tbuckley/cabot-search huggingface dataset:
Abstract 18180: Excellent Negative Predictive Value of Pulmonary Vein CT Angiogram in Detecting Left Atrial Appendage Stasis and Thrombus in a Large Clinical Cohort
Authors: Lin Wang, Elana Koss, Kathleen Rapelje, Stephanie Kampfer, Hong Meng, Nathaniel Reichek, Joseph Levine, Kadiyala Madhavi, Jie J Cao
Journal: Circulation (2014)

Background: While TEE is well established for detection of left atrial appendage (LAA) stasis and thrombus the role of pulmonary vein CT angiography (CTA) is controversial. We investigated the negative predictive value (NPV) of pulmonary vein CTA in detecting LAA stasis and thrombus in a large clinical cohort. Methods: Consecutive patients with a history of atrial fibrillation (AF) who had undergone pulmonary vein CTA and TEE within 24 hours were reviewed. TEE findings included LAA stasis (grade 1 to 4) and thrombus. Negative TEE findings were defined as no or grade 1 stasis and the absence of thrombus. CTA was performed using a bolus tracking protocol without ECG gating. In addition to qualitative evaluation of LAA filling defects, signal intensity of the LAA tip and ascending aortic blood signals were assessed. Using TEE as a reference standard, CTA was assessed for its NPV in detecting LAA stasis and thrombus. Result: In 833 patients, the median age was 61±11 years and 75% were male. During TEE 40% of patients were in AF or atrial flutter. There were 809 (97.1%) negative TEEs, 10 (1.2%) with grade 2 stasis, 9 (1.1%) with grade 3, and 5 (0.6%) with grade 4. Two patients with thrombi also had grade 4 stasis. Among 670 CTA negative patients, 669 (99.9%) were negative by TEE with only one false negative with grade 2 stasis by TEE. The NPV of CTA was excellent (99.9%) while the positive predictive value (PPV) was limited (14.1%) due to frequent false positive findings which did not differ significantly between patients in AF and patients in normal sinus rhythm. Quantitative analysis of signal intensity in the LAA tip did not improve PPV significantly, while the NPV remained high. Receiver operating characteristic analysis showed that the PPV and NPV using an LAA tip blood signal intensity cutpoint of ≤100 HU or a ratio of LAA tip/aorta blood signal intensity of ≤0.59 were 26%, 92%, and 12%, 100%, respectively. Conclusion: While PPV is limited, pulmonary vein CTA has excellent NPV and is a promising alternative to TEE for exclusion of clinically significant LAA stasis and thrombus. Confirmation of these findings in prospective multicenter clinical trials may lead to substantial reductions in the need for TEE in management of AF.
The state of systemic immune dysfunction in patients with metastatic melanoma
Authors: W. K. Nevala, C. Vachon, C. Scott, A. Leontovich, S. N. Markovic
Journal: Journal of Clinical Oncology (2008)

9067 Background: Immunotherapeutic strategies are often used for the treatment of patients with advanced melanoma. Although successful in pre-clinical models, clinical efficacy remains limited. One explanation for this discrepancy is the state of the host’s immune system (immunocompetent mouse vs immunocompromised cancer patient). We’ve previously reported that repeated peptide immunization of patients with metastatic melanoma lead to peptide-specific tolerance, not active immunity, which correlated with tumor progression. Further studies revealed that plasma from patients with advanced melanoma inhibited normal dendritic cell function in vitro, indicating the existence of a soluble mediator of immune dysfunction. These observations lead to our current effort to understand the differences in immune homeostasis in patients across stages of melanoma. Methods: Immune homeostasis was ascertained by analysis of relative frequencies of NK, dendritic and T-cells present in peripheral blood, plasma levels of 27 cytokines, and the functional state of antigen specific T-cells in 85 patients with benign and/or dysplastic nevi, 72 patients with stage I- III melanoma and 32 with stage IV melanoma. Matched expression array analysis of tumor biopsies from 19 of the 32 stage IV melanoma patients was performed as well. The data was analyzed using analysis covariance, adjusting for age, gender, and batch with logarithmic or square root transformation of parameters to achieve normality. Results: Notably, the cytokine levels for the Th2 cytokines, IL-4 (78 vs 4.4pg/ml), IL-10 (14 vs 3.8pg/ml), and IL-13 (13 vs 2.3pg/ml), in tumor bearing (stage IV) versus early stage (benign nevi-stage III) patients were significantly higher (p-value<0.02). Matched expression microarray analysis revealed that tumor cells transcribe immunologically relevant molecules that could contribute to the observed Th2 dominant state of systemic chronic inflammation. Conclusions: Tumor bearing, unlike tumor free or non-melanoma patients, appear to exhibit a state of systemic Th2 dominance (chronic inflammation) potentially explaining some of the observed immune dysfunction and poor clinical outcomes of immunotherapeutic interventions in patients with stage IV melanoma. No significant financial relationships to disclose.
Phase I trial of the epothilone B analog BMS-247550 (ixabepilone) in children with refractory solid tumors
Authors: B. C. Widemann, E. Fox, W. J. Goodspeed, A. Goodwin, M. Cohen, T. Fojo, A. D. Colevas, F. M. Balis
Journal: Journal of Clinical Oncology (2005)

8529 Background: The epothilone B analog ixabepilone is a novel non-taxane microtubule stabilizing agent with in vitro and in vivo activity in adult and pediatric cancer models that are naturally insensitive to paclitaxel or have developed resistance to paclitaxel. In adults, the maximum tolerated dose (MTD) on a daily x 5 days (d) q 21d schedule was 6 mg/m2/d IV over 1 hour. Dose limiting toxicity (DLT) was neutropenia. Methods: Children (median age, 9.5yr; range, 2–18yr), with refractory solid tumors (osteosarcoma n=2, rhabdomyosarcoma n=2, Wilms tumor n=2, hepatoblastoma n=2, other sarcoma n=5, other n=3) were entered on this phase I trial to determine the toxicity profile, DLTs, MTD, and pharmacokinetics (PK) of ixabepilone on the daily x 5 d q 21d schedule. The starting dose level was 3 mg/m2/d (n=3), with escalations to 4.5 (n=4), 6 (n=3), 8 (n=3), and 10 (n=3) mg/m2/d. PK sampling was performed after the first dose, and plasma concentrations were assayed with LC/MS/MS. Dose levels and PK sampling times were identical to the adult daily x 5 d phase I trial. Results: No DLTs (grade ≥3 non-hematologic toxicity, or grade 4 neutropenia for ≥5 days, or grade 4 thrombocytopenia on ≥2 days) were observed at dose levels 1–4 during the first treatment cycle. At dose level 5 (10 mg/m2/d) the MTD was exceeded with dose-limiting neutropenia (n=1) and fatigue (n=1) in 2 patients. The 8 mg/m2 dose level is being expanded to 6 patients. Grade ≥2 non-DLTs during cycle #1 included gr. 3–4 neutropenia (n=7), gr. 2–3 anemia (n=8), gr. 2 fatigue (n=2), and gr. 2 constipation (n=2). Sensory neuropathy (n=4) and thrombocytopenia (n=4) did not exceed gr.1. Five patients had stable disease for 2–13 cycles (median, 5). The mean terminal half-life of ixabepilone (14.8±6h), the volume of distribution at steady state (352 L/m2), and the clearance (489 ml/min/m2) (n=9), were similar to adult values. Conclusions: Ixabepilone is well tolerated in children on the daily x5d schedule at doses exceeding the adult MTD. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb
Docetaxel Administered on a Weekly Basis for Metastatic Breast Cancer
Authors: Harold J. Burstein, Judith Manola, Jerry Younger, Leroy M. Parker, Craig A. Bunnell, Rochelle Scheib, Ursula A. Matulonis, Judy E. Garber, Kathryn D. Clarke, Lawrence N. Shulman, Eric P. Winer
Journal: Journal of Clinical Oncology (2000)

PURPOSE: To evaluate the safety and efficacy of weekly docetaxel in women with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women were enrolled onto a study of weekly docetaxel given at 40 mg/m 2 /wk. Each cycle consisted of 6 weeks of therapy followed by a 2-week treatment break, repeated until disease progression or removal from study for toxicity or patient preference. Fifty-two percent of patients had been previously treated with adjuvant chemotherapy; 21% had received prior chemotherapy for metastatic breast cancer, and 31% had previously received anthracyclines. All patients were assessable for toxicity; two patients were not assessable for response but are included in an intent-to-treat analysis. RESULTS: Patients received a median of 18 infusions, with a median cumulative docetaxel dose of 720 mg/m 2 . There were no complete responses. Twelve patients had partial responses (overall response rate, 41%; 95% confidence interval, 24% to 61%), all occurring within the first two cycles. Similar response rates were observed among subgroups of patients previously treated either with any prior chemotherapy or with anthracyclines. An additional 17% of patients had stable disease for at least 6 months. The regimen was generally well tolerated. There was no grade 4 toxicity. Only 28% of patients had any grade 3 toxicity, most commonly neutropenia and fatigue. Acute toxicity, including myelosuppression, was mild. Fatigue, fluid retention, and eye tearing/conjunctivitis became more common with repetitive dosing, although these side effects rarely exceeded grade 2. Dose reductions were made for eight of 29 patients, most often because of fatigue (n = 5). CONCLUSION: Weekly docetaxel is active in treating patients with metastatic breast cancer, with a side effect profile that differs from every-3-weeks therapy.
A phase I study of IV aflibercept (Afl) in combination with R-CHOP in untreated patients (pts) with B-cell lymphoma.
Authors: F. Kuhnowski, C. Thieblemont, F. Jardin, F. Broussais-Guillemot, M. Meignan, J. Cabecadas, P. Gaulard, H. Tilly, C. Oprea, C. Haioun
Journal: Journal of Clinical Oncology (2010)

8010 Background: In malignant lymphoma, angiogenesis has been associated with adverse outcome or more aggressive clinical behavior. This correlation has been established in groups of patients with a large heterogeneity regarding lymphoma subtypes and treatment regimens. Afl is an angiogenesis inhibitor that inactivates circulating VEGF. Methods: This phase I study was designed to evaluate the safety and preliminary anti- tumor activity of Afl when administered in combination with R-CHOP every 3 weeks (R-CHOP21), for 6-8 cycles in B-cell lymphoma. Biomarkers (endogenous VEGF, CD31, CD34, microvessel density, VEGF-R, endothelial progenitor cells) were also explored. Results: Between March 2008 and March 2009, 25 pts (M/F 15/10), median age 62 (range 37-78), were treated with Afl dose levels of 3 mg/kg (DL1, N=3) and 6 mg/kg (DL2, N=22) combined with R-CHOP21. Lymphoma histology types were: diffuse large B-cell (DLBCL) (N=15), follicular (N=8), mantle cell (N=1) and marginal zone (N=1). The Ann Arbor stage at diagnosis was I-II (7 pts) and III-IV (18 pts). Eighty percent of pts had elevated endogenous VEGF values at baseline (superior to 30 pg/mL).Main grade 3 or 4 study drug related AEs included hypertension (N=8), febrile neutropenia (N=4) and asthenia (N=4) and were present only at dose level 6 mg/kg. One dose limiting toxicity at DL2 was observed: grade 3 headache and arthralgia. No proteinuria and no other major cardiovascular events were reported.Main specific related AE was grade 1/2 reversible dysphonia (18 pts). Response rate at the end of the treatment based on IWC and PET criteria (Cheson. JCO. 2007.) was: 80% complete responses and 20% partial responses. PFS and biomarkers data will be provided. Conclusions: The selected dose of 6 mg/kg of Afl used in all on-going phase III trials in combination with R-CHOP21 is feasible and well tolerated in B-cell lymphoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis
Do socioeconomic factors and insurance explain racial/ethnic disparities in receipt of recommended breast cancer care?
Authors: R. A. Freedman, K. S. Virgo, Y. He, A. Pavluck, E. P. Winer, E. M. Ward, N. L. Keating
Journal: Journal of Clinical Oncology (2010)

574 Background: Few data are available about how race/ethnicity, insurance, and socioeconomic status (SES) interrelate to influence breast cancer treatment. We examined care for a large national cohort of breast cancer patients to assess whether insurance and SES explained racial/ethnic differences in care. Methods: Among 662,117 white, black, and Hispanic women diagnosed with invasive breast cancer during 1998-2005 at hospitals reporting to the National Cancer Database, we used multivariable logistic regression to assess the probability of definitive locoregional therapy, hormone receptor testing, adjuvant hormonal therapy, and adjuvant chemotherapy, adjusting for patient and tumor characteristics. In additional models, we included insurance and area-level SES to determine whether these variables explained observed racial/ethnic disparities. Results: Most women were white (86%), 10% were black, and 4% were Hispanic. Most had private insurance (51%) or Medicare (40%). Among eligible patients, 80% of stage I/II patients had definitive locoregional therapy, 98% of stage I-IV patients had hormone receptor testing, and 53% and 50% of stage I-III patients received adjuvant hormonal therapy and chemotherapy, respectively. In adjusted models, black (vs. white) women had lower odds of definitive locoregional therapy (odds ratio [OR] = 0.91; 95% CI = 0.88-0.94), adjuvant hormonal therapy (OR = 0.90; 95% CI = 0.87-0.93), and adjuvant chemotherapy (OR = 0.88; 95% CI = 0.84-0.91). Hispanic women also had less adjuvant hormonal therapy than white women (p = 0.009). Hormone receptor testing did not differ by race/ethnicity. Insurance was associated with definitive locoregional therapy and adjuvant systemic therapies while area SES was not associated with any outcome. Racial disparities persisted despite adjusting for insurance and SES, although differences for definitive locoregional therapy and chemotherapy were slightly attenuated. Conclusions: Insurance and SES explained very little of the racial/ethnic differences in receipt of recommended breast cancer therapies. Further study is required to better understand the reasons for disparities and to assure receipt of standard care. No significant financial relationships to disclose.
Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group.
Authors: K I Pritchard, A H Paterson, N A Paul, B Zee, S Fine, J Pater
Journal: Journal of Clinical Oncology (1996)

Associations between thromboembolism and malignancy, usually widespread, and between thromboembolism and hormonal and/or chemotherapy have been previously reported. We performed a randomized trial of tamoxifen 30 mg/d for 2 years (T) versus T plus 6 months of intravenous chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) for postmenopausal women with involved axillary nodes and positive estrogen receptor (ER) or progesterone receptor (PgR) status following primary therapy for breast cancer.We observed one or more thromboembolic events in 48 of 353 women (13.6%) allocated to receive T plus CMF in comparison to five of 352 women (2.6%) randomized to receive T alone (P < .0001). Six women in the T plus CMF arm, but none randomized to receive T alone, suffered two thromboembolic events while an study therapy. There were also significantly more women who developed severe (grade 3 to 5) thromboembolic events in the T plus CMF arm than in the T arm (34 v five; P < .0001). Most thromboembolic events (39 of 54) occurred while women were actually receiving chemotherapy (P < .0001). Thromboembolic complications resulted in more days in hospital and more deaths than any other complication of therapy, including infection, in this trial.Thromboembolism related to the addition of CMF chemotherapy to tamoxifen as adjuvant therapy in this group of women represents a relatively common and serious complication that may outweigh any benefits offered by this additional therapy.
Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer.
Authors: M A Cobleigh, K Dowlatshahi, T A Deutsch, R G Mehta, R C Moon, F Minn, A B Benson, A W Rademaker, J B Ashenhurst, J L Wade
Journal: Journal of Clinical Oncology (1993)

PURPOSE Considerable attention has been focused on the chemopreventive properties of fenretinide against carcinogen-induced rodent mammary cancer. Less is known about its direct antitumor effects. The combination of tamoxifen and fenretinide is more effective than tamoxifen or fenretinide alone in prevention of rat mammary cancer. However, the combined toxicity of tamoxifen plus fenretinide in humans is unknown. Therefore, we performed a phase I/II trial in women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, previously untreated metastatic breast cancer. PATIENTS AND METHODS Groups of three patients received tamoxifen 20 mg/d, or tamoxifen plus fenretinide 100, 200, 300, or 400 mg/d. Patients who received fenretinide enjoyed a 3-day "drug holiday" every 4 weeks. Serum levels of fenretinide and its major metabolites were monitored. Patients were monitored for known toxicities of tamoxifen and vitamin A analogs, as well as for response. RESULTS There were no significant adverse effects on renal, hepatic, hematologic, or lipid values. Nyctalopia, photophobia, cheilitis, and pruritus were not observed. Improvement or stabilization of disease occurred in 12 of 15 patients. CONCLUSION We conclude that tamoxifen administered with fenretinide is nontoxic. Phase III trials of tamoxifen versus tamoxifen plus fenretinide are warranted.
Abstract 14020: Effect of Endothelial Specific Overexpression of a Destabilized Endothelial Nitric Oxide Synthase Variant on Blood Pressure and Vascular Endothelial Function
Authors: Stephanie Kumpf, Tatsiana Suvorava, Marc Oppermann, Martina Weber, Georg Kojda
Journal: Circulation (2012)

Essential hypertension is associated with endothelial dysfunction and reactive oxygen species (ROS) are considered to play a role here. To investigate whether dysfunctional vascular eNOS might contribute to the regulation of blood pressure we overexpressed two different eNOS variants by the endothelial specific tie-2 promoter. Hence wildtype eNOS (eNOS-tg) or respectively a destabilized eNOS (C101A-eNOS-tg) were introduced into the vasculature of C57BL/6 mice. Destabilization of eNOS was induced via replacement of a cysteine residue by alanine resulting in impaired eNOS dimer stability, increased superoxide and decreased NO biavailability in stably transfected HEK cells. Western blot analysis e.g. in aortic tissue proved the vascular specific overexpression of eNOS in C101A-eNOS-tg (149.7±8%, n=8, p<0.05) and eNOS-tg (228.7±15%, n=6, p<0.05) compared to transgene negative littermates. Superoxide levels were increased in C101A-eNOS-tg (214.1±30%, n=5, p<0.05) but not in eNOS-tg (89.4±8%, n=6; both vs. cont...
Lung cancer in women: The Spanish female-specific database WORLD 07
Authors: N. Vinolas, M. Magem, P. Garrido, A. Artal, J. De Castro, R. G. Campelo, D. Isla, E. Felip, M. Amador, R. Rosell
Journal: Journal of Clinical Oncology (2009)

8084 Background: Lung cancer is the leading cause of cancer mortality among women in many countries. Gender differences have been reported, most of them based on retrospective analysis. Methods: WORLD07 is a prospective, multicenter, epidemiologic female-specific lung cancer database developed by the Spanish Lung Cancer Group. Data on demographics, previous cancer history, reproductive and hormonal status, diet, alcohol, tobacco, and occupational information are being collected just as histology, stage, treatment and survival. Results: From October 2007 to Nov 2008, 342 female newly diagnosed of lung cancer were collected in an e-database in 20 Spanish centers. Patients (p) characteristics are: median age 61.7 years (y) (range: 36 - 87); Caucasian: 98.2%; Marital status (%): married 67.7, unmarried 11.2, divorced 7.1, widow 14. Educational level (%): basic 57.4, secondary 29.1, university 13.5. Median age of menarche 12.7 y. Children: 79.4% (median: 2); Median age of first child 27 y. Oral contraceptive: 30.6%. Pre-menopausal 15.4%,postmenopausal 84.6%. Median age of menopause 46.7 y. HRT: 5.3%. Median duration of HRT: 4.4 y. Obesity: 11.3%. Smoking habit (%): never (passive smoker/no exposition)/former/current smokers: 42 (42.8/57.2) /19 /39; Median packs/year 72.4. Former smokers: 1–5/5–10/10–15/&gt;15 y (%): 51/11.8/7.8/29.4. Work exposure 3.5%. Alcohol consumption 3.2%. Familial history of cancer: 45.5% (lung cancer 29.7%). Previous history of cancer 13.8% (breast 33.3%). Current lung cancer histology (%): adenocarcinoma/BAC/squamous/large cell/NOS: 70.4/5.7/10.4/7.9/5.7. SCLC 11.8%. TNM I/II/III/IV (%): 16/3.9/28.7/51.4. Surgical treatment 24.7 % (lobectomy/pneumonectomy/exploratory: 85.5/9.2/5.3%). Available data of 122 stage IV NSCLC p: 74.6% receive chemotherapy, 92.3% of them two drugs and 68.9 % platinum-based (59% cisplatin). EGFR mutations analysis 7.9%. Conclusions: According this series, 42% of Spanish lung cancer women are never smokers and 70.4% have adenocarcinoma. Other collected information, choice of treatment and survival outcomes will be also analyzed. No significant financial relationships to disclose.
Early evaluation of response to neoadjuvant chemotherapy in stage IIIC-IV epithelial ovarian cancer patients by <sup>18</sup>FDG-PET and CA 125: Preliminary findings from the Arianna Project 02
Authors: N. Cacciari, S. Fanti, C. Zamagni, M. Rosati, F. Massari, A. Musto, F. Rosati, P. De Iaco, B. Melotti, A. Martoni
Journal: Journal of Clinical Oncology (2006)

15039 Background: Early evaluation of response to primary chemotherapy (PSC) in epithelial ovarian cancer (EOC) pts could allow to administer a proper number of cycles in order to obtain optimal results. Arianna Project 02 is aimed to investigate early tumor response to PSC correlating a set of routine and experimental hystological, biological and gene-expression profile data with clinical data before, during and after PSC. Methods: Stage III-IV EOC received 6 cycles of carboplatin AUC 5 and paclitaxel 175 mg/m 2 and are evaluated at baseline and before each cycle by 18 FDG-PET, CA 125, circulating tumor cells and experimental circulating bio-markers. Ultrasounds, CT scan and pelvic MRI are done at baseline and every other cycle. This preliminary report is focused on the correlation between changes of PET and CA 125 serum levels and pathological response. Results: Up to now 6 out of 11 pts completed PSC and surgery. Baseline tumoral 18 FDG uptake expressed as Standardized Uptake Value (SUV) and CA125 were abnormal in all pts (SUVmax range: 12.1–20; CA 125 range: 416–2026 U/ml, upper normal limit 35 U/ml). One complete and 4 partial pathological remissions &gt; 90% and one no change were observed. Mean (with range) SUVmax and CA125 decrease (Δ SUV and Δ CA125) measured after the 1st, 2nd, 3rd and last cycle of PSC in the 5 responders are similar (table). In the non-responder SUV decreased by 63% after the 1st cycle of PSC, but increased to baseline value after the 2nd cycle and remained unchanged until surgery, while CA 125 progressively decreased from 416 U/ml to 47 U/ml. Conclusions: These preliminary findings indicate that the behaviour of PET and CA 125 in responders are similar. More data are necessary to define the role of PET in the early evaluation of response to PSC in EOC pts. The study is still ongoing and the relationship between evaluation performed by PET and CA125 and by CT scan, ultrasound and pelvic MRI will be presented at ASCO meeting. [Table: see text] No significant financial relationships to disclose.