group A: 10.5%; Group B: 19% OR: 0.67 IC: 0.34- 1.70; I 2 = 0%). There were 5 trials included to evaluate blood loss, with 1481 patients (168 Group A and 1313 Group B). The overall transfusion rate was 1.9%, without difference between groups (Group A = 3,5% and Group B = 1.7% - OR:3.24 IC:0.87- 12.06; I 2 = 0%). The estimate perioperative bleeding rate was significantly lower in patients using aspirin during surgery (OR:-33.74 IC:-44.99, -22.49, I 2 = 92%). The hospital stay length was similar between groups (OR:0 IC:-0.04, 0.04; I 2 = 0%). Conclusions: Low dose aspirin does not correlate with larger peri-operatory surgical morbidity, transfusion rate or hospital stay. The blood loss was lower in the aspirin intake group, but this fact should be interpreted with caution due to the high heterogeneity among studies. RARP in patients under continuous aspirin intake was feasible and safe.
MET and ALK in glioblastoma multiforme (GBM): Comparison of IHC and FISH.
Authors: Kimary Kulig, Roger E McLendon, Susan C. Locke, Debra R. Young, Xiaoyin Zhong, Lori L. Hudson, Amy Pickar Abernethy
Journal: Journal of Clinical Oncology (2012)

2021 Background: GBM, the most common and lethal malignant primary brain tumor in adults, has an overall one-year life expectancy of 33.7%. Personalized medicine on the basis of predictive biomarkers remains elusive in GBM; however a recent case report showed clinical improvement after treatment with a mesenchymal-epithelial transition (MET) inhibitor. The authors of that report ascribe clinical response to the MET inhibitor, but the drug is also an inhibitor of anaplastic lymphoma kinase (ALK). We explored the co-expression, gain, or amplification of both MET and ALK by IHC and FISH in GBM. Methods: A convenience sample of 56 available tumors from gross-resected GBM cases within the Duke Brain Tumor tissue bank was stained for MET using clone 8F11 (Leica) and for ALK using clone 5A4 (Novocastra). FISH employed the LSI ALK (2p23) breakpoint-spanning dual-color DNA probe and the LSI D7S486 (MET)/CEP 7 dual color DNA probe (Vysis). Results: Of 56 GBM cases, MET was expressed in 69.6% and ALK in 17.9% by IHC. By FISH, gain or amplification was found in 100% of cases for MET and in 48.2% for ALK. Co-expression of MET and ALK by IHC was 14.3% and 48.2% by FISH. Co-expression by either IHC or FISH was also 48.2%. OS estimation for this cohort is premature, with 77% of patients still alive. Conclusions: MET and ALK are (co-)expressed in a significant proportion of GBM. IHC detection of MET and ALK did not correlate well with FISH results, suggesting that gene gain or amplification does not necessarily lead to abnormal MET and ALK protein expression or that IHC methods or antibodies used can be optimized. Prior studies reported MET amplification in GBM as low as 4%. Our study indicates that MET gain/amplification and protein expression may be much higher, having implications for MET-targeted therapy. Additionally, co-expression of ALK and MET has implications for dual inhibitors of these signaling pathways as well as resistance mechanisms. Our continued work will explore significance of MET and ALK as predictors of therapeutic response, with careful control for clinically relevant patient and disease characteristics. [Table: see text]
Phase II study of everolimus as a salvage treatment after failure of fluoropyrimidine and platinum in patients with metastatic gastric cancer positive for pS6<sup>Ser240/4 </sup>expression.
Authors: Ji Hyun Park, Min-Hee Ryu, Young Soo Park, Soon Auck Hong, Baek-Yeol Ryoo, Sook Ryun Park, Changhoon Yoo, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2015)

4057 Background: Everolimus is a macrolide derivative of rapamycin which inhibits mTOR. Our previous phase II study in 2nd line setting showed that everolimus had no significant activity with 1.7 months of median progression-free survival (PFS) in unselected population with gastric cancer (GC) and suggested that pS6Ser 240/4 might be a potential predictive biomarker of everolimus (Yoon et al, Br J Cancer. 2012;106:1039). In this study, we aimed to evaluate the efficacy and safety of everolimus in 2nd line GC patients selected by pS6Ser240/4 expression. Methods: The primary endpoint was 4-month PFS rate. Patients with metastatic or recurrent GC positive for pS6Ser240/4 were enrolled after failure of fluoropyrimidine and platinum. pS6Ser240/4positivity was defined as immunostain of 10% or more cancer cells with moderate or strong intensity. Patients received everolimus 10 mg p.o. once daily until disease progression or unacceptable toxicity. Results: Between December 2011 and May 2013, a total of 45 patients were enrolled. Median age was 58 years (range 34-78). Thirty-nine (86.7%) patients had ECOG performance status 0-1, and 6 (13.3%) had 2. In addition to fluoropyrimidine and platinum, 14 (31.1%) and 5 (11.1%) patients received docetaxel and irinotecan, respectively. One (2.2%) patient achieved a partial response and 26 (57.8%) showed stable disease. With a median follow-up of 13.3 months (range, 9.9-24.1) in surviving patients, the median PFS was 2.6 months (95% CI, 1.9-3.2), and 4-month PFS was 25.6%. The median overall survival was 5.8 months (95% CI, 5.1-6.6). Grade 3 or 4 drug-related toxicities in > 5% of patients included neutropenia (13.3%), anemia (13.3%), stomatitis (8.9%), and pneumonia (6.7%). Conclusions: Everolimus was safe, and it showed better activity in the current study which included biomarker-selected patients, compared with our previous study in biomarker-unselected population. Currently, further biomarker analysis is ongoing. Clinical trial information: NCT01482299.
포스터발표 : 그랜드볼룸 ; CD133 발현이 높은 간암세포에서 침윤성과 EMT관련 유전자 발현의 증가 (초)
Authors: 나득채, 이재은, 유정은, 오봉경, 최기홍, 정구흥, 박영년
Journal: Clinical and Molecular Hepatology (2010)
Met and HGF inhibition in triple-negative breast cancer cell lines.
Authors: Patricia Brid Gaule, Denis Collins, Naomi Walsh, Michael J. Duffy, John Crown, Norma O'Donovan
Journal: Journal of Clinical Oncology (2013)

1066 Background: Basal-like breast cancer (BLBC) is associated with high expression of c-Met. c-Met and its ligand HGF may be rational therapeutic targets for BLBC. We evaluated expression of c-Met and response to c-Met/HGF inhibition alone/in combination with other targeted therapies in triple-negative breast cancer (TNBC) cell lines. Methods: Expression and phosphorylation of c-Met was measured by immunoblotting. qRT-PCR was used to measure HGF mRNA. Cell proliferation was measured by acid phosphatase assay after 5 day treatment with a c-Met inhibitor (CpdA), HGF monoclonal antibody, rilotumamab, a panHER inhibitor (neratinib) and a SRC kinase inhibitor, (saracatinib). Invasion through 0.4 μm Matrigel coated membranes was measured for two cell lines. Results: c-Met and p-Met were detected in 7 and 4 of the 7 TNBC cell lines tested, respectively. HGF mRNA was not detectable in any of the TN cell lines. CpdA inhibited growth in 4 TN cell lines with IC 50 values ranging from 2.1-7.6 μM. Rilotumumab did not inhibit growth, however combined treatment with CpdA and rilotumumab resulted in significantly increased growth inhibition in 3 of 5 cell lines (Table). CpdA in combination with neratinib significantly improved growth inhibition in MDA-MB-468 cells, and in combination with saracatinib significantly improved growth inhibition in 3 of 5 cell lines (Table). CpdA also inhibited invasion of CAL-85-1 cells by 21.4% (± 10.4%) but not HDQ-P1cells. Conclusions: c-Met may represent a viable molecular target in TNBC. Dual targeting of Met and HGF and/or with EGFR or SRC may increase the efficacy of c-Met inhibition in TNBC. [Table: see text]
Relevance of MIA and S-100 to monitor BRAF inhibitor (iBRAF) therapy in metastatic melanoma patients.
Authors: Miguel F. Sanmamed, Sara Fernandez-Landazuri, Eduardo Castanon, Jose Echeveste, Maria D. Lozano, Miguel A. Idoate, Jose Luis Perez-Gracia, Alvaro Gonzalez, Salvador Martin-Algarra
Journal: Journal of Clinical Oncology (2013)

9074 Background: MIA and S-100 have been proposed as tumor markers for patients with melanoma, but they are not widely accepted. BRAF V600E mutation has been reported in more than 50% of melanomas. Recently, selective BRAF inhibitors have proved to be more active than DTIC in first line treatment of BRAF V600E melanoma patients. The aim of the present work is to evaluate the utility of MIA and S-100 during iBRAF treatment. Methods: BRAF V600E mutation was analyzed in 77 patients with metastatic melanoma by automated direct sequencing in tumor DNA. Tumor markers (MIA, S-100 and LDH) were studied in serum from all patients. Sixteen of these patients received iBRAF therapy (11 Vemurafenib, 5 Dabrafenib) and tumor markers were analyzed sequentially: baseline, best response and progression. MIA and S-100 were determined by immunometric methods and LDH by a spectrophotometric assay. The cut-off points were MIA=9 ug/L, S-100=0.1 ug/L, and LDH=290 U/L. Non-parametric statistical analysis was performed. Results: Forty-three patients had BRAF V600E mutation and 34 were wild type (WT). The percentage of cases with MIA above the cut-off in patients with V600E mutation was significantly higher than in the WT group (76.3% vs. 52.9%; p&lt;0.05), while the frequency of elevated S-100 and LDH was similar. Among patients treated with iBRAF, the response rate was 87.5% (5 CR, 9PR). In responding patients, MIA and S100 levels decreased dramatically, but not LDH (Table). At the time of this report, thirteen patients have progressed. Upon progression, MIA and S-100 increased significantly above levels achieved at best response (Table). Conclusions: Serum MIA and S-100 are potentially useful markers in the clinical and follow-up management of patients receiving iBRAF therapy. Validation in a larger series is needed. [Table: see text]
A phase II trial of second-line irinotecan and capecitabine after failure of first line infusional 5-fluorouracil and folinic acid in metastatic colorectal cancer (MCRC)
Authors: A. M. Willer, R. D. Hofheinz, A. Wein, U. Gnad-Vogt, S. Saussele, R. Hehlmann, A. Hochhaus
Journal: Journal of Clinical Oncology (2004)

3752 Background: The efficacy of a first line therapy with a combination of irinotecan and the oral fluorpyrimidine capecitabine has been demonstrated in the first line treatment of MCRC in several clinical trials. The aim of this trial was to evaluate the efficacy of this combination as second line therapy for MCRC after failure of infusional 5-fluorouracil and folinic acid. Methods: Patients were recruited at two institutions to receive 6 x weekly irinotecan 70 mg/m2 and capecitabine 1000mg/m2 daily for two weeks followed by one week rest. Treatment was repeated on day 57. In patients older that 65 years only 75% of normal doses were administered. Results: 27 patients were enrolled. Patient characteristics: M/F 20/7, median WHO performance status 1 (range 0–2), median age 66 years (range 55–79). In these patients, a median of 2 treatment cycles (range 1–8) has been administered. Main toxicities (NCI-CTC grade III/IV) were: diarrhoea 23%, nausea/vomiting 4%, renal insufficiency 8%. No hematological toxicity grade III/IV was observed. Postponement of therapy was necessary in 23% of the patients. Median dose intensity was 90% for irinotecan and 85% for capecitabine in cycle one, respectively. Partial remissions were seen in 5% (95% CI: 0–15%) and stable disease in 43% of our patients. Median progression-free interval was four months and median overall survival 14 months (range 3–17 months). 36% of the patients received oxaliplatin-base third-line therapy. Conclusions: This second line regimen with capecitabine and irinotecan yielded a tumor control in 50% of the patients. The toxicity profile was comparable to irinotecan monotherapy. No significant financial relationships to disclose.
Predictive Value of Mutation Analysis in the Diagnostic Approach to Patients with Unexplained Cytopenia
Authors: Luca Malcovati, Anna Gallì, Erica Travaglino, Ilaria Ambaglio, Ettore Rizzo, Elisabetta Molteni, Chiara Elena, Silvia Catricalà, Elisa Bono, Antonio Bianchessi, Gabriele Todisco, Elisa Rumi, Virginia Valeria Ferretti, Elli Papaemmanuil, Seishi Ogawa, Mario Cazzola
Journal: Blood (2016)
Signs of Hypofibrinolysis in Patients with Unprovoked Idiopathic Venous Thromboembolism
Authors: Fernanda Dutra Santiago Bassora, Fernanda Andrade Orsi, Graziela Silveira Araujo Alves, Silmara Aparecida De Lima Montalvão, Kiara Zapponi, Anna Virginia Calazans Romano, Marina Pereira Colella, Erich Vinicius de Paula, Joyce Maria Annichino-Bizzacchi
Journal: Blood (2015)