tbuckley/cabot-search huggingface dataset:
Use of genetic variants to predict clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line 5-FU or capecitabine in combination with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV)
Authors: H. Singh, A. Pohl, A. El-Khoueiry, G. Lurje, W. Zhang, D. Yang, Y. Ning, J. Shriki, S. Iqbal, H. Lenz
Journal: Journal of Clinical Oncology (2009)

4070 Background: Recent studies suggested polymorphisms involved in angiogenesis related genes associated with clinical outcome in pts treated with the VEGF-inhibitor bevacizumab. (Schneider et al. JCO 2008, Manegold et al ASCO 2008). We evaluated functional polymorphisms involved in angiogenesis- (VEGF, KDR, IL-6, CXCR1 and-2), apoptosis (p53) and cell-proliferation (MMP2,-7 and-9, ICAM)-related pathways in an expanded patient cohort for their potential prognostic or predictive role in clinical outcome. Methods: Genomic DNA was extracted from 79 mCRC pts (treated with first-line FOLFOX/BV or XELOX/BV at USC) from peripheral blood. Genotyping was performed using PCR-RFLP assays or direct sequencing. Results: 79 pts (47 men, 32 women) with a median age of 56 years (range 29–81), were treated with either FOLFOX/BV (33 pts) or XELOX/BV (46 pts). Radiologic response: 2/79 pts (3%) CR, 41/79 pts (52%) PR, 32/79 pts (41%) SD and 3/79 pts (4%) DP. At a median follow-up of 32.0 months (range: 1.4- 47.8 months), the median time to progression was 10.8 months (95% CI: 8.1–14.9). We found IL-6 G- 174C (p=0.025, Fisher's exact test) and p53 codon 72 (p=0.029, Fisher's exact test) polymorphisms associated with response to BV-therapy. Furthermore, there were statistically significant associations between genomic polymorphisms in MMP-9, CXCR-1 and PFS (p=0.023 and p=0.014, respectively, log-rank test). Pts with 2 G- alleles in CXCR-1 G+2607C (median PFS=13.7 months, 95% CI:8.4–16.4) and pts homozygous for the C-allele in MMP-9 C-1562T (median PFS= 13.9 months, 95% CI: 10.1–15.8) had longer PFS compared to pts with any C-allele in CXCR-1 G+2607C (median PFS = 7.9 months, 95% CI: 6.9–10.2) and pts with any T-allele in MMP-9 C-1562T (median PFS 7.2 months, 95% CI: 5.3–11.0), respectively. Conclusions: These are the first data to predict clinical outcome in mCRC pts treated with FOLFOX/BV or XELOX/BV. Our data demonstrate that functional polymorphisms in angiogenesis related genes predict response and PFS in pts treated with the angiogenesis- inhibitor BV. However, confirmation of these findings in larger, prospective genotype-guided clinical trials is warranted. [Table: see text]
Efficacy of crizotinib in children with relapsed/refractory ALK-driven tumors including anaplastic large cell lymphoma and neuroblastoma: A Children's Oncology Group phase I consortium study.
Authors: Yael P. Mosse, Frank M. Balis, Megan S Lim, Julie Laliberte, Stephan D Voss, Elizabeth Fox, Rochelle Bagatell, Brenda Weigel, Peter C. Adamson, Ashish M Ingle, Charlotte H Ahern, Susan Blaney
Journal: Journal of Clinical Oncology (2012)

9500 Background: Genetic aberrations in the anaplastic lymphoma kinase (ALK) gene are found in anaplastic large cell lymphoma (ALCL), neuroblastoma (NB) and other tumors.Crizotinib,a small molecule inhibitor of ALK and c-Met, is active in non-small cell lung cancers (NSCLC) harboring an ALK translocation. We performed a phase 1 dose-escalation and pharmacokinetic (PK) trial of crizotinib in patients (pts) with refractory solid tumors and ALCL. Methods: Crizotinib was administered bid without interruption in 28 day cycles using the rolling-six design. Six dose levels (100, 130, 165, 215, 280, 365 mg/m 2 /dose) have been evaluated (A1). Pts with confirmed ALK fusion proteins, mutations or amplification (A2) could enroll at one dose level lower than part A1 and those with NB could enroll on a separate stratum (A3). PK studies were performed on day 1 and at steady state (SS). ALK genomic status in tumor tissue was evaluated and qPCR was used to measure NPM-ALK fusion transcript in bone marrow and blood samples of ALCL pts. Results: 70 pts were enrolled, 57 fully evaluable for toxicity, [median (range) age 9.9 yrs (1.1–21.3)]: 29 on A1, 18 on A2, and 10 on A3. In A1, 2/7 pts developed DLT (grade 3 dizziness, grade 5 intra-tumoral hemorrhage) at 215 mg/m 2 and 1/6 pts developed DLT (grade 4 liver enzyme elevation) at 365 mg/m 2 . In A2, 1 grade 4 DLT (neutropenia) occurred at 165 mg/m 2 ; in A3, no DLTs occurred. Mean (±SD) C ave (=AUC 0-12h /12h) of crizotinib at SS was 466±114 ng/mL at 215 mg/m 2 /dose (n=5), 443±121 ng/mL at 280 mg/m 2 /dose (n=8), and 720±230 ng/mL at 365mg/m 2 /dose (n=4). Response data for pts with ALCL (six at 165 mg/m 2 , two at 280 mg/m 2 ) approved for release by the Data Safety Monitoring Committee demonstrates 7/8 (88%) complete response (CR) rate to date. RT-PCR data for 6 of these pts at 57 time points was obtained and will be described. In addition, 2 pts with NB have had CRs, one with a documented ALK mutation. One patient with an inflammatory myofibroblastic tumor and one with NSCLC had PRs. Conclusions: Inhibition of ALK in pediatric pts with ALK-driven tumors occurs with minimal toxicity and is associated with objective anti-tumor activity.
Abstract 16294: Adipose Tissue Lipolysis Determines the Cardiac Phenotype During Exercise
Authors: Foryst-Ludwig Anna, Michael C Kreissl, Schirbel Andreas, Christiane Sprang, Beata Hoeft, Verena Benz, Erin E Kershaw, Ulrich Kintscher
Journal: Circulation (2012)

We have recently shown that exercise-induced cardiac hypertrophy is regulated in a sex-specific manner. In accordance with increased exercise-mediated hypertrophic responses, female mice showed inc...
Outcomes in white (W) patients (pts) and those of African (A) descent receiving adjuvant therapy for colon cancer (CC)
Authors: G. Yothers, W. Blackstock, N. Wolmark, R. M. Goldberg, M. J. O’Connell, J. Benedetti, J. Dignam, D. J. Sargent
Journal: Journal of Clinical Oncology (2007)

4017 Background: Published reports suggest that CC pts of A descent have inferior survival compared to W pts. Whether these differences are explained by clinical factors at diagnosis, socioeconomic factors impacting access to care, or intrinsic differences in the biology of the tumors or the response to therapy is unclear. Pts in clinical trials have data collected for important baseline clinical factors and should receive comparable oncologic care regardless of socioeconomic factors. Methods: We analyzed data from 13,435 individual pts on 11 phase III adjuvant CC trials accrued from 1977 to 2002. Analysis was restricted to stage II and III pts, with race reported as black or white. Endpoints were overall survival (OS - time to death), recurrence-free survival (RFS - time to recurrence or death), and recurrence-free interval (RFI - time to recurrence censoring for death). Cox models stratified by study controlled for gender, stage, age, and treatment type (rx) to determine the effect of race. Kaplan-Meier estimates (KM) were adjusted (adj) by the Xie-Liu method for study, gender, stage, age, and rx. Results: A pts (n=1134, 8.4%) were younger than W (median 58 vs 61, p&lt;0.001) and more likely female (55 vs 45%, p&lt;0.001). A pts had poorer OS than W pts ( table ). OS results were consistent in subsets defined by gender, stage, and age. RFS results were attenuated compared to OS, but still favored improved RFS in W pts ( table ). RFI results were further attenuated and not significantly different by race ( table ). Conclusions: Even with identical rx for CC in controlled clinical trials, A pts have poorer OS and RFS than W pts. The OS deficit was consistent across subgroups, and neither deficit was explained by differences in gender, stage, age, or rx. RFI was similar for both races, suggesting that the OS and RFS differences may be largely due to deaths unrelated to CC. [Table: see text] [Table: see text]
Relationship between insulin-like growth factor-1 and human testicular cancer
Authors: A. H. Kortsaris, N. Diamantopoulos, G. Galaktidou, C. Andreadis, A. L. Boutis, C. Zavos, D. Mouratidou
Journal: Journal of Clinical Oncology (2006)

4586 Background: Insulin-like growth factor (IGF) has an established role in various types of cancer inducing cellular proliferation, possessing anti-apoptotic properties, and stimulating angiogenesis. We have recently published the concept that IGF-1 system might also be implicated in the pathogenesis of testicular germ cell tumors. The present study aims to elucidate our initial concept by measuring IGF-1, IGF-binding protein (IGFBP)-3, and their molar ratio in patients with testicular cancer. Methods: We measured serum IGF-1 and IGFBP-3 using solid phase Elisa in 48 patients (mean age 31,6±8,07 years) with testicular cancer who underwent chemotherapy, and in 10 healthy male, age-matched (mean age 31.2 ± 2.54), controls. Three serum samples were obtained from patients with testicular cancer: prior to chemotherapy (baseline), before cycle 3, and 9–14 months after completion of chemotherapy. One serum sample was obtained from controls. Results: Baseline mean serum IGF-1, IGFBP-3, and molar ratio IGF-1:IGFBP-3 were 254.3 ± 242 ng/ml, 3541 ± 1740 ng/ml, and 0.293 ± 0.268 in patients, and 145.8 ± 110 ng/ml, 5440 ± 3504 ng/ml, and 0.108 ± 0.168 in controls (p = 0.048, p = 0.016, and p = 0.047, respectively). Mean IGF-1, IGFBP-3, and IGF-1:IGFBP-3 before cycle 3 were 242.4 ± 177.6 ng/ml, 3606 ± 2491 ng/ml, and 0.28 ± 0.234 (p = NS in all 3 parameters). Not all 48 patients have as yet completed chemotherapy; however, preliminary results from 10 patients show a trend for normalization in mean values of the third sample (IGF-1: 157.5 ± 129.4 ng/ml, IGFBP-3: 4500 ± 2351 ng/ml, and IGF-1:IGFBP-3: 0.141 ± 0.128), comparable to those of healthy controls. A trend for higher baseline IGF-1 values was noticed in patients with poor prognosis (n = 6, IGF-1: 367.5 ± 228.7 ng/ml) compared to those with good prognosis (n = 28, IGF-1: 211.1 ± 207.8 ng/ml). Conclusions: These results confirm our initial concept that IGF-1 system may play a significant role in testicular cancer. The trend showing that chemotherapy decreases IGF-1, IGFBP-3, and their ratio to normal, may provide evidence that these parameters can be useful surrogate markers for diagnosis and surveillance of testicular tumor growth. No significant financial relationships to disclose.
POT1 GERMLINE MUTATIONS MAY EXPLAIN A SUBSET OF FAMILIAL GLIOMA : A REPORT FROM THE GLIOGENE CONSORTIUM
Authors: Melissa Bondy, Matthew Bainbridge, Shalini Jhangiani, Ali Jalali, Sharon E. Plon, Georgina Armstrong, Jonine Bernstein, Elizabeth Claus, Faith Davis, Richard Houlston, Dora Il'yasova, Robert Jenkins, Christoffer Johansen, Daniel Lachance, Rose Lai, Ching Lau, Ryan Merrell, Sara Olson, Siegal Sadetzki, Joellen Schildkraut, Sanjay Shete, Jill Barnholtz-Sloan, Margaret Wrensch, Beatrice Melin, Richard A. Gibbs
Journal: Neuro-Oncology (2013)

POT1 GERMLINE MUTATIONS MAY EXPLAIN A SUBSET OF FAMILIAL GLIOMA : A REPORT FROM THE GLIOGENE CONSORTIUM
Ovarian tumours associated with pregnancy
Authors: E. V. Bakhidze
Journal: Journal of Clinical Oncology (2006)

15063 Background: Ovarian cancer occurs in 1.5–5.6% of all combination of malignant tumours and pregnancy. The purpose of this study was to review patients with ovarian tumours in pregnancy, the efficiency of the available methods of treatment and their prognosis. Methods: A retrospective research of the data about 52 patients with ovarian tumours associated with pregnancy who were operated in The N.N.Petrov Research Institute of Oncology from 1960 to 2002. Results: From 52 patients with ovarian tumours associated with pregnancy there were 40 patients (76.9%) with benign tumours and 12 patients (23.1%) with malignant tumours. Middle age of patients was 24.9 ± 5.2 years. Among malignant tumours there were 4 epithelial tumours, 7 herm cell tumours (6 were dysgerminoma and 1 choriocarcinoma) and 1 sex cord-stromal tumour. 9 patients had I stage, 2 had II stage and 1 patient had III stage by FIGO. 14 patients with benign and 7 patients with malignant tumours was operated during the pregnancy: 13 patients (9 with benign, 4 with malignant tumours) were operated during I trimester, 4 patients (3 with benign, 1 with malignant tumours) were operated during II trimester and 4 patients (2 with benign, 2 with malignant tumours) were operated during III trimester of pregnancy. 26 patients with benign tumours and 7 patients with malignant tumours were operated after delivery or abortion. All patients with benign tumours were treated by unilateral salpingoophorectomy. 6 patients with malignant tumours were treated by organ-preserving operations. The 5-year free reccurance survival rate was 83.3% in patients operated during I trimester both for radical and organ preserving operations. The 5-year free reccurance survival rate was 50% in patients operated during II, and 33.3% in patients operated during III trimester. In 6 patients with Ia stage dysgerminoma associated with pregnancy the 5-year free reccurance survival rate was 100%. Conclusions: Benign ovarian tumours associated with pregnancy occur in much more cases (76.9%). Among malignant ovarian tumours the non-surface epithelial tumours occur more often (66.6%). The majority of patients with malignant ovarian tumours who were operated during pregnancy had I stage by FIGO (75%). Prognosis depended not on but on stage and hystotype of tumour and trimester of pregnancy in which patients were operated. No significant financial relationships to disclose.
Association of personal and family history with decision to undergo risk-reducing salpingo-oophorectomy in <i>BRCA</i> mutation carriers
Authors: N. D. Kauff, E. Wadsworth, D. J. Goldfrank, M. E. Robson, J. Lee, K. Lafaro, S. Aaron, L. Norton, R. R. Barakat, K. Offit
Journal: Journal of Clinical Oncology (2005)

9560 Background: BRCA mutations carriers are at substantially increased risk to develop both breast and ovarian cancer. Current risk-reduction recommendations include consideration of risk-reducing salpingo-oophorectomy (RRSO) once childbearing is complete. Despite evidence supporting the efficacy of this approach, many patients do not pursue this option. In order to further evaluate this issue, we examined predictors of RRSO uptake in a large cohort of prospectively ascertained BRCA mutation carriers. Methods: Medical records of all women with a BRCA1 or BRCA2 mutation identified between 6/1995 and 12/2003 with ovarian tissue at risk and enrolled on one of two prospective follow-up studies were evaluated. Univariate analysis of demographic variables hypothesized to be predictive of RRSO uptake was performed. Variables significant in univariate analysis were analyzed in a multivariate logistic regression model. Results: Of 339 women meeting the study criteria, 213 (62.8%) elected to undergo RRSO after receiving genetic testing results. On univariate analysis, age ≥ 40 (Odds Ratio (OR) 5.99, 95% CI [3.67, 9.78]}, personal history of breast cancer (OR 2.09, [1.33, 3.27]), parity (OR 2.43, [1.49, 3.94]) and post-menopausal status (OR 3.11, [1.89, 5.13]) were predictive of uptake of RRSO. Family history of breast (OR 0.72, [0.46, 1.13]) or ovarian cancer (OR 1.60, [0.87, 3.00]) in a 1st degree relative was not predictive of RRSO uptake. On multivariate analysis, only age ≥ 40 (OR 4.92, [2.69, 9.00]) or history of a live birth (OR 2.25, [1.29, 3.90]) were predictive of uptake of RRSO. Conclusions: The decision to undergo RRSO in BRCA mutation carriers was not significantly impacted by personal history of breast cancer or family history of breast or ovarian cancer. Thus, other factors most likely play a central role. Given the high uptake of RRSO in this series, it appears that risk notification based in genetic counseling is highly effective in influencing preventive behaviors, independently of all other factors except age and parity. No significant financial relationships to disclose.
Abstract 19698: Altered Dendritic Cell Network in Chronic Heart Failure - Implications for Chronic Inflammation
Authors: Mohamed Ameen Mohamed Ismahil, Tariq Hamid, Guihua Zhou, Justin R Kingery, Sumanth D Prabhu
Journal: Circulation (2012)

Although activation of Th1 inflammatory pathways is a hallmark of chronic heart failure (HF), underlying changes in immune effector cells are poorly understood. Dendritic cells (DCs) are orchestrators of T-cell polarization, and thereby can regulate Th1 and Th2 responses. We hypothesized that alterations in the local and systemic DC network, and tissue DC trafficking, underlie the pro-inflammatory state in HF. Post-infarction HF was studied in adult C57BL/6 mice 8 wks following left coronary ligation; sham operated mice served as controls. Pathological remodeling and HF were verified by echocardiography, hemodynamics, gravimetry and histology. Cardiac interstitial cells were isolated by collagenase digestion of the heart followed by density gradient centrifugation; standard isolation procedures were used to isolate splenic, BM, and PB cells. We characterized two major DC subsets using flow cytometry: 1) classical DCs (cDCs, CD11c+B220-) that initiate adaptive immune responses and enhance interferon production from T cells, and 2) plasmacytoid DCs (pDCs, CD11c+B220+) that upon proper stimulation can produce pro-inflammatory cytokines that polarize T cells to a Th1 phenotype or, alternatively, suppress adaptive immunity. Compared with sham-operated mice, HF mice exhibited significantly (p &lt; 0.05) increased cDCs in PB (3.65±0.34 vs 1.36±0.27%), spleen (3.65±0.41 vs 2.35±0.22%), and heart (4.22±0.15 vs 3.1±0.40%), but no changes in BM. A major cDC subset, CD11c+B220-CD8+ cells, preferentially endocytose dying cells and stimulate Th1 CD4+ T cell responses. In HF mice, these cDCs significantly (p &lt; 0.01) increased in PB (0.17±0.018 vs 0.053±0.017%) and spleen (0.35±0.035 vs 0.21±0.027%). Additionally, there were significant (p &lt; 0.05) increases in pDCs in the heart (2.55±0.44 vs 0.60±0.30%), spleen (2.32±0.40 0.90±0.11%) and BM (1.30±0.10 vs 1.02±0.08%), but no changes observed in PB as compared with sham. Hence, we conclude that in HF, there are augmented cDCs and pDCs locally in the heart and selective alterations in the PB, spleen, and BM that together support the development of systemic Th1 responses. A better understanding of DC networks in HF can elucidate the mechanisms of pathological inflammation and lead to novel therapeutic approaches.
Integration of oncology palliative care in a regional health care system.
Authors: Connie Edelen, Nicole Koesel
Journal: Journal of Clinical Oncology (2014)

34 Background: Early incorporation of palliative medicine in cancer care has been shown to be associated with improved symptom control, quality of life, and patient and family satisfaction however integration in the outpatient setting remains deficient nationwide. Regional healthcare systems carry the additional challenge of providing consistent quality care across a diverse geographic area. We performed a retrospective review of oncology palliative care utilization in a regional healthcare system following the implementation of a fully integrated model of palliative care. Methods: In 2012, Levine Cancer Institute (LCI) and Carolinas Palliative Care collaborated to establish palliative care access across its 12-site regional cancer center. This was a transition from a vendor service to a fully embedded clinic at multiple LCI locations. The new model offered full time outpatient multidisciplinary services in addition to an inpatient oncology palliative care consult service. Standardization of care and early integration were augmented by the creation of symptom management guidelines and tumor treatment pathways with built in recommendations for palliative/supportive care. Results: New oncology palliative care referrals increased from 150 annually to over 475 in the first 12 months. The top diagnoses were lung (16%), breast (11%), and head and neck cancer (7.2%) with pain and symptom management as the primary reason for consultation. Ten symptom management pathways have been published for regional utilization, enabling primary palliative care and serving as a trigger for palliative specialist consultation. A toolkit was created to identify operational needs, clinical tools, and staffing at each site. Conclusions: The growth of oncology palliative care utilization by 317% demonstrates the success of a fully embedded program. This multidisciplinary model is being standardized across regional sites to ensure access to primary and secondary palliative care. Additional clinic sites and the application of telemedicine for rural areas are in development. Future research is needed to document outcomes associated with palliative care integration across the cancer trajectory in a regional healthcare system.
Rituximab resistance and its association with changes in the internal domain of CD20 antigen and down-regulation of pro-apoptotic protein Bax and Bak in both rituximab-resistant cell lines (RRCL) and diffuse large B-cell lymphoma (DLBCL) patient (pt) samples
Authors: N. M. Reddy, F. J. Hernandez-Ilizaliturri, S. Olejniczak, J. Knight, M. S. Czuczman
Journal: Journal of Clinical Oncology (2006)

17509 Background: Resistance to rituximab (R) has been observed in lymphoma pts. To define the molecular basis for rituximab resistance we developed various RRCL and previously demonstrated changes in CD20 structure, membrane reorganization following rituximab exposure and deregulation of pro-apoptotic proteins Bax/Bak leading to rituximab/chemotherapy resistance. In our current work we evaluated changes in the structure/expression of CD20 and/or pro-apoptotic proteins in primary tumor specimens from DLBCL pts treated with rituximab in combination with CHOP (R-CHOP). Methods: We obtained frozen lymphoid material from patients with DLBCL who achieved a remission (sensitive lymphoma) or failed (resistant lymphoma) R-CHOP therapy. Protein lysates were obtained from each sample. Structural changes in CD20 were determined by Western blotting using various antibodies recognizing epitopes located in the internal (GST77 and 1439) and external domain (rituximab) of CD20. In addition, we studied the expression of Bax and Bak. Results: Variability in the expression and structure of CD20 was found in the pt samples. Rituximab binding to its surface CD20 antigen was preserved in all patients. However, differences in C- and N-terminal expression were found across DLBCL specimens. In addition, down-regulation of Bax/Bak was observed in some pts with resistant lymphomas. Patients who responded to R-CHOP were noted to either have an intact CD20 and/or express Bax/Bak. On the other hand, resistant lymphomas had altered CD20 isoforms and a downregulation of Bax/Bak. Conclusions: Our current preliminary data suggests a positive correlation to our pre-clinical data generated from B-cell NHL cell-lines and will be evaluated in a larger number of primary NHL tumor specimens. No significant financial relationships to disclose.
Abstract 12340: Enhancing the Diagnosis of Coronary Artery Disease via Deep Sequencing of Whole Blood
Authors: Benjamin K Yang, Justin Ertle, Ian Toma, Palak Shah, Soheil Sadri, Nahal Konjedi, Ramesh Mazhari, Jonathan Reiner, Richard Katz, Georges St. Laurent, Tim McCaffrey
Journal: Circulation (2012)

Objective: To discover specific and unique RNA transcripts expressed in patients who develop coronary artery disease (CAD). Methods: Venous whole blood was collected from 110 patients without a his...