tbuckley/cabot-search huggingface dataset:
A phase II study of first-line single agent of gefitinib in patients (pts) with stage IV non-small cell lung cancer (NSCLC)
Authors: R. Suzuki, Y. Hasegawa, K. Baba, H. Saka, H. Saito, H. Taniguchi, M. Yamamoto, S. Matsumoto, K. Kato, K. Shimokata
Journal: Journal of Clinical Oncology (2005)

7082 Background: Gefitinib has shown modest activity in pts with recurrent NSCLC after platinum-based chemotherapy. However, the activity of gefitinib as first-line chemotherapy remains unknown. We report the results of a phase II study to evaluate the efficacy of a single agent of gefitinib in chemonaive pts with stage IV NSCLC. Methods: Inclusion criteria included: stage IV NSCLC without previous chemotherapy, measurable lesion, 20≤age<75, ECOG PS 0 or 1, PaO2≥70 torr, and adequate bone marrow, renal, and hepatic functions. Patients with interstitial pneumonia were strictly excluded by chest computed tomography. Treatment: Gefinitib was administered orally 250 mg once a day and was continued until there was disease progression or severe toxicity. In these cases, carboplatin and paclitaxel chemotherapy was performed as a second-line treatment. Toxicity Criteria and response was evaluated using NCI-CTC Criteria and RECIST Criteria. Quality of life (QOL), using EORTC-QLQ-C30 and LC-13, was also evaluated before the therapy and at 4, 8, 12, and 24 weeks. Results: Thirty-four pts were enrolled between May 2003 and September 2004, and all of them were eligible. Patient characteristics: male/female = 21/13, median age = 64 (range 43–73), ECOG PS 0/1 = 16/18, and adenocarcinoma/squamous/others = 25/5/4. Nine pts achieved partial response. The response rate was 26.5% (95% CI: 11.7–41.3%). Toxicities: skin rash grade 1 (14), grade 2 (5), grade 3 (1); hepatic toxicity grade 1 (2), grade 2 (4), grade 3 (4); diarrhea grade 1 (6); and no pulmonary toxicities. The Global Health status revealed no significant difference between the therapy (before and at 4, 12, and 24 weeks). For the other scales, improvement of insomnia (at 12 weeks), worsening of hair loss and financial difficulties (at 12 weeks) were observed. Conclusions: The single agent of gefitinib is active in chemonaive pts with advanced NSCLC. Gefinitib is well tolerated in these patients. As for QOL, the global health status was not changed during the therapy. No significant financial relationships to disclose.
Incidence of diagnosed VTE among elderly Americans in the year following stage III or IV colon cancer diagnosis.
Authors: C. D. Mullins, K. A. Bikov, N. C. Onwudiwe, B. S. Seal, N. Hanna
Journal: Journal of Clinical Oncology (2010)

3603 Background: Cancer patients are at increased risk of venous thromboembolism (VTE). VTE risk varies with cancer treatments and patient clinical and sociodemographic characteristics, including age. Methods: Patients older than 65 diagnosed with stage III or IV colon cancer (CC) during 2004 or 2005 within the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database were included. Patients were excluded if they participated in a managed care Medicare plan since administrative claims data from managed care plans are incomplete. Crude rates of VTE during the year following diagnosis by various demographic, clinical and treatment patient characteristics were calculated. Factors associated with VTE incidence were explored in adjusted analyses for the patients without chemotherapy and patients with chemotherapy that preceded VTE. Results: Crude rates of VTE during the year after CC diagnosis were 13.8% across all patients, 17.1% for African Americans, 13.8% for non-Hispanic Whites, 12.8% for Hispanics, and 7.7% for other racial/ethnic groups. VTE rates were 13.2% and 14.7% for stages 3 and 4, respectively. VTE was more common among patients with a VTE during the 12 months before CC diagnosis (38.2%) and those who received any chemotherapy (14.1%), biologics (22.6%) or newer chemotherapy (e.g., irinotecan or oxaliplatin) with or without biologics (16.2%) as compared to a 5FU/L-based regimen. Multivariable logistic regression results confirmed the impact of prior VTE (OR 4.27, 95% CI 3.38-5.39), African American race (OR 1.25, 95% CI 1.02-1.53), and receipt of newer chemo agents and biologics (OR 1.28, 95% CI 1.08-1.52) on increased risk of VTE. Conclusions: Approximately 1 out of every 7 elderly Americans with stage III or IV colon cancer has a VTE diagnosis within the first year following diagnosis. The odds of VTE are impacted by prior VTEs, treatment-related variables, such as chemotherapy and use of biologic agents and demographic characteristics such as African-American race. These results suggest that there is a need to incorporate appropriate VTE prophylaxis regimens into treatment guidelines for these patients to minimize the incidence and sequelae. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis Amgen, Bayer, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Lilly, Merck, Novartis, Pfizer, sanofi-aventis sanofi-aventis Pfizer, sanofi-aventis GlaxoSmithKline, Novartis, Pfizer, sanofi-aventis
Abstract 230: Regional Variation in Intrinsic Mechanics of Arterial Vascular Smooth Muscle Cells in Spontaneously Hypertensive Rats
Authors: Jia-Jye Lee, Lo Lai, Hongyu Qiu, Kevin D Costa
Journal: Circulation Research (2014)

Aims: An increased aortic stiffness is a fundamental manifestation of hypertension (HT). Our previous study showed that intrinsic mechanical properties of aortic vascular smooth muscle cells (VSMC) are an important contributor to the increased large artery stiffness in HT. However, whether VSMC mechanics of smaller arteries is also altered in HT remains unknown. The goal of this study is to test our hypothesis that the VSMC elastic and adhesive properties vary along the arterial tree reflecting the regional heterogeneities of physiological loading and geometric properties of the artery wall. Methods and Results: Primary VSMCs were isolated from the thoracic aorta (TA) and renal artery (RA) of adult spontaneously hypertensive rats (SHR) (16 weeks old, male) and age-matched Wistar-Kyoto normotensive (WKY) rats. Atomic force microscopy (AFM) was used to measure mechanical properties of individual VSMC at 37°C. Local apparent elastic modulus (Eap) was determined using Hertz contact analysis for a cone to model the indentation force curve, and maximum adhesion force (Fad) was obtained from the retraction force curve; results were shown as mean (±SD) (n=10 cells per condition) and compared using two way ANOVA. Eap of VSMCs from the TA was significantly higher in SHR (7.0± 1.3 kPa) vs. WKY (5.3 ± 1.5 kPa; p &lt; 0.001) and Fad was significantly larger in SHR (39.9 7.2 pN) vs. WKY (30.6 10.9 pN; p &lt; 0.01). No difference was found between SHR and WKY in VSMCs from renal artery in terms of Eap (4.5 0.8 kPa vs. 4.8 0.9 kPa; p = 0.59) and Fad (23.1 5.2 pN vs. 28.0 7.0 pN; p = 0.17). Although no difference was observed in cell shape represented by the cellular length:width ratio (p &gt; 0.25), stiffness and adhesion of VSMC from TA were significantly higher vs. RA in SHR (p&lt;0.0001) but not in WKY (P&gt;0.35), indicating that the altered mechanics of VSMC in hypertension is more prominent in the large conduction vessel compared to the small artery. Conclusion: Intrinsic stiffness and adhesion of isolated VSMC are elevated preferentially in the thoracic aorta of SHR rats; the regional variations may associate mechanistically with increased aortic tissue stiffness in hypertension.
Phase I study of PF-03446962, a fully human mab against ALK 1, a TGFβ receptor involved in tumor angiogenesis.
Authors: L. W. Goff, F. G. De Braud, R. B. Cohen, J. Berlin, C. Noberasco, H. Borghaei, E. Wang, D. Hu Lowe, W. J. Levin, C. Gallo-Stampino
Journal: Journal of Clinical Oncology (2010)

3034 Background: Transforming growth factor β (TGF β) is a cytokine able to regulate many biological processes, including tissue development and remodeling, cellular proliferation and survival. At the vascular level, the activity of TGFβ is exerted by selectively binding to its receptor, activin receptor like kinase 1 (ALK-1), through TGFβRII, which triggers a downstream signaling involving intracellular and nuclear proteins (SMADs and Id1) and leading to transcriptional upregulation of pro-angiogenic factors. PF-03446962 is a fully human mAb against ALK-1 with dose dependent antiangiogenic activity as demonstrated in nonclinical studies in a chimera mouse model bearing human tumors xenograft. Methods: A phase 1 trial in patients with solid tumors is ongoing. Primary objective is to identify the MTD; secondary end points include safety profile, PK, antitumor activity, circulating endothelial cells (CEC), soluble proteins related to TGFβ and blood flow evaluation by contrast enhanced ultrasound (CE-US). Results: 23 patients (13 M/ 10 F, ECOG 0-1), have been enrolled. Five dose levels (0.5 to 4.5 mg/kg) have been explored. The sixth cohort is ongoing at 6.75 mg/kg. PF-03446962 is administered IV on day 1, 29 and then q 2 weeks. PK data support the proposed regimen to maintain drug levels over the EC50 over cycles. The t1/2 is 325 hrs at the dose of 4.5 mg/kg. With the exception of asymptomatic pancreatic enzyme elevation and platelets decrease in a single patient treated at 2.0 mg/kg, no grade 3 or 4 adverse events related to the drug have been reported so far. One PR lasting 13 weeks in a patient with hepatocellular carcinoma resistant to anti-VEGF therapy, and SD (27 and 21 weeks) in a thymic carcinoma and pseudomixoma peritonei were observed. CE-US data are suggestive of a reduction in blood flow in metastatic hepatic lesions between screening and day 15 post therapy. Conclusions: PF-03446962 is a first in class mAb targeting ALK-1. Treatment with PF-03446962 has been safe and is well tolerated in the first 5 dose levels. CE-US suggests potential vascular changes in liver metastasis and preliminary evidence of clinical activity was also observed. The study is ongoing and updated results will be presented at the meeting. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer Pfizer Pfizer
Predictors of lymph node count in colon adenocarcinoma.
Authors: K. L. Mathis, R. Pendlimari, E. Green, D. J. Sargent, H. Nelson
Journal: Journal of Clinical Oncology (2010)

3606 Background: Colon cancer (CC) lymph node (LN) count has become a national quality metric for surgery and pathology. We conducted a single institution study, examining 1,941 CC patient (pt) records for pt, tumor, surgeon, and pathology variables to determine whether factors other than surgeon and pathology factors might influence LN counts. Methods: We included all pts undergoing elective segmental colon resection for stage I-III primary CC at Mayo Clinic Rochester from January 1, 1995, through December 31, 2005. Pts with noninvasive and stage IV disease, a known genetic predisposition to develop CC, inflammatory bowel disease, and those undergoing more than a segmental colectomy were excluded, leaving 1941 pts (581 stage I, 730 stage II, 627 stage III). Results: The tumor location was right colon in 1,075 (55%), transverse 135 (7%), left colon 198 (10%), and sigmoid 533 (27%). The median LN number examined was 13 (range 0-70). Results of the univariate analysis are shown in the Table. While the majority of these variables show statistically significant associations with LN count, the R2 values indicate that the associations are weak (e.g. tumor grade only explains 1.4% of variability in the number of LNs examined). Even for the most significant factor associated with LN count, procedure type, median LN count was 17 for right hemicolectomy vs. 12 for other surgery types. Conclusions: In this large, single institution series,LN count was not influenced by surgeon and pathologist volume. Procedure type (right colectomy vs. transverse/left/sigmoid colectomy) and tumor size, although only modestly predictive, were the most important variables predicting LN harvest. Key variables influencing lymph node count are outside the control of the surgeon and pathologist and should be considered in modified quality metrics. Association of pt, tumor, surgical, and pathology variables with LN count Variable p value R2 value Gender 0.004 0.004 Age 0.043 0.002 BMI 0.015 0.003 Diabetes 0.043 0.002 Smoking history 0.004 0.005 Use of immunosuppressive drugs 0.017 0.003 Tumor location <0.0001 0.098 Tumor grade <0.0001 0.014 Tumor size <0.0001 0.059 T stage <0.0001 0.032 Procedure <0.0001 0.108 Specimen length <0.0001 0.050 Surgeon volume (≥100 cases) 0.281 Pathologist volume (≥50 specimens) 0.357 No significant financial relationships to disclose.
Preliminary results of a randomized study of adjuvant radiation therapy in resectable adult retroperitoneal soft tissue sarcomas.
Authors: T J Kinsella, W F Sindelar, E Lack, E Glatstein, S A Rosenberg
Journal: Journal of Clinical Oncology (1988)

Between January 1980 and September 1985, 35 adult patients with resectable retroperitoneal soft tissue sarcomas were entered on a randomized trial comparing two forms of adjuvant radiation therapy. Fifteen patients received the experimental therapy consisting of intraoperative radiotherapy (IORT) to 20 Gy using high-energy electrons followed by low-dose (35 to 40 Gy) postoperative external beam irradiation. Twenty patients received standard therapy consisting of high-dose (50 to 55 Gy) postoperative external beam irradiation. With a minimum follow-up of 15 months, there is no significant difference in the actuarial disease-free survival (DFS) and overall survival (OS) comparing the two groups (median DFS, 34 months; median OS, 38 months). At 5 years follow-up, approximately 40% of patients are alive and 20% of patients remain disease-free. Although there is a trend towards an improvement in in-field local control in the experimental arm, the predominant pattern of failure in both groups was locoregional within the retroperitoneum and/or peritoneal cavity. Acute and late radiation enteritis were significantly reduced in the experimental group. However, four experimental patients developed late (greater than 6 months following treatment) peripheral neuropathy believed related to the use of IORT; all four recovered. We conclude that there is no difference in the therapeutic effectiveness of the combination of IORT and low-dose external beam radiation compared with conventional high-dose radiation as adjuvant treatment in retroperitoneal sarcomas, although the former appears to be less toxic. Newer combined modality treatment strategies are discussed to improve the prognosis in these patients.
What is a clinically significant improvement in the intensity of fatigue among cancer patients?
Authors: S. G. Reddy, E. Pace, T. Zhang, E. Bruera
Journal: Journal of Clinical Oncology (2006)

8560 Background: Fatigue is the most common symptom in cancer patients. The FACIT-F fatigue subscale and the ESAS Fatigue 0–10 are the most commonly used scales for research and clinical care, respectively. However, clinically significant improvement has not been well established. Methods: We reviewed the data from 3 RCTs of fatigue in 194 patients. In all cases patients completed the FACIT-F and ESAS at baseline and Day 8. All patients also provided a global benefit score [1=not beneficial, 7=greatly important] during Day 8 reflecting their global perception of fatigue improvement. All patients who reported their global perception as ≥ 4 [moderate improvement, consistent benefit] were considered to have a clinically significant improvement. We determined the median [25–75% quartiles] change in ESAS and FACIT-F as well as their screening performance when using the clinically significant difference to define responder status. Results: Mean age was 56 ± 12 years. 72 patients [37%] were female. Median baseline FACIT-F and ESAS scores were 18 ± 8 and 7.5 ± 1.7, respectively. Patients who reported a clinically significant improvement had a median [quartiles] change of 4 [3–6 ] in ESAS and 17 [9–25 ] in FACIT-F sub score resulting in a specificity of 72% for ESAS and 93% for FACIT-F, respectively. The sensitivity, positive predictive value and negative predictive value for ESAS were 66%, 56%, and 78%, and for FACIT-F were 52%, 81%, 76%, respectively. The correlation between global benefit score and change in ESAS was 0.57 [p&lt;0.001], global benefit score and change in FACIT-F was 0.61 [p=0.001], and change in FACIT-F and change in ESAS was 0.62 [p≤0.001]. Conclusions: A difference in ≥ 4 in the ESAS and ≥ to 17 in the FACIT-F can be considered clinically significant in patients with cancer fatigue. The FACIT-F score showed higher specificity. Improvements in the FACIT-F score reported in clinical trials of fatigue are frequently not clinically significant. More research is needed to better characterize responder status in cancer fatigue. No significant financial relationships to disclose.
Factors predicting treatment responsiveness and prognosis in node-negative breast cancer. The International (Ludwig) Breast Cancer Study Group.
Authors: A M Neville, R Bettelheim, R D Gelber, J Säve-Söderbergh, B W Davis, R Reed, J Torhorst, R Golouh, H F Peterson, K N Price
Journal: Journal of Clinical Oncology (1992)

PURPOSE An international trial (formerly Ludwig Trial V) has been conducted in 1,275 subjects to ascertain if perioperative chemotherapy is beneficial for node-negative breast cancer patients and to identify subgroups of patients who benefit from this therapy. PATIENTS AND METHODS Node-negative breast cancer patients were randomized to receive either one cycle of perioperative chemotherapy or no adjuvant treatment. A detailed pathology review was conducted in 1,203 of the 1,275 patients enrolled. Stepwise Cox regression analysis was used to search for factors either predicting chemotherapeutic responsiveness and/or influencing disease-free survival (DFS). RESULTS As expected, primary tumor size, grade, and the presence of peritumoral vascular invasion are the most important prognostic factors. Perioperative chemotherapy provides a DFS advantage at 5 years of median follow-up and such treatment is more effective for estrogen receptor-negative than for estrogen receptor-positive tumors, for histologic grade 2 and 3 than for grade 1 tumors, and for patients in whom no axillary lymph node metastases were found even after serial sectioning and review by the Central Pathology Laboratory. CONCLUSION Hormone receptor status and tumor grade are important factors for predicting responsiveness to perioperative chemotherapy in node-negative breast cancer.
Increased internalization of complement inhibitor CD59 may contribute to endothelial inflammation in obstructive sleep apnea
Authors: Memet Emin, Gang Wang, Francesco Castagna, Josanna Rodriguez-Lopez, Romina Wahab, Jing Wang, Tessa Adams, Ying Wei, Sanja Jelic
Journal: Science Translational Medicine (2016)

Reduced protection against complement attack mediates endothelial inflammation in obstructive sleep apnea.
Absolut Lymphocyte Count At Diagnosis Is Predictive Of Survival In Patients With Classical Hodgkin Lymphoma: A Retrospective Multicenter Brazilian Study
Authors: Guilherme Fleury Perini, Egyla M Cavalcante, Joao Garibaldi Rezende, Davimar Miranda Borducchi, Fernanda Cunha Vieira, Danielle Leão Cordeiro Faria, Renato S Tavares, Camila Almeida Amaral, Fabio S P Santos, Nelson Hamerschlak, Karin Zattar Cecyn, Eni Maria Souza, Adriana M. Damasco Penna, Otavio C.G. Baiocchi
Journal: Blood (2013)
Determining relevant biomarkers from tissue and serum that may predict response to single agent lapatinib in trastuzumab refractory metastatic breast cancer
Authors: K. L. Blackwell, H. Burstein, M. Pegram, A. M. Storniolo, V. M. Salazar, J. E. Maleski, X. Lin, N. Spector, S. H. Stein, M. S. Berger
Journal: Journal of Clinical Oncology (2005)

3004 Background: Lapatinib is an oral tyrosine kinase inhibitor that potently inhibits both ErbB1 and ErbB2 tyrosine kinase activity. Results of two Phase II trials in metastatic breast cancer (MBC) suggest activity of lapatinib in trastuzumab (T) pretreated patients. The main objective of this report was a combined biomarker analysis from these two large studies to evaluate correlations between clinical parameters, tissue/serum biomarker expression and response to lapatinib. Methods: Eligible patients had MBC with disease progression following T-containing regimens in the 1st phase II study and were anthracycline, taxane, capecitabine and T exposed in the 2nd phase II study. Tumor tissues were obtained on each patient from the time of most recent biopsy. Using standard IHC techniques, tumors were stained for: ErbB1-4, IGF1R, truncated ErbB2 (p95), heregulin and p-Erk 1/2. Sequential quanitation of extra-cellular domain (ECD) for both ErbB1 and ErbB2 were obtained. Results: Investigator reported efficacy data on the first 81 patients from the combined trials demonstrates a total of 19 patients progression-free at 16 weeks of which 7 achieved an objective response (CR or PR). The mean T exposure in the 1st study was 46 weeks and in the 2nd study 84 weeks. As of Dec 2004, both studies have completed accrual with a total of 215 patients. For the initial 37 tumors analyzed, IHC data indicate only 6/37 patients overexpressed both ErbB1 and ErbB2. To date, over 100 tumor tissues have been collected and tested for ErbB1-4, IGF1R, p95, heregulin, and p-Erk 1/2. Initial data suggest that expression levels of ER, PR and ErbB1 may be related to lapatinib response in T pre-treated patients. Declines of ErbB2 ECD at both week 4 and week 8 appear to predict response to lapatinib. A multivariate analysis for response predictors, including all collected tumors, sequential ECD levels and clinical parameters will be performed. Conclusions: Inhibition of both ErbB1 and ErbB2 with lapatinib represents a promising approach in the treatment of MBC. This analysis of potential predictive molecular phenotypes for response to lapatinib in T-resistant tumors will be the most extensive to date. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline Aventis, Genentech, GlaxoSmithKline GlaxoSmithKline
Immune biomarkers of treatment failure for a patient with renal cell carcinoma on a Phase I trial of pembrolizumab plus radiotherapy
Authors: Gregory Alexander, Joshua Palmer, Madalina Tuluc, Jianqing Lin, D Craig Hooper, Bo Lu
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Pembrolizumab is an antibody designed against programmed cell-death protein-1 (PD-1), which is expressed on the surface of activated T cells. Tumor cells can upregulate PD-L1, which binds to PD-1 and mediates T cell anergy. By antagonizing the PD-1/PD-L1 binding, pembrolizumab can