tbuckley/cabot-search huggingface dataset:
Using biologic knowledge to discover molecular correlations between human renal cell carcinoma pathways.
Authors: Vanessa Medina Villaamil, Guadalupe Aparicio Gallego, Francisco Gomez Veiga, Manuel Valladares Ayerbes, Maria Quindós Varela, Natalia Fernandez Nunez, Aurea Molina Diaz, Isabel Santamarina Cainzos, Luis Miguel Anton Aparicio
Journal: Journal of Clinical Oncology (2014)

451 Background: Renal cell carcinoma (RCC) is known to be resistant to chemotherapy. There is need for the identification of biomarkers capable to determine RCC prognosis factors and metastatic potential obtainable from non-invasive or minimally invasive techniques. Our aim was to derive predictive models which could predict more accurately than any one factor alone. Methods: To studythe cascade of events leading to the formation and progression of RCC, we assessed 29 markers by immunohistochemistry and qRT-PCR using tissue micro-array (TMA). Results: Multivariate logistic regression showed the best proteins combination for node status (NOTCH1 and GLUT5) and pelvis invasion (EGFR and DLL3). ROC curve analyses were made to analyse the accuracy of the best candidate proteins; it should be noted NOTCH1 and GLUT5 for node status prediction (AUC=0.833, 95% CI, 0.744-0.922; p&lt;0.001) and EGFR and DLL3 for pelvis invasion (AUC=0.777, 95% CI, 0.631-0.922; p=0.007). Furthermore, we carried out the correlation between these candidate proteins and all mRNA measured in order to deepen in the cellular transcripts traffic associated with them. To highlight the correlation between high DLL3 protein levels and low Hif1-β expression, and the negative correlation between GLUT5 protein and low levels of Baxβ. Conclusions: In the age of individual therapy, the approach to percutaneous image-guided RCC biopsy procedures plays an expanded role. Applying a 2 mm punch needle for constructing a TMA we could describe for the first time how are combined and correlated 29 markers in regression equations to predict in the most optimal way a number of pathological variables associated with RCC. [Table: see text]
Health care resource utilization and costs of cancer patients with cancer-related anemia.
Authors: J. Brown, T. K. Le, J. Xie, C. E. Muehlenbein, R. McCracken, M. Howard, J. Wooldridge
Journal: Journal of Clinical Oncology (2011)

e16510 Background: Cancer-related anemia (CRA) is common in hematological malignancies and some solid tumors. The purpose of this study was to describe the resource utilization and costs of cancer patients with anemia (CPWA) and cancer patients without anemia (CPWoA) overall and in a subgroup who received chemotherapy during the study period. Methods: De-identified data from a large administrative claims database (Thomson Reuters MarketScan) was used for this retrospective study. This study included patients ≥ 18 years, a cancer diagnosis (ICD-9 codes 140.x - 208.x, 230.x - 239.x) in 2007 and 2 years of continuous pharmaceutical and medical benefit enrollment between January 1, 2006, and December 31, 2008 (12 months prior to and post first cancer diagnosis in 2007). Descriptive statistics were used to describe the characteristics of the study population overall, with and without anemia and across chemotherapy subgroups. Chi-square and Wilcoxon tests were used to make statistical comparisons. Results: A total of 617,922 cancer patients were included, and 6% had a diagnosis for anemia. Of the CPWA, 13% (5,004) had undergone chemotherapy during the 12-month post period, compared to 7% (40,025) of the CPWoA. Resource use and costs for each group during the 12-month post period are described below. Conclusions: In both the overall and chemotherapy subgroups, cancer patients with anemia had higher resource utilization and total medication and drug costs compared to patients without anemia. Even after excluding costs for supportive-care drugs (including ESAs) and transfusions, costs for CPWA were higher than CPWoA, suggesting substantial other health care costs incurred by these patients. These findings suggest an unmet need for the treatment of CRA. Overall Chemotherapy subgroup CPWA (N=38,989) CPWoA (N=578,933) CPWA (N=5,004) CPWoA (N=40,025) At least 1 ESA prescription 2.1% 0.12% 2.6% 0.32% At least 1 blood transfusion 2.4% 0.04% 5.1% 0.16% Total mean supportive-care drug costs $1,500 $500 $3,000 $1,200 Total mean transfusion costs $1,500 $1,700 $1,500 $2,100 Total mean medical visits 52 25 66 34 Total mean medical and drug costs $39,000 $13,000 $59,000 $22,000
The significance of EGFR pathway mutations for the efficacy of first line treatment with bevacizumab in metastatic colonrectal cancer.
Authors: Izuma Nakayama, Eiji Shinozaki, Takeru Wakatsuki, Yosuke Kumekawa, Mariko Ogura, Takashi Ichimura, Daisuke Takahari, Masato Ozaka, Mitsukuni Suenaga, Keisho Chin, Nobuyuki Mizunuma, Toshiharu Yamaguchi
Journal: Journal of Clinical Oncology (2015)

699 Background: After analysis of minor RAS mutations (KRAS exon3, 4/NRAS) in FIRE-3 or PRIME study, so called all RAS mutation would be being regarded as a biomarker for anti-EGFR antibodies. BRAF and PIK3CA mutation would be a candidate of biomarkers for anti EGFR targeted therapies. However it remains unknown whether EGFR pathway mutations affect the efficacy of bevacizumab in Stage.‡W CRC. Methods: Of the 1,001 consecutive patients of CRC in our institute between Nov 2006 and Dec 2013, we examined RAS, PIK3CA and BRAF mutational status, 141 patients received systemic chemotherapy for the first line treatment of Stage.‡W. Among them, 96 patients were administered chemotherapy with bevacizumab. Overall survival (OS), Time to Treatment Failure (TTF) and Objective Response Rate (ORR) were evaluated by mutational status. Results: Baseline characteristics were as follows (n=141): median age, 63; male/female, 80/61; ECOG PS 0-1/2, 135/4; chemotherapy with bevacizumab/chemotherapy with anti-EGFR antibodies/cytotoxic agent alone, 96/22/23;KRAS (codon 12,13) wild-type (WT)/RAS wild-type(WT), 89/80; PIK3CA mutation (exon 9/exon 20)/BRAF mutation, 11(5/6)/13. Median OS and TTF were 32.1 and 8.0 months respectively. In chemotherapy with bevacizumab, ORRs were 46.3% (all cases), 55.3% (KRAS WT), 54.5% (RAS WT) and 60.6% (all WT) respectively. ORR was gradually improved by focusing therapeutic target on all wild population. However, there were no significant differences in TTF and OS among them. PIK3CA mutation had a trend toward shorter TTF of bevacizumab (p=0.056). This trend was observed in PIK3CA mutation on exon 20 but not observed exon 9. BRAF mutation had significantly associated with poor OS not only for bevacizumab cases but also all therapies. Conclusions: In our study, profiling of EGFR pathway mutations may not contribute to enrich patients with benefit from chemotherapy with bevacizumab.
RNA expression profiling of ERCC1, BRCA1, TUBB3, and STMN1 in non-small cell lung cancer by a multiplex branched DNA liquidchip technology (MBL) for predicting the efficacy of chemotherapy.
Authors: Q. Zhou, J. He, H. Yang, X. Luo, J. Xu, L. Ren-Heidenreich
Journal: Journal of Clinical Oncology (2010)

e21020 Background: It is very important to measure these RNA levels before chemotherapy. However, tumor specimens are usually preserved in formalin-fixed and paraffin-embedded (FFPE) slides and the RNA are partially damaged; from which the conventional RT-qPCR method can not detect RNA expression levels accurately. Methods: A novel MBL technology was developed for semi-quantitative measurement of ERCC1, BRCA1, TUBB3, and STMN1 RNA in FFPE slides. Without extracting RNA, 329 FFPE samples from patients with NSCLC were directly used to measure RNA expression levels of ERCC1, BRCA1, TUBB3 and STMN1 with the MBL technology. The RNA levels were classified as low (L), medium (M) and high (H) based on the quartile values. Results: These values were then applied to 24 patients who were treated with platinum and 19, with both platinum and anti-microtubule agents (Table). Patients with higher ERCC1 and BRCA1 RNA levels had poor response to platinum. Drug resistance to anti-microtubule agents was also related to higher TUBB3 and STMN1 RNA levels. Conclusions: This novel MBL technology is a sensitive, accurate, fast and robust technology that allows clinical applications to measure ERCC1, BRCA1, TUBB3 and STMN1 RNA levels in FFPE samples for predicting clinical responses to platinum and anti- microtubule agents. This platform is currently used in China for clinical pharmacogenomic diagnosis in personalized chemotherapy for NSCLC to measure RNA levels of ERCC1, BRCA1, TUBB3, and STMN1 as well as TYMS, RRM1, TOP2A, EGFR, PDGFR, VEGFR1, VEGFR2, KIT, HER2/neu, IGF1R, etc. mRNA Sample size Expression levels CR + PR SD + PD* ERCC1 24 L and M 76.9% (10/13) 23.1 (3/13) H 18.2% (2/11) 81.8% (9/11) BRCA1 24 L and M 61.5% (8/13) 38.5% (5/13) H 36.4% (4/11) 63.6% (7/11) TUBB3 19 L and M 47.7% (7/15) 53.5 (8/15) H 0.0% (0/4) 100% (4/4) STMN1 19 L and M 60.0% (6/10) 49.0% (4/10) H 11.1% (1/9) 88.9% (8/9) Abbreviations: SD, stable diseases; PD, progressive diseases; PR, partial response; CR, complete response. No significant financial relationships to disclose.
Chromosome 8 alterations and PTEN loss in Gleason grade 3 tumor to predict the presence of unsampled grade 4 tumor: Implications for active surveillance.
Authors: Bruce J. Trock, Robert B. Jenkins, Jonathan W. Said, Samson Fine, Beatrice Knudsen, Helen L. Fedor, Bora Gurel, Tamara L Lotan, Angelo M De Marzo
Journal: Journal of Clinical Oncology (2014)

93 Background: A key eligibility criterion in many active surveillance (AS) programs is that the biopsy exhibit only Gleason pattern 3 (G3) for a Gleason score of 6 or less. However, 25 to 35% of biopsy Gleason 6 is upgraded to Gleason 7 or higher in the prostatectomy (RP) specimen. Thus, there is a great need for biomarkers that, when measured on G3 tissue in a Gleason 6 biopsy, can predict the presence of unsampled higher grade tumor in the whole prostate. We evaluated PTEN loss by immunohistochemistry (IHC), and PTEN deletion, chromosome 8q (MYC) gain and 8p (LPL) loss by fluorescence in situ hybridization (FISH) for their ability to predict unsampled G4 tumor. Methods: A tissue microarray (TMA) was constructed of RP tissue from three groups of patients (n=50 per group) whose prostates exhibited only Gleason 3+3, only 3+4, or only 4+3 tumor, matched on age, year of RP, and race. In each patient, multiple cores sampled only from areas of G3 were evaluated for PTEN deletion by FISH, PTEN loss by IHC, and chromosome 8p/8q alterations by FISH. Biomarker results were compared between Gleason 6 versus 7 tumors using conditional logistic regression. Results: Patients underwent RP in 2001 to 2009, had median age 60, and median prostate-specific antigen 5.2; 63% of tumors were organ confined. In univariate analyses 8q gain (odds ratio OR=8.9, p&lt;.0001), 8p loss (OR=6.9, p&lt;.0001), PTEN loss by IHC (OR=5.7, p=.025), but not PTEN deletion by FISH (OR=1.5, p=.477) were significantly more common in G3 cores from Gleason 7 tumors than G3 cores from Gleason 6 tumors. In multivariable analyses, 8q gain (OR=6.2, p=.002) and 8p loss (OR=5.2, p=.0002) remained highly significant. At least one high risk biomarker (8q gain, 8p loss, PTEN loss, or PTEN deletion) was found in 35.7% of Gleason 3+3 versus 77.1% of Gleason 3+4 versus 91.3% of Gleason 4+3 tumors, p&lt;.0001. Adjustment for confounding factors did not change the results. Conclusions: Chromosomal 8q gains (MYC), 8p loss (LPL), and PTEN loss measured in Gleason G3 TMA cores strongly differentiate whether the core comes from Gleason 6 or Gleason 7 tumor. If validated in biopsy Gleason 6 cores to predict prostatectomy Gleason 7 tumor these biomarkers could facilitate safe selection of men for active surveillance.
Value of mismatch repair deficiency for predicting complete pathologic response to preoperative chemoradiation in rectal carcinoma.
Authors: Samuel Aguiar, Paula Mendonca Taglietti, Maria D. Begnami, Celso Abdon Mello, Erika Maria Monteiro Santos, Ademar Lopes
Journal: Journal of Clinical Oncology (2014)

639 Background: The objective of this study is to investigate the value of mismatch repair deficiency (MMR) in rectal cancers as a predictive fator of response to chemoradiation in rectal cancer. Methods: We evaluated a consecutive cohort of 109 patients with locally advanced rectal carcinomas, treated with a total dose of 5,040 cGy of preoperative radiation therapy, concomitant with infusional 5-FU-based chemotherapy. Radical surgery (TME) was performed in all patients. MMR status was determined by imunohistochemistry in tumor tissue from biopsies prior to chemoradiation. The primary endpoint was complete pathologic response (pCR). Results: 63 patients (57.8%) were male, and the mean age was 60 years (range from 28 to 93). The rate of pCR was 18.3%. Among clinical variables (age, sex, distance to dentate line, per-treatment CEA level, and clinical assessment of response), only clinical complete response (cCR) was significant associated with cPR (p=0.009). Only two patients (1.8%) presented tumors with MMR deficiency. These 2 patients had cPR. Despite the very low rate of MMR deficiency, the association with cPR was significant (p=0.032). Conclusions: Considering the low rate of MMR deficiency found, we do not consider MMR status as a good tool for predicting pathologic response to chemoradiation in rectal cancer. Further investigation can be considered among the subgroup of Lynch syndrome patients.
Effect of matrix metalloproteinase-2 on the ability of human dendritic cells to prime inflammatory T<sub>H</sub>2 cells via an IL-12 and OX40L dependent pathway.
Authors: E. Godefroy
Journal: Journal of Clinical Oncology (2010)

10622 Background: Antigens expressed by melanoma cells (MAA) and recognized by T lymphocytes have been used in various immunization strategies to treat cancer patients. However, the therapeutic efficacy of these approaches remains limited. Because MMP-2 (matrix metalloproteinase-2) activity is critical for melanoma progression, this protein represents a unique antigen for vaccine therapy. Methods: CD4+ T cells were stimulated with overlapping MMP-2 peptides. After 12 days, MMP-2-specific responses were determined by intracellular staining of cytokines. Specific T cells from positive samples were enriched and cloned using limiting dilution. Cytokine production was assessed by ELISA, intracellular staining, or cytometric bead array method. Results: We identified 11 novel CD4 MMP-2-derived epitopes, and showed that the corresponding T cells, detected in the CD45RO+/CD62L- memory fraction, displayed an inflammatory TH2 profile, i.e. mainly secreting TNF, IL-4 and IL-13 and expressing the TH2-specific transcription factor GATA-3. In contrast, CD4+ T cells that recognize other associated MAAs were typically TH1. Interestingly, naïve T cells primed with active MMP-2 gave rise to TH2 specific cells, while naïve T cells primed with peptides generated IFNg-secreting specific cells, consistent with a TH1 profile. Accordingly, we showed that the MMP-2 enzyme inhibited IL-12p35 production and induced OX40L expression by DCs. Both events were responsible for the TH2 skewing of MMP-2-specific T cells and other MAA-specific T cells. Furthermore, MMP-2 specific TH2 cells were found in 13 tumor-infiltrating lymphocyte populations out of the 31 melanoma patients tested. Conclusions: The protease activity of MMP-2 influences DC phenotype, more precisely IL-12 production and OX40L expression, which are responsible for the observed TH2 lineage commitment of MMP-2-specific T cells and other MAA-specific T cells. These findings open the way to therapeutic strategies skewing these already frequent and diverse MMP-2-specific responses towards a more efficient anti-tumor TH1 phenotype to treat melanoma patients. No significant financial relationships to disclose.
Practice patterns and outcomes of rivaroxaban usage in patients with cancer.
Authors: Carmelita P. Escalante, Ali Zalpour, Juhee Song, Marsha N. Richardson, Tony Lam, Josiah Halm, SWamique Yusuf, Shuwei Gao
Journal: Journal of Clinical Oncology (2016)

194 Background: Patients with cancer have an increased risk of venous thromboembolism (VTE) and frequently require anticoagulation. In addition, many patients with cancer also have comorbidities such as atrial fibrillation (AF) and are on stroke prevention. Rivaroxaban (RV) is an oral (factor Xa inhibitor) used in these scenarios; however, there is little experience utilizing this agent in patients with cancer. Our aim is to describe practice patterns and outcomes of RV usage in patients with cancer. Methods: We conducted a retrospective study of 62 patients with cancer receiving RV for at least 5 days for VTE or non-valvular AF from 1/1/2012 through 10/31/2015. Practice patterns included RV perioperative use and blood and platelet transfusions. Outcomes of interest were recurrent VTE and bleeding. Descriptive statistics were utilized to summarize demographic and clinical variables. Results: Of 62 patients with cancer, the mean age was 62 years (range 31-83), 50% were male, and 77% white. The most common cancer types were gastrointestinal 9 (15%), sarcoma 9 (15%), and breast and hematologic each with 8 (13%). Of those, 49 (79%) had VTE, 9 AF (15%), and 4 (7%) had both. 42 (68%) patients were switched to RV from a prior anticoagulant, the majority from low molecular weight heparin. 22 (36%) had RV withheld temporarily; 15 due to surgical procedure and 5 due to bleeding. 5 (33%) received bridging anticoagulation prior to surgery. RV was held a mean of 2 days prior to surgery and resumed 9 days post-op. 14 (21%) received blood and 2 (3%) received platelet transfusions while on RV. 2 (3%) patients had VTE recurrence while on RV. 18 (29%) discontinued RV due to bleeding, 5 (28%) due to hematuria and only 1 patient due to thrombocytopenia (6%). There were no major bleeds or deaths related to RV. Conclusions: RV was used in solid and hematologic cancers. The majority were transitioned from another anticoagulant. Although VTE recurrence was low, discontinuation of RV due to bleeding was higher. Further study of the use of RV in patients with cancer is needed for continued guidance of appropriate and safe usage.
Chemotherapy in patients ≥ 80 with advanced non-small cell lung cancer: combined results from SWOG 0027 and LUN 6
Authors: P. J. Hesketh, R. Lilenbaum, K. Chansky, A. Dowlati, P. Graham, J. Crowley, D. R. Gandara
Journal: Journal of Clinical Oncology (2005)

7147 Background: Recent trials have demonstrated the efficacy of chemotherapy in elderly(defined as > age 70) patients(pts) with advanced non small cell lung cancer(NSCLC). The risks/benefits of chemotherapy in the “very” old pt with NSCLC have been poorly defined. We report treatment outcome in the combined cohort of pts ≥ 80 from trials conducted by the Southwest Oncology Group (S0027) and an investigator-initiated multi center trial (LUN 6). Methods: Eligibility: histologically proven NSCLC; age ≥ 70 performance status (PS) 0 - 1 or PS 2 any age; stage IIIB/IV; no prior chemotherapy; adequate organ function. Treatment: S0027 - vinorelbine (VLB) 25mg/m2 d1,8 q 21 days x 3 cycles, followed by docetaxel (DOC) 35mg/m2 d1,8,15 q 28 days x 3 cycles; LUN 6 - DOC 35mg/m2 d1,8,15 q 28 days or 75 mg/m2 q 21 days. Of the 228 (pts) treated, 49 (21.5%) - (26 LUN 6 and 23 S0027) were ≥ 80. Pt characteristics: M/F 22/27; median age(range) 82 (80–87); stage IIIB/ IV 9/40; PS 0–1/2 37/12. Results: Outcome is compared in the combined ≥ 80 group to the < 80 S0027 (N=94) group. Response: ≥ 80 - partial(PR) 4 (8%), stable(SD) 22 (44.9%); < 80 - PR 16 (17%), SD 25 (27%); survival (median) ≥ 80 PS 0/1 - 7 mo PS 2 - 4 mo, < 80 PS 0/1 - 11 mo PS 2 - 5 mo; (1-year) ≥ 80 PS 0/1 - 32% PS 2 - 0%, < 80 PS 0/1 (N=60) - 43% PS 2 (N=34) - 15%. Treatment was well tolerated. Grade 3/4 ANC: ≥ 80 14/49(29%), < 80 28/91 (31%); Grade 3/4 plts: ≥ 80 1/49 (2%), < 80 0/91 (0%); Other grade 2/4 toxicities: ≥ 80 38/49 (78%), < 80 87/91 (96%). Grade 5 toxicity: ≥ 80 group - 2 (4%); < 80 - 3 (2%). Conclusions: 1.These chemotherapy regimens were associated with an encouraging disease control (PR+SD) rate (53%) in pts ≥ 80 with advanced NSCLC, with good tolerance. 2. In good PS (0–1) pts, survival was shorter in the ≥ 80 group compared to the < 80 group (7 vs. 11 mo). For PS 2 pts survival was comparable in the ≥ 80 and < 80 groups (4 vs 5 mo). 3. Selected octogenarian patients with advanced NSCLC may benefit from single agent chemotherapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis, GlaxoSmithKline Aventis, GlaxoSmithKline Aventis
Potential impact of prior high-dose IL-2 on the outcomes of sunitinib (Su) treatment (tx) in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Eli Rosenbaum, Maya Gottfried, Hans J. Hammers, Mario A. Eisenberger, Michael Anthony Carducci, Victoria J. Sinibaldi, Victoria Neiman, David Sarid, Eliahu Gez, Henry Hayat, Avivit Peer, Avishay Sella, Wilmosh Mermershtain, Keren Rouvinov, Raanan Berger, Daniel Kejzman
Journal: Journal of Clinical Oncology (2014)

494 Background: Targeted txs are the tx of choice in most mRCC pts. However, HDIL2 which may produce durable responses in a small percentage of cases, is still an option in carefully selected pts. While the effect of prior HDIL2 on the outcome of targeted txs in mRCC pts is poorly defined, a recent single center report (Birkhäuser FD, Cancer J 2013) revealed an improved disease-specific survival in pts treated with prior HDIL2. We aimed to study the effect of prior HDIL2 tx on outcome of mRCC pts treated with sunitinib. Methods: Records from 302 mRCC pts treated with Su from 2004 to 2013 in 9 centers across 2 countries were retrospectively reviewed. We compared the response rate, progression free survival (PFS), and overall survival (OS), between post HDIL2 pts (n=27) and individually matched tx naïve pts (n=27). Progression free survival and overall survival were determined by Cox regression. Results: All pts had prior nephrectomy and clear cell histology. The groups were matched by age (median 61), gender (male 74%), Heng risk (favorable 37%, intermediate 59%, poor 4%), sunitinib induced hypertension (67%), sunitinib dose reduction/treatment interruption (41%), smoking status (active 7%), use of angiotensin system inhibitors (41%), the presence of more than one metastases site (96%), and pre-tx neutrophil to lymphocyte ratio (&gt; 3 in 22%). Furthermore, they were balanced regarding the presence of lung (68%), liver (31%), and bone (43%) metastases, and the use of bisphosphonates (32%). In prior HDIL2 versus tx naïve pts, objective response was partial response/stable disease 89% (n=24) versus 74% (n=20), and progressive disease at first imaging evaluation within the first 3 months (mos) 11% (n=3) versus 26% (n=7) (p=0.29, OR 2.4). Median progression free survival was 21 versus 12 mos (HR 2.3, p=0.005), and median overall survival 25 versus 20 mos (HR 2.2, p=0.013). Conclusions: In metastatic renal cell carcinoma patients treated with sunitinib, prior high dose IL-2 therapy may improve the outcome.