tbuckley/cabot-search huggingface dataset:
Macrophage galactose-type C-type lectin receptor for DC targeting of antitumor glycopeptide vaccines.
Authors: M. Nuti, I. Zizzari, C. Napoletano, A. Rughetti, H. Rahimi, M. Antonilli, F. Bellati, F. Di Costanzo, T. Irimura, H. Wandall, H. Clausen, P. Benedetti Panici
Journal: Journal of Clinical Oncology (2011)

e13528 Background: Dendritic cells (DCs) are the most potent antigen presenting cells and are employed in cancer vaccination. Several receptors are being studied in order to identif strategies to increase DCs activating capacity. The C-type lectin macrophage galactose type C-type lectin (MGL), expressed by DCs, is a receptor involved in the recognition of GalNAc (Tn)-carrying antigens. In this study we investigated the possibility of stimulating MGL receptor to increase DC performance by using the MUC1 based glycoimmunogen Tn-MUC1 (MUC19Tn) and the anti-MGL antibody (MLD-1). Methods: DCs were derived from PBMCs of 10 healthy donors and were analyzed before and after MGL engagement using MUC19Tn and MLD-1, as stimulators. DC phenotype, endocytosis, migration and IL-10/IL-12 secretion were evaluated by cytofluorimetry. Allo T cell-stimulating capacity and IFNg and IL-2 T cell production were estimated by 3H-thymidine uptake and ELISpot assay, respectively. DC intracellular signaling and MGL oligomerization were studied by Western Blot and confocal microscopy. Results: MGL engagement induces homo-trimers and homo-dimers on DC plasma membrane, promotes the phosphorylation of Erk 1/2 MAP kinases and triggers NFkB classical pathway. The activation of intracellular signals leads to DC phenotypic maturation, with a concomitant reduction of phagocytosis and an enhanced migration capacity (25-30%). After MGL activation, DCs induce a strong proliferation of allogeneic T cells and stimulate high levels of IFNg and IL-2 secretion by both CD8 and CD4 T cells. Conclusions: These results demonstrate that MGL engagement profoundly affects DC plasticity inducing and directing a Th1 immune response. Moreover, MGL receptor expressed on human DC can be targeted by glycopeptide based vaccines with adjuvant activity and tumor specificity.
Sunitinib, sorafenib, temsirolimus, or bevacizumab in the treatment of metastatic renal cell carcinoma (RCC): A review of health economic evaluations
Authors: J. Norum, C. Nieder, M. Kondo
Journal: Journal of Clinical Oncology (2009)

e17539 Background: Renal cell carcinoma (RCC) is the most prevalent kidney cancer and the 5-year overall survival figure in metastatic disease (mRCC) is about 10%. New targeted drugs (sunitinib, sorafenib, bevacizumab, temsirolimus) have shown activity in the treatment of mRCC, but they are all associated with a significant burden of cost. Methods: To support decision makers in their allocation of resources, cost-effectiveness models are constructed to compare the costs and outcomes of anticancer therapy. The PubMed, ASCO abstracts, Google, and the Igaku Chuo Zasshi databases were searched in November 2008 with key terms: kidney, renal, cancer, cost, sunitinib, sorafenib, temsirolimus, and bevacizumab. Seven studies reporting data on cost-effectiveness were revealed. Three of them were published in full text versions. The countries of application were United Kingdom, Canada, United States, Finland, and Japan. An analytical checklist was applied to the seven economic evaluations. Results: The review reveals figures of cost per LYG or QALY in the range €22,648 to €203,692, depending on line setting and drug focused. The results were limited by short follow up periods and the consequently fact that premature data had to be implemented in the Markov models. When compared, sunitinib has the lowest cost-effectiveness figure. Second-line therapy dose not seem to offer valid incremental cost-effectiveness ratios (ICERs) below accepted cost-effectiveness thresholds. As long as cross-over to the experimental arm is allowed (based on improvement in progression free survival) overall survival data are difficult to interpret and the cost difference between the treatment and the control arm minimised. Conclusions: The review revealed ICERs with a wide range. Sunitinib has the lowest cost-effectiveness figure. Second-line therapy does not look cost-effective. [Table: see text]
Use of T-cell proliferation to predict survival and recurrence in patients with resected colorectal liver metastases.
Authors: A. V. Maker, H. Ito, Q. Mo, L. Qin, R. P. DeMatteo, L. H. Blumgart, Y. Fong, S. K. Maithel, W. R. Jarnagin, M. I. D'Angelica
Journal: Journal of Clinical Oncology (2010)

10571 Background: Immune responses correlate with prognosis in primary colorectal cancer. The role tumor immunity has in metastatic disease is less clear. We hypothesize that patient survival and tumor recurrence correlate with lymphocyte proliferation in resected colorectal liver metastases (CRLM). Methods: Microarray gene analysis was performed on viable liver tumor specimens from 96 patients who underwent liver resection for CRLM from 2000-2007. A Cox proportional hazards model was utilized to identify genes associated with overall survival (OS), recurrence-free survival (RFS), and liver specific RFS. Gene ontology (GO) enrichment analysis of these significant genes was used to rank biologically relevant processes using the EASE software. For significant immunologic genes on GO analysis, survival probabilities were assessed using the Kaplan-Meier method. Results: Liver recurrence developed in 45 patients (47%), and 39 patients (41%) died of disease during a median follow-up period of 30 months. GO analysis identified and ranked unique biologic processes that significantly correlated with OS, RFS and liver RFS. Differential expression of genes that specifically function in T-cell proliferation were significant predictors of OS and liver RFS, and the most significant predictor of RFS (#1 of 309 biologic processes, p = 0.002). Specific immunologic gene analysis determined that high tumor expression of the genes TNFSF14/LIGHT, IL10, IL18, and low expression of NCK1 was associated with improved OS, RFS, and liver RFS (p < 0.0006). These genes were not found to be significantly associated with other clinical predictors of survival (size of primary, primary node status, CEA, disease free interval, or number of CRLM), or the administration of preoperative chemotherapy. Conclusions: We have identified an immune profile of genes (LIGHT, IL10, IL18, and NCK1) that function in T-cell proliferation and that are associated with survival and disease recurrence in patients who undergo resection of CRLM. This study genetically characterizes the immunologic milieu of CRLM and has identified markers of the anti-tumor immune response for further validation studies. No significant financial relationships to disclose.
Postremission Treatment with Chemotherapy or Allogeneic Stem Cell Transplantation (Allo-SCT) in Adults with Acute Myeloid Leukemia (AML) -JALSG AML-97 Trial-.
Authors: Hisashi Sakamaki, Shuichi Miyawaki, Shigeki Ohtake, Fumiharu Yagasaki, Kinuko Mitani, Shin Matsuda, Yuji Kishimoto, Yasushi Miyazaki, Norio Asou, Yoshiaki Ogawa, Sumihisa Honda, Ryuzo Ohno
Journal: Blood (2004)
Breast cancer treatment and recurrence in octogenarians.
Authors: Adam Harris, Sarah A. McLaughlin, Cameron Adkisson, Sanjay Prakash Bagaria, Tammeza Gibson, Nancy N. Diehl, Barbara A. Pockaj
Journal: Journal of Clinical Oncology (2012)

94 Background: Octogenarian breast cancer (BrCa) patients accept less aggressive BrCa treatment due to decreased life expectancy, increased comorbidities, and high likelihood of death from other causes. Unfortunately little data exist stratifying octogenarian outcomes by disease risk. We sought to characterize treatment and recurrence patterns in patients &gt;80yo. Methods: Retrospective review identified 432 women &gt;80yo treated surgically for stage 0-3 BrCa between 11/99-8/11. We gathered clinicopathologic data and classified patients by disease risk as DCIS only, low risk (&lt;2cm and ER positive and node negative), or high risk (&gt;2cm or ER negative or node positive). We compared recurrence rates and estimated survival by Kaplan-Meier curves. Results: Among the 432 women, disease was found by mammogram in 86%, treated with BCT in 64%, and predominantly ER-positive (87%). We classified patients as having DCIS only (N=61), low risk (N=205), or high risk (N=166) disease. We identified the following deviations from standard treatment guidelines: 68% DCIS BCT and 38% high risk BCT patients did not have radiation therapy, 25% low risk BCT patients had surgery only, 51% low risk patients did not take adjuvant hormonal therapy, and 40% high risk patients had no adjuvant chemo/hormonal therapy. At 5 and 10 years the overall estimated survival was 63% and 31%, respectively. Overall, 19/432 (5%) patients developed recurrence (table 1). Patients needing mastectomy for high risk disease had significantly higher risk of recurrence than high or low risk BCT patients (p=0.02). Of the 19 recurrence patients, 7/19 (37%; 1 DCIS, 1 low risk, 5 high risk) occurred despite standard multimodality treatment, while12 (63%; 3 low risk, 9 high risk) had the initial tumor treated less aggressively due to patient choice (n=9) or medical co-morbidities (n=3). Conclusions: Significant deviations from treatment guidelines occur in women &gt;80yo. Those with high risk disease should be counseled accordingly and encouraged to receive adjuvant treatment as two thirds of women &gt;80yo will live at least 5 years. [Table: see text]
Association of <i>HER2 </i>and <i>ErbB3 </i>molecular alterations with afatinib sensitivity in platinum-refractory metastatic urothelial carcinoma (UC) in a phase II trial.
Authors: Noura Choudhury, Alexa Campanile, James Lloyd Wade, Tatjana Antic, Walter Michael Stadler, Yusuke Nakamura, Peter H. O'Donnell
Journal: Journal of Clinical Oncology (2015)

312 Background: Platinum-refractory UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ErbB3 are frequent in UC and may represent viable targets for novel therapies. We aimed to investigate whether afatinib, an oral, irreversible Erb family blocker, has clinical benefit in metastatic UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC who received ≤1 chemotherapy in the metastatic setting received afatinib 40 mg/day continuously until disease progression or intolerable toxicity.Primary endpoint was 3-month progression-free survival (PFS3), with drug deemed promising if ≥42% pts had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman). Results: 15 ptshave enrolled: median age 66 (44-78), 11 M/4 F, ECOG PS 0 in 20%, PS 1 in 80%, Hb&lt;10 g/dl in 20%, liver metastases in 13%, median time from prior chemotherapy=4.4 mo. Rash (73%), diarrhea (33%), and fatigue (13%) were the most common drug-related toxicities; 1 pt required dose-reduction (grade 3 fatigue). 3/14 pts (21%) had PFS3 (1 partial response (PR), 2 stable disease); 1 pt has not reached 3 mo on therapy. All 3 responders had molecular alterations in Erb genes: 1 pt with 4 copies of HER2 achieved PR and responded for 6.9 mo; 1 pt with Gly284Arg ErbB3 mutation responded for 7 mo; and 1 pt with 73 copies of HER2 and Arg103Gly ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. None of the 10 non-responders had alterations in these four genes. Time to progression/discontinuation was 8.1 mo in pts with molecular alterations vs. 1.8 for pts without alterations (p=0.02). Conclusions: Afatinib demonstrates activity in platinum-refractory UC, with all responders bearing HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. These data support ongoing testing of afatinib as a potential therapy for refractory UC in marker-selected pts. Clinical trial information: NCT02122172.
A randomized phase II study of sapacitabine, an oral nucleoside analogue, in elderly patients with AML previously untreated or in first relapse or previously treated MDS
Authors: G. Garcia-Manero, S. Luger, P. Venugopal, L. Maness, M. Wetzler, S. Coutre, W. Stock, G. Borthakur, J. Chiao, H. Kantarjian
Journal: Journal of Clinical Oncology (2009)

7021 Background: Sapacitabine is a novel nucleoside analogue with a unique ability to cause irreparable single-strand DNA breaks and induce G2 cell cycle arrest. It is orally administered and has demonstrated promising anti-leukemic activity against relapsed or refractory AML and MDS in a phase 1 trial. We are conducting a multi-center, open-label, randomized phase 2 study to evaluate 3 dosing regimens of this drug. Methods: Eligible patients must be ≥70 years with AML previously untreated or in first relapse or ≥60 years with MDS previously treated with hypomethylating agents. The planned sample size is 60 AML patients and 60 MDS patients. Patients are to be randomized 1:1:1 to receive one of the 3 dosing regimens. The primary efficacy endpoint is 1-year survival. Secondary efficacy endpoints include rate of CR, CRi, or hematological improvement (HI) and response durations. Results: As of December 2008, 60 AML and 13 MDS patients were enrolled and had ≥ 30 days of follow-up. Preliminary efficacy data were available for the AML stratum. Overall response rate is 31% (13% CR/CRp, 5% PR and 13% HI). Median time to CR/CRp is 3–4 cycles (range 1–7). Eight deaths of all causes occurred within 30 days of randomization and all were in the AML stratum (13%). One death was considered to be possibly related to sapacitabine. Common adverse events (all grades, regardless of causality) included fatigue, nausea, vomiting, diarrhea, constipation, anemia, leukopenia, febrile neutropenia, neutropenia, thrombocytopenia, dyspnea and peripheral edema, most of which were mild to moderate in intensity. Conclusions: These interim data suggest that sapacitabine is safe and active across all 3 dosing schedules. Updated data will be presented at the meeting. [Table: see text] No significant financial relationships to disclose.
Patterns of initial treatment and survival among older patients with glioblastoma multiforme: Evidence from SEER-Medicare data
Authors: L. J. McGarry, N. Morissette, C. C. Earle, D. Thompson, A. M. Liepa
Journal: Journal of Clinical Oncology (2007)

6625 Background: There is a lack of published data describing routine treatment patterns for glioblastoma multiforme (GBM), particularly in older patients (pts). We report on initial therapies used for treatment of newly diagnosed GBM and related survival among US pts aged 65 years and older. Methods: GBM pts (ICD-O histology codes 9440–9442) were identified in the SEER-Medicare database from 1992 to 2002 and followed through 2004 or until death. Included in the analysis were pts aged 65+ years at diagnosis with no prior cancer diagnosis, enrolled in Medicare Parts A and B, and not enrolled in a Medicare health maintenance organization (HMO). Initial treatment was defined as treatment received within 1 month prior to or 3 months after diagnosis. Use of first-line treatment for GBM was analyzed over all pts, as well as by year of GBM diagnosis; Kaplan-Meier methods were used to assess survival by initial treatment. Results: 3,407 pts met all eligibility criteria. Median age at GBM diagnosis was 75 years; 51.3% of pts were male and 91.9% were white. 88.4% of pts aged 65–74 received active treatment (craniotomy, chemotherapy and/or radiotherapy [RT]), compared to 76.7% of pts aged 75–84, and 50.4% of pts aged 85+. Craniotomy plus RT was the most common initial treatment (40.4% of all pts), followed by craniotomy only (14.9%), RT only (14.7%) and craniotomy plus RT plus chemotherapy (7.8%). Complexity of treatment tended to decrease with age: multiple treatment modalities were used in 62.1% of pts aged 65–74, 42.7% of pts aged 75–84 and 21.3% of pts aged 85+. No notable trend in distribution of initial treatments was observed over the 10-year study period. Pts undergoing craniotomy plus RT plus chemotherapy survived longest (median: 7.6 months; 95% confidence interval: 7.2–8.3 months), followed by those undergoing craniotomy plus RT (6.5; 6.2–7.1). Pts undergoing craniotomy only (2.1 months; 2.0–2.2) and receiving no treatment (2.0; 1.5–2.1) had the shortest survival. Conclusions: The majority of pts aged 65 years or older receive active treatment for newly diagnosed GBM. Among these pts, receipt and complexity of treatment is highest for younger pts and tends to decrease with age. More aggressive initial therapy is associated with longer survival. No significant financial relationships to disclose.
A cytokine and angiogenic factor (CAF) plasma signature for selection of sorafenib (SR) therapy in patients (pts) with metastatic renal cell carcinoma (mRCC)
Authors: J. Heymach, E. Jonasch, X. Wang, D. Z. Du, S. Yan, L. Xu, M. H. Herynk, K. S. McKee, H. T. Tran, N. M. Tannir, A. J. Zurita
Journal: Journal of Clinical Oncology (2009)

5114 Background: SR, an oral inhibitor of Raf kinase, RET-receptor (R), VEGFR-1, 2, and 3, PDGFR-β, FLT-3, and c-KIT tyrosine kinases, has been shown to prolong progression-free survival (PFS) in mRCC after cytokine failure. In a phase II trial, mRCC pts were randomized to first line treatment with SR vs. SR plus interferon (IFN) to assess whether combination therapy improved PFS. Both treatment arms showed similar outcomes (Tannir et al, ASCO. 2008). Here we investigated predictive and prognostic biomarkers in plasma. Methods: Pts received SR 400 mg PO BID or same dose SR plus IFN 0.5 MU SC BID. Plasma was collected from 69 pts at baseline (BL; SR 34, SR+IFN 35), 59 on day (D) 28, and 57 pts on D56. We used multiplex bead suspension arrays to measure concentrations of 54 CAFs, including VEGF, PDGFbb, EGF, HGF, MMP-9, and multiple chemokines and interleukins (IL). Osteopontin (OPN), soluble carbonic anhydrase 9 (sCA9), placental growth factor (PlGF), collagen type IV (ColIV) and sVEGFR-2 were measured by ELISA. The primary objective of this analysis was to establish a CAF signature based on a set of individual markers at BL with a significant and differential impact on the association between treatment arm and PFS. Results: Among 52 CAFs available at BL, higher than median EGF concentrations associated with poor outcome independently of treatment arm, whereas low IL-2 had the opposite effect (p = 0.003 for both). Only OPN showed a significant treatment by factor interaction at BL (p &lt; 0.01), suggesting that OPN has a differential effect on PFS in the two arms. Pts with high OPN benefitted more from single agent SR (7.74 vs. 3.93 mos for the combination; p = 0.007), but no differences were found for those with low OPN. Lower than median on-treatment increases in sCA9 (D28, p = 0.01) and GRO-alpha (D56, p = 0.04) on SR only were also associated with a better outcome. A 6-marker CAF signature at BL containing OPN, sCA9, VEGF, sVEGFR-2, ColIV, and TRAIL demonstrated predictive value on PFS. Conclusions: A CAF signature showed potential value in predicting differential benefit from single agent SR vs. SR+IFN in mRCC. Broad-based screening of circulating CAFs may identify predictive and prognostic biomarkers in the context of clinical trials. [Table: see text]
Genotyping Melanoma in Colombia
Authors: H. Carranza, A.F. Cardona, C.A. Vargas, P. Archila, J. Otero, L. Bernal, O. Arrieta, J. Rodríguez, J. Insuasty, D. Lopera, A. Jimenez Orozco, M. Lema, I. Durango, A. Yepes, G. Rojas-Uribe, R. Duarte, L.R. Gomez Wolf, D. Torres
Journal: Annals of Oncology (2014)
Symptom clusters in newly-diagnosed brain tumor patients
Authors: J. Gleason, D. Case, S. Rapp, E. Ip, M. Naughton, J. Butler, K. McMullen, V. Stieber, P. Saconn, E. Shaw
Journal: Journal of Clinical Oncology (2006)

8587 Background: A symptom cluster is 2 or more co-occurring symptoms. Patients with brain tumors experience disease and treatment-related symptoms that impact their health-related quality of life (QOL). Identifying symptom clusters will facilitate treatment and improve QOL outcomes. Methods: 66 patients were enrolled in a phase III, placebo-controlled, double-blind, prospective randomized clinical trial assessing the effect of prophylactic d-methylphenidate (d-MPH) on QOL in newly diagnosed brain tumor patients receiving brain radiation therapy (RT). Inclusion criteria were: age ≥ 13 years, primary or metastatic brain tumor, partial or whole brain RT with a total dose of ≥ 2,500 cGy in ≥ 10 fractions, KPS ≥ 70, and life expectancy ≥ 3 months. Patients received d-MPH 5–15 mg BID (or placebo) starting week 1 of RT and continuing for 8 weeks post-RT. QOL data were collected at baseline, the end of RT, and 4, 8, and 12 weeks following RT using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) and the Center for Epidemiologic Studies Depression Scale (CES-D). Symptom data were analyzed using exploratory factor analysis, multi-dimensional scaling (MDS), and cluster analysis. Results: The study failed to show a treatment effect for d-MPH (Butler J et al, Int J Radiat Oncol Biol Physics 63 [Supp1]:80, 2005).Thus, both d-MPH and placebo patients were analyzed together. 58 and 48 patients were analyzed at baseline and the end of RT, respectively. Two symptom clusters were identified using exploratory factor analysis and supported by MDS and cluster analysis: an expressive language cluster including difficulty reading, writing, and finding the right words, and a mood cluster including feeling sad, anxious, and having depressed mood. Conclusions: Two symptom clusters were identified in patients undergoing brain RT: an expressive language cluster and a mood cluster. This suggests that interventions that target both cognitive function and mood should be utilized. Further research on symptom clusters in cancer patients is needed. This study was supported by NCI grant 1 U10 CA81851. No significant financial relationships to disclose.
Phase I trial of escalating doses of weekly everolimus (RAD001) in combination with docetaxel for the treatment of metastatic breast cancer (MBC)
Authors: S. L. Moulder, E. Rivera, J. Ensor, A. Gonzalez-Angulo, M. Christofanilli, D. Booser, S. Giordano, A. Brewster, G. Hortobagyi, H. Tran
Journal: Journal of Clinical Oncology (2009)

1066 Background: Inhibition of mTOR with everolimus (E) may improve efficacy in combination with docetaxel (D), but both drugs are metabolized by CYP3A4, thus a pharmacokinetic (PK) interaction may also exist. Methods: 15 patients (pts) with MBC were treated with docetaxel and everolimus using the continuous reassessment method (CRM) to determine maximum tolerated dose (MTD). Docetaxel doses were 40–75 mg/m 2 IV on day 1 of a 21 day cycle. Everolimus doses were 20–50 mg PO on days 1 and 8 of a 21 day cycle (except cycle 2, where only day 8 was given to allow single agent PK analyses of both drugs). Response was measured every 2 cycles using RECIST. Results: Median age= 58 years and 77% of pts had &gt;2 prior chemotherapies for MBC. Initially 2 of 2 pts treated (D= 75 mg/m2, E= 30 mg) developed DLT (neutropenic fever/infection), prompting a mandatory PK evaluation for all pts enrolled in subsequent cohorts. A second cohort of 3 patients (D=60 mg/m2, E=20mg) had no DLT, but no pts received day 8 of E due to grade 3–4 neutropenia. PK analyses demonstrated a 42% lowered (-42%) D clearance at the 60 mg/m2 in the presence of E (n=1). Subsequent cohorts were accrued at D=40 mg/m2 with escalating doses of E (Table). For the entire group, an 18% decrease (-18%) in D clearance was observed when D was administered concomitantly with E. High interpatient variability of D clearance was observed (range +16% to -135%). No pts had CR/PR, but 6 had SD&gt;4 cycles and 2 had SD=8 cycles. Conclusions: Weekly everolimus appears to cause widely variable and unpredictable changes in docetaxel clearance making this combination unfeasible. [Table: see text] No significant financial relationships to disclose.