tbuckley/cabot-search huggingface dataset:
Analysis of optimal timing of gefitinib in sensitive non-small cell lung cancer (NSCLC) patients: Should we use gefitinib as first-line chemotherapy?
Authors: H. Kenmotsu, K. Goto, Y. Naito, Y. Nishiwaki, K. Kubota, H. Ohmatsu, S. Niho, K. Yoh, K. Nagai, N. Saijo
Journal: Journal of Clinical Oncology (2009)

8068 Background: In gefitinib-sensitive NSCLC such as Asian origin, adenocarcinoma, and never/light smoker, the superiority of gefitinib relative to carboplatin/paclitaxel as first-line chemotherapy was recently demonstrated (IPASS). However, the optimal timing of this agent is still controversial. Methods: To assess the optimal timing of gefitinib for sensitive NSCLC, we retrospectively reviewed 720 NSCLC patients treated with this agent at National Cancer Center Hospital East between 2002 and 2008. Results: A total of 190 patients responded to gefitinib monotherapy (response rate 26%) were analyzed in this study. Forty-four patients (23%) were treated with gefitinib as first-line chemotherapy, and 146 (77%) as second or more-line chemotherapy. Patient characteristics (first-line/second or more-line) were as follows: median age (range) 68 (44–82)/64 (33–82); female 84/67%; non-smoker 80/57%; PS0–1 84/74%; adenocarcinoma 93/97%; stage IV 43/54%; recurrence after surgical resection 45/26%. There were some imbalances between the two groups in terms of female (p=0.0296) and recurrence after surgical resection (p=0.0187). Although 64% of second or more-line group received platinum-based chemotherapy in their clinical course, only 27% of first-line group received it. Median follow-up time was 17.2 months. Progression free survival (PFS) from the start of gefitinib was similar between first-line and second or more-line groups (median PFS: 11 vs. 11 months, p=0.3085). However, overall survival (OS) from the start of first-line chemotherapy was significantly longer in second or more-line group (median OS: 23 vs. 33 months, p=0.0298). Conclusions: Even if gefitinib is administered to sensitive patients as first-line or second or more-line chemotherapy, it should have similar efficacy. The significantly longer survival in second or more-line group may be on account of more percentage of patients receiving platinum-based chemotherapy. No significant financial relationships to disclose.
Vascular volume expansion and thermally induced asthma
Authors: IA Gilbert, CJ Winslow, KA Lenner, JA Nelson, None McFadden ER
Journal: European Respiratory Journal (1993)

To determine whether a relationship exists between intravenous infusion of isotonic fluid and reactivity to hyperpnoea, eight normal and eight asthmatic subjects underwent rapid intravascular administration of approximately 2 l of warm normal saline, by itself and before and after hyperventilation of cold air. In the asthmatic subjects, saline infusion mirrored the obstruction seen with hyperventilation; whereas, in normal subjects saline produced more bronchial narrowing than hyperventilation. When the two stimuli were given together, the timing of the infusion altered the asthmatic subjects' responses. Giving fluid early in the hyperventilation challenge blunted obstruction, whereas giving it later amplified the airway narrowing. Similar findings, but on a smaller scale, occurred in normal subjects. These data demonstrate that sudden elevations in intrathoracic vascular volume with warm saline produce airway obstruction that is quantitatively similar to that seen with hyperventilation in asthmatic individuals. They also demonstrate that these two stimuli interact together in such a manner that a common mechanism may exist to account for the decrease in airflow.
Novel Hydroxamic Acid-Derived HDAC Inhibitor LBH589 Potently Activates Intrinsic and Extrinsic Apoptotic Pathways, and Induces Tubulin Hyperacetylation in Multiple Myeloma.
Authors: Laurence Catley, Yu-Tzu Tai, Teru Hideshima, Dharminder Chauhan, Ellen Weisberg, Tanyel Kiziltepe, Paola Neri, Pierfrancesco Tassone, Richard Versace, Peter Atadja, Nikhil C. Munshi, Kenneth C. Anderson
Journal: Blood (2005)
Role of the type III TGF-b receptor in mediating immunosuppression during breast cancer progression.
Authors: B. A. Hanks, J. D. Lee, M. Morse, T. M. Clay, H. K. Lyerly, G. C. Blobe
Journal: Journal of Clinical Oncology (2010)

10577 Background: Elevated levels of TGF-b expression are associated with poor prognosis in breast cancer and TGF-b is an immunosuppressive cytokine that is thought to play an essential role in tumor immune evasion. It has been previously demonstrated that human breast cancers undergo loss of the type III TGF-b receptor (TbRIII) with clinical progression and that this correlates with diminished levels of soluble TbRIII (sTbRIII). Based on these observations, we hypothesized that the downregulation of TbRIII in breast cancer enhances TGF-b-mediated immunosuppression and promotes the metastatic progression of this disease. Methods: We haveperformed in vivo tumor studies using TbRIII-expressing and non- expressing 4T1 breast cancer cell lines (4T1-RIII, 4T1-neo) in immunocompetent and immunosuppressed hosts while monitoring metastasis via bioluminescent imaging analysis. Primary tumors were resected and subjected to rt-PCR, immunohistochemistry (IHC), and flow cytometry (FC) to analyze CD8+ T cell and FoxP3+ regulatory T cell populations. We have performed various co-incubation studies using bone marrow- derived DCs (BMDCs) and the conditioned media (CM) of both 4T1-neo and 4T1-RIII cell lines followed by p-SMAD2 western blot analysis, surface FC, and in vitro T cell proliferation assays. Results: Semi-quantitative rt-PCR analysis of primary tumor tissue showed enhanced CD4 and CD8 expression in 4T1-RIII tumors while IHC revealed an increased number of FoxP3+ cells in 4T1-neo tumors. BMDC co-incubation with 4T1-RIII and 4T1-neo CM demonstrated differential effects on DC maturation status and their T cell stimulatory capacity. Conclusions: Our data suggests that the loss of TbRIII in metastatic breast cancer could facilitate TGF-b-mediated suppression of tumor immune surveillance. This effect may involve the modulation of DC physiology. These results imply that inhibiting TGF-b signaling by restoring levels of sTbRIII may augment the efficacy of current immunotherapeutic approaches to the treatment of metastatic breast cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Bristol-Myers Squibb, Genentech, Novartis, Onyx, Pfizer, Roche, sanofi-aventis
Comparison of self-reported outcomes with arm functional measurements in early breast cancer patients undergoing nodal biopsy in NSABP Protocol B-32
Authors: S. R. Land, J. A. Kopec, T. B. Julian, A. Brown, D. N. Krag, S. Harlow, M. Ritter, J. P. Costantino, N. Wolmark, P. A. Ganz
Journal: Journal of Clinical Oncology (2005)

6039 Background: Restricted range of motion (ROM), edema, peripheral neuropathy and other symptoms in the arm, hand and chest are relatively frequent complications of lymph node resection in women undergoing breast cancer surgery. NSABP Protocol B-32, a randomized trial of axillary dissection versus sentinel node resection in early stage breast cancer, provided a unique opportunity to compare objective and patient-reported measures of arm function edema and neuropathy, and to assess the effects of functional impairments on social participation and quality of life (QOL). Methods: ROM was measured with a goniometer on 4 occasions: prior to surgery, 1 week after surgery, 2–3 weeks, and 6 months. Arm edema (water displacement method) and neuropathy (clinical evaluation) were assessed pre-surgery and every 6 months for 3 years. Multi-item scales were used to measure patient-reported symptoms, arm-related disabilities, and overall QOL. Spearman correlations and linear mixed effects modeling were used to analyze the relationships between objective and patient-reported measures over time. Results: Of 749 patients enrolled in the QOL sub-study, 742 performed timely assessments. Arm mobility was correlated with all arm/hand symptoms, with correlations ranging from 0.19 (numbness or “pins and needles”) to 0.30 (weakness). Observer-reported neuropathy was also correlated with all self-reported symptoms, with correlations ranging from 0.19 (skin sensitivity) to 0.58 (numbness or “pins and needles”). Correlations with edema were smaller, ranging from 0.03 to 0.16. There was 82% agreement between observer- and self-reported neuropathy. ROM in the surgically-treated arm, edema and neuropathy were highly significant predictors of functional limitations (p<0.001, p=0.019 and p<0.001, respectively) and arm/breast symptoms (p<0.001, p=0.018 and p<0.001, respectively). Conclusions: Correlations between self-reported symptoms and clinical measures of arm function are moderate, suggesting that both types of variables are important to assess. ROM, edema, and neuropathy are strong predictors of self-reported ability to perform daily activities. No significant financial relationships to disclose.
Combined therapy for stage III-IV head and neck cancer: preliminary results.
Authors: S H Krasnow, M H Cohen, A Johnston-Early, M L Citron, B E Fossieck, C M Mauk, A Yenson, F P Banda, S Lunzer, H O deFries
Journal: Journal of Clinical Oncology (1984)

As part of a combined modality treatment program using chemotherapy, surgery, and/or radiotherapy, 25 patients with previously untreated stage III or IV head and neck cancer received initial combination chemotherapy. Pathologically confirmed complete remission was noted in nine patients (36%). The overall objective major response rate (with all patients included in analysis) was 68%. The chemotherapy regimen included bleomycin, cisplatin, vinblastine, methotrexate, and 5-fluorouracil. A novel concept of drug scheduling was used, based on chemotherapy-induced improvement in RBC deformability. The underlying concept is that improved RBC deformability results in improved capillary blood flow and thereby, increased drug delivery to tumor cells. Treatment resulted in moderate hematologic and renal toxicity with no treatment-related deaths. This exceptionally high, pathologically confirmed complete response rate will hopefully provide a mechanism by which combined modality therapy can adequately be tested for its ability to prolong survival of patients with advanced head and neck cancer.
Evaluation of the incidence and prognostic value of mutant epidermal growth factor receptor (EGFRvIII) protein expression in head and neck squamous cell carcinomas (HNSCC) using AQUA.
Authors: E. Pectasides, G. Fountzilas, P. Kountourakis, P. Gouveris, C. Sasaki, D. Duffey, D. Rimm, B. Burtness, D. Psyrri
Journal: Journal of Clinical Oncology (2010)

5538 Background: EGFR VIII represents a common form of mutant EGFR and has been described in several cancers, mainly glioblastoma. Data derived from cell line and xenograft models indicate that EGFRVIII expression is implicated in resistance to targeting wild-type EGFR in HNSCC. Two studies (Sok et al, Hama et al) have evaluated the incidence of EGFRVIII expression in HNSCC. Sok et al reported the presence of EGFRVIII in 42% of HNSCC using immunohistochemistry and reverse transcription polymerase chain reaction whereas Hama et al reported no EGFRVIII mutation in HNSCC by sequencing full-length EGFR. We sought to evaluate the incidence and prognostic significance of EGFRVIII in a cohort of HNSCC who had not received EGFR-targeted therapy. Methods: A tissue microarray composed of 102 specimens from primary HNSCC cases was constructed. Protein expression for EGFRVIII was analyzed using an immunofluorescence-based assay that provides an automated, quantitative analysis of expression within subcellular compartments (AQUA). Primary study endpoints were progression-free PFS) and overall survival (OS). Survival analysis was performed by Kaplan-Meier method with log-rank test for determining statistical significance. Results: Mean follow-up time for the cohort was 42 months. EGFRVIII mutation was detected in 48% of HNSCC and was commonly found in conjunction with wild-type EGFR. No association between EGFRVIII and gender, stage or histologic grade was observed. However, laryngeal carcinomas expressed higher levels of EGFRvIII compared to oral cavity and oropharyngeal carcinomas (mean AQUA score 42 vs. 13 and 14 respectively, p < 0.001). In univariate survival analysis there was no significant correlation between EGFRVIII expression and PFS (p = 0.561) or OS (p = 0.962). Multivariable analysis also failed to identify EGFRVIII as prognostic factor in HNSCC. Conclusions: We found that EGFRVIII is detected in 48% of HNSCC and is associated with larynx subsite. There is no correlation between EGFRVIII expression and outcome. These results need to be validated in larger HNSCC cohorts and to be correlated with EGFRVIII mRNA expression. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration HistoRx HistoRx
Gene expression profile analysis of paclitaxel-induced changes in the MDA-MB231 human breast cancer xenograft model
Authors: A. Groulet, O. Duchamp, A. Gonçalves, V. Forestier, N. Borie, S. Debono, V. Fert, P. Genne, A. Koki, N. Guilbaud
Journal: Journal of Clinical Oncology (2004)

3196 Background: Paclitaxel (Taxol) is a microtubule binding agent routinely used in cancer treatment. Paclitaxel has been shown to be efficacious in patients with advanced and metastatic breast cancer, as well as in the adjuvant setting in early breast cancer. Numerous preclinical studies using various cancer cell lines have contributed to identify potential mechanisms of action of paclitaxel. However, little data are available on the molecular effects of paclitaxel in-vivo. Methods: We conducted cDNA micro-array and antitumor activity analysis to investigate molecular alterations and tumor growth inhibition induced by paclitaxel exposure in the MDA-MB231 mouse xenograft model. Tumor cells (2 x 107 cells/mouse) were subcutaneously implanted into nude mice. Mice were ranked according to tumor volume and randomized to receive either 15 mg/kg paclitaxel or vehicle from day 1 to 5 following randomization. Animals were sacrified and tumor and healthy mouse subcutaneous tissues harvested 6 hr following dosing on days 2 and 5, and immediately frozen in liquid nitrogen. MDA-MB231 cells exposed for 24 hr to 100 nM paclitaxel or vehicle in-vitro were also obtained in parallel experiments. Total RNAs were extracted and analyzed on cDNA microarrays containing ca. 9000 genes. Results: Kinetic analysis of paclitaxel-treated tumor tissues revealed strong in-vivo antitumor activity (T/C = 6.5%) at relevant pharmacologic doses and transcriptional alterations involving various intracellular pathways or systems, including apoptosis, mitotic regulation, cell cycle control, microtubule regulation, and cytoskeletal remodeling. Several differences were identified in paclitaxel-treated tumor tissues compared to drug-exposed cultured cells, and may explain discordant phenotypes of response between in-vitro and in-vivo evaluation. Conclusions: Gene expression profiling of drug effect in-vivo may improve preclinical assessment of anti-cancer compounds. In addition, such an approach may identify potential surrogate markers of drug effects that can be monitored in the clinical setting to predict clinical activity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ipsogen SAS; Oncodesign
New method for immunoprofiling of the tumor microenvironment of cancer patients by opal multiplex quantitative immunofluorescence (IF) assay
Authors: Nikoletta L Kallinteris, Joseph Shan, Jeffrey Meyer, Adam C Yopp, Athur Frankel, Sean R Downing, Brenda S Robertson, Cliff Hoyt, Steven King, Carlo Bifulco, Carmen Ballesteros-Merino, Bernard Fox
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Bavituximab is a novel chimeric IgG1 monoclonal antibody targeting the membrane phospholipid, phosphatidylserine (PS), externalized on the luminal surface of endothelium in tumors, tumor cells, and tumor exosomes under stressor conditions in the tumor microenvironment. PS exposure
Selective inhibition of ADAM metalloproteases blocks HER-2 extracellular domain (ECD) cleavage and potentiates the anti-tumor effects of trastuzumab
Authors: P. Scherle, X. Liu, J. Li, J. Fridman, Y. Li, W. Yao, W. Williams, R. Levy, K. Vaddi, R. Newton, S. Friedman
Journal: Journal of Clinical Oncology (2006)

13021 Background: HER-2, a member of ErbB family of receptor tyrosine kinases, is an important regulator of cell proliferation and survival, and is a clinically validated target of therapeutic intervention in HER-2 positive metastatic breast cancer patients. In HER-2 overexpressing cells, the extracellular domain (ECD) is frequently cleaved, rendering the remaining transmembrane portion of HER-2 (p95) constitutively active. The presence of both serum ECD and cellular p95 protein have been linked to poor clinical outcome as well as reduced effectiveness of some therapeutic treatments, suggesting that signaling via p95 is clinically relevant and may represent an attractive target for therapeutic intervention. Methods: Through medicinal chemistry efforts, we have identified a series of potent, selective small molecule inhibitors of ADAM metalloproteases, exemplified here by INCB7839. These compounds were tested both in vitro and in vivo for inhibition of HER-2 ECD cleavage and anti-tumor activity in the HER-2 overexpressing BT-474 cell line. Inhibition of circulating HER-2 ECD levels was monitored in a phase I multiple dose escalation study in healthy volunteers. Results: We demonstrate that these inhibitors effectively blocked HER-2 cleavage in HER-2 overexpressing human breast cancer cell lines. When used in combination, INCB7839 dramatically enhanced the antiproliferative activity of suboptimal doses of the anti-HER-2 antibody, trastuzumab, in HER-2 overexpressing/shedding breast cancer cell lines, accompanied by reduced ERK and AKT phosphorylation. Consistent with these in vitro data, INCB7839 reduced serum ECD levels in tumor-bearing mice and enhanced the antitumor effect of trastuzumab in a xenograft tumor model derived from the HER-2 overexpressing BT-474 breast cancer cell line. In a phase I clinical trial, INCB7839 demonstrated a dose-dependent decrease in the circulating levels of HER-2 ECD present in healthy volunteers. Conclusions: Collectively, these findings suggest that blocking HER-2 cleavage with selective ADAM inhibitors, especially in combination with anti-HER-2 antibody therapy, may represent a novel approach for treating HER-2 overexpressing breast cancer patients. [Table: see text]
Does the day or season of operation predict biochemical recurrence after radical prostatectomy?
Authors: A. L. Hirsh, D. J. Lee, G. Hruby, M. C. Benson, J. M. McKiernan
Journal: Journal of Clinical Oncology (2009)

e16162 Background: Outcomes in hospital based medicine are associated with the experience and availability of the medical staff, as mortality and morbidity rates increase each summer with new medical graduates. Hospital staff members are thought to be more fatigued and less available towards the end of the week and on weekends. However it is not known if there is a difference of outcomes based on the season or day of the week. We sought to identify if different seasons or surgical days of the week can predict poor outcomes and biochemical recurrence (BCR) in radical prostatectomy (RP). Methods: A retrospective analysis of the Columbia Urologic Oncology database was performed. 1865 consecutive men underwent RP from 1991 to 2008 by three surgeons. Data was collected in an institutional review board approved registry, with median follow up of 36 months. BCR was defined as two consecutive PSA levels &gt; 0.2 ng/ml. Stratified cox regression methods were used to model the relationship between surgeon, preoperative variables, season, day of the week, and BCR. Winter was defined as December through February, spring as March through May, summer as June through August, and fall as September through November. Results: The mean age of the men undergoing RP was 61.2 years (37–79), with a mean preoperative PSA of 8.12. 424 men (22.7%) had positive surgical margins, and the mean estimated blood loss (EBL) was 1119cc. Patient age (p=0.68), preoperative PSA (p=0.32), EBL (p=0.51), and positive surgical margin rate (p=0.78) were not significantly different between each day. Men undergoing RP did not have different rates of BCR according to the day of the operation (p=0.58) or season (p=0.997). The particular season and day of the operation were not significantly associated with BCR, and were not independent predictors of BCR in a multivariable model after adjusting for preoperative PSA, Gleason sum, tumor stage, and surgeon. Conclusions: Patient surgical outcomes and BCR rates after RP are not associated with the particular season or day of the week of the procedure. These findings suggest that men undergoing RP do not need to be concerned about the particular season or day when scheduling the procedure. No significant financial relationships to disclose.
Patterns of Total Costs of Care for Newly Diagnosed Multiple Myeloma (MM) Patients
Authors: Steven R. Arikian, Dejan Milentijevic, Gary Binder, Mara Silvia Monzini, X Henry Hu, Yasir Nagarwala, Mohamad A. Hussein, Frank A. Corvino, Andy Surinach, Saad Z. Usmani
Journal: Blood (2014)
Incidence of human papillomavirus (HPV)-related head and neck cancers in the U.S. from 1998–2003: Pre-HPV vaccine licensure
Authors: M. Saraiya, K. Kawaoka
Journal: Journal of Clinical Oncology (2007)

6003 Background: While smoking and alcohol are implicated in the majority of head and neck cancers, human papillomavirus (HPV) has been responsible for 15–35% of head and neck cancers worldwide. In head and neck sites such as the oropharynx, tonsil, and tongue, HPV is associated with 50–90% of squamous cell cancers. Recent recommendation of an HPV vaccine, protecting against infection with HPV types 16 and 18 have prompted this current assessment of the burden of squamous cell cancers (SCC) at these sites. Methods: Using data from CDC’s National Program of Cancer Registries and/or NCI’s SEER Program for cases diagnosed from 1998–2003, covering 83% of the U.S. population, we assessed the squamous cell cancers (SCC) of the base of tongue, oropharynx, and tonsil in the U.S. population on the basis of age group, gender, race/ethnicity, stage, US region, and year of diagnosis. Incidence rates were age- adjusted to the 2000 U.S. standard population and are expressed per 100,000 individuals. Results: The average annual incidence rates per 100,000 individuals during 1998–2003 are: base of tongue, 1.16 (95% confidence interval 1.14–1.18); oropharyngeal, 0.90 (95% CI 0.89–0.92); and tonsillar, 1.35 (95% CI 1.34–1.37). Blacks have the highest incidence of base of tongue, oropharyngeal, and tonsillar SCC (1.25, 1.61, and 1.47, respectively) while Asian/Pacific Islanders have the lowest incidence (0.37, 0.25, and 0.49, respectively). The South has the highest incidence of base of tongue, oropharyngeal, and tonsillar SCC (1.24, 1.06, and 1.52 respectively). Tonsillar cancer had the highest incidence rates for Whites, Asian/Pacific Islanders, American Indians/Alaska Natives, and Hispanics (1.37, 0.49, 0.85, and 0.89, respectively), but oropharyngeal cancer was the highest in Blacks (1.47). Both base of tongue and tonsillar SCC show a significant annual increase (2.68%, 2.96%, respectively). Conclusions: Increasing incidence rates among those head and neck cancers that are HPV- associated such as tonsillar and base of tongue suggest that the HPV vaccine may have a significant impact on these cancers. No significant financial relationships to disclose.