tbuckley/cabot-search huggingface dataset:
Pediatric phase I trial and pharmacokinetic (PK) study of ispinesib (SB715992): A Children’s Oncology Group phase I consortium study
Authors: A. Souid, R. L. Dubowy, D. Greenwald Triplett, A. M. Ingle, J. Sun, S. M. Blaney, P. C. Adamson
Journal: Journal of Clinical Oncology (2008)

10014 Background: Ispinesib is a highly specific inhibitor of kinesin spindle protein (KSP), a member of the kinesin superfamily associated with the mitotic spindle apparatus. In preclinical studies in pediatric tumor models, ispinesib exhibited activity in Wilms tumor, rhabdoid tumor and rhabdomyosarcoma. Ispinesib, 18 mg/m2 every 21 days, has demonstrated activities with non-small cell lung, ovarian, and especially, advanced breast cancers. The maximum tolerated dose (MTD) on another schedule (days 1, 8 and 15 of a 28-day cycle) was 7 mg/m2; the dose limiting toxicity (DLT) was neutropenia. The current study was conducted to determine the DLT and recommend phase II dose on days 1, 8 and 15 of a 28-day cycle in children with relapsed or refractory solid tumors. Methods: Ispinesib was administered as a 60-min IV infusion on days 1, 8 and 15 of a 28-day cycle. Cohorts of 3–6 patients (≥1 to ≤ 21 yr) were enrolled at dose levels of 5, 7, 9, and 12 mg/m2/dose. Plasma PK were obtained with the initial dose. Results: Twenty one (10 females) patients with a median (range) age of 9 (1–19) years were enrolled. Six patients were not fully evaluable for toxicity: 5 had progressive disease prior to completing cycle 1 and one patient missed the day-8 dose. No DLT was observed at 5 or 7 mg/m2 dose levels. Dose-limiting neutropenia occurred in 1/6 and 1/3 patients at 9 and 12 mg/m2 dose levels, respectively. Accrual is ongoing at 12 mg/m2. There have been no objective responses. Two patients had stable disease, one for 3 cycles (alveolar soft part sarcoma) and one for 5 cycles (ependymoblastoma). The median end of infusion plasma concentration at 5, 7 and 9 mg/m2 dose levels were 0.19 (n=2), 0.35 (n=4) and 0.35 (n=4) μM, respectively. The terminal t1/2 ranged from 1.3–38.2 hr (median, 16.5 hr). Conclusions: Ispinesib PK in pediatric patients appears similar to those in adults. Ispinesib at 9 mg/m2/dose weekly × 3 every 28 days is well tolerated in pediatric patients, a 29% increase over the MTD in adults on this schedule. The 12 mg/m2 dose continues to be evaluated. No significant financial relationships to disclose.
Effect of gefitinib on EGFR Mutated Lung Cancer Cell Lines
Authors: H. Salimi-Moosavi
Journal: Journal of Clinical Oncology (2005)

3172 Background: EGFR is frequently overexpressed in many cancerous tumors such as lung, colon, breast and brain. Receptor tyrosine kinase inhibitors (TKI) such as gefitinib (Iressa) and Tarceva have been widely used for targeted therapy in cancer. These drugs inhibit the EGFR kinase activity by binding the ATP pocket within the catalytic domain. The inhibition of EGFR blocks MAP Kinase and PI3K-Akt pathways, and therefore, preventing cell proliferation and tumor growth. Recent clinical studies of patients with NSCLC showed that Tarceva is most effective in population with EGFR mutation. We describe a multiplexed proximity-based eTag assays for EGFR and Her family receptor dimerization following signaling phosphorylations, to study the effect Iressa on EGFR inhibition in lung cancer cell lines with mutant EGFR. Material and Methods: Lung cancer cell lines such as NCI-358 and NCI-1734 expressing wild type EGFR and NCI-1650 expressing mutant EGFR (in-frame deletion delE746-A750) and NCI-1975 expressing EGFR with missense mutation L858R were selected. These cell lines were treated with Iressa for 1–16 h followed by 100 ng/ml of EGF stimulation. EGFR/Her receptors were analyzed for receptor dimerization and downstream signaling pathway activation. Results: Her1/1 and Her1/2 were detected in both wild type and mutant cell cell lines. Upon treatment with Iressa, the EGFR phosphoryltion was inhibited in both wild type and mutant lung cancer cell lines, but the IC50s for cell lines with mutant EGFR were ∼50–100 times lower. Her1/1 and Her1/2 dimerization significantly increased in all cell lines following stimulation with Iressa. The MAP kinase pathway was inhibited upon treatment with Iressa, and like EGFR inhibition, the IC50s for mutant cell lines were 50–100 times lower as compared to wild type cell lines. Conclusion: We used the multiplexed eTag Assay system to study the effect of Iressa on EGFR in model cell lines, which express wild type and mutant EGFR. The results indicated that these EGFR inhibitors are more effective in cells with mutant EGFR. No significant financial relationships to disclose.
A Rapid Cytotoxic Antibody Test to Determine Species of Cell Cultures&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Arthur E. Greene, Lewis L. Coriell, Jesse Charney
Journal: JNCI Journal of the National Cancer Institute (1964)

The dye exclusion test as a criterion of specific immune cytotoxicity was adapted for rapid and simple identification of species of origin of tissue culture cells. Twenty-one cell lines of human or animal origin reacted specifically with antisera prepared against homologous, hut not against heterologous, cell types. Antibodies to monkey and human-derived strains did not exhibit cross-reactions in these studies, and identification of cell lines of the two species was readily accomplished. Freshly trypsinized cells and two cell lines removed from frozen storage were easily identified. Cell lines received from other laboratories with incorrect species designation could be easily tested and their species of origin identified.
Multicenter study of intravenous busulfan, cyclophosphamide, and etoposide (IV Bu/Cy/VP-16) as conditioning regimen for autologous stem cell transplantation in patients with non-Hodgkin’s lymphoma
Authors: J. Kim, Y. Chae, D. Kim, J. Baek, D. Yang, J. Lee, H. Kim, H. Shin, J. Jung, S. Bae
Journal: Journal of Clinical Oncology (2006)

17544 Background: The current study aimed to evaluate the efficacy and toxicity of the combination of intravenous busulfan, cyclophosphamide, and etoposide (IV Bu/Cy/VP-16) as a preparative regimen prior to autologous hematopoietic stem cell transplantation (ASCT) in patients with non-Hodgkin’s lymphoma (NHL). Methods: Forty patients with relapsed (n = 24) or high-risk (n = 16) lymphoma were enrolled into the study. High-dose chemotherapy consisted of intravenous busulfan (0.8 mg/kg i.v. q 6 hr from day-7 to day-5), cyclophosphamide (50 mg/kg i.v. on day-3 and day-2), and etoposide (400 mg/m 2 i.v. on day-5 and day-4). Results: The median age of patients was 34 years (range, 17–63 years), and 21 (52.5%) patients were male. Pathologic subtypes were as follows: diffuse large B cell (n = 20), peripheral T cell, unspecified (n = 8), extranodal NK/T cell (n = 4), angioimmunoblastic T cell (n = 3), anaplastic large cell (n = 4), nodal marginal zone B cell (n = 2), and lymphoblastic (n = 3). The median dose of infused CD34+ cells and MNC was 3.95 (range, 0.7–20.6) × 10 6 and 8.12 (range, 3.0–13.6) × 10 8 , respectively. WBC and platelet were successfully engrafted after ASCT in all patients, and the median days of engraftment of WBC and platelet was 12 (range, 9–48) and 27 (range, 8–263) days, respectively. After the ASCT, 34 complete responses (CR; 85.0%) and 4 partial responses (PR; 10.0%) were confirmed. Thirty-three (82.5%) patients experienced a fever without documented infection, while 2 patient developed fungal infection. However, there was no treatment-related death. After median follow-up duration of 360 (range, 83–639) days, 33 patients are in continuous complete remission, 4 patients are alive in relapse, and 3 patients died of disease. The estimated event-free and overall survival rate at 1.5-year was 80.9 ± 10.0 % and 92.5 ± 5.7 %, respectively. Conclusions: IV Bu/Cy/VP-16 was found to be well-tolerated and effective as a conditioning regimen in patients with NHL. Accordingly, this regimen can be regarded as an alternative high-dose treatment option in the ASCT for NHL. No significant financial relationships to disclose.
Exploratory analysis of the influence of nephrectomy status on temsirolimus efficacy in patients with advanced renal cell carcinoma and poor-risk features
Authors: T. Logan, D. F. McDermott, J. P. Dutcher, A. Makhson, J. Mikulas, A. Berkenblit, L. Galand, M. Krygowski, G. R. Hudes
Journal: Journal of Clinical Oncology (2008)

5050 Background: Temsirolimus (TEMSR), a novel inhibitor of the mammalian target of rapamycin, has demonstrated significantly longer overall survival (OS) (P=.008) and progression-free survival (PFS) (P<.001) vs interferon alfa (IFN) in patients with previously untreated advanced renal cell carcinoma (RCC) and poor-risk features (Hudes et al., NEJM 2007;356:2271). In poor-risk populations, a high percentage of patients do not have nephrectomy prior to systemic treatment. This retrospective subgroup analysis evaluated the influence of prior nephrectomy on outcomes in patients treated with TEMSR or IFN. Methods: Patients received IFN 3 million units [MU] subcutaneously 3x weekly, escalating to 18 MU, or TEMSR 25-mg intravenous infusion weekly. Kaplan-Meier analysis and a Cox proportional hazards model were used to analyze OS and PFS for the 2 patient subsets (no nephrectomy vs nephrectomy). Results: In each treatment arm, 33% of patients did not receive nephrectomy prior to treatment (IFN, 68/207; TEMSR, 70/209). There was no association between risk factors and nephrectomy status within the 2 treatment arms. Median OS was longer for TEMSR vs IFN (Table), resulting in reduced hazard ratios (HR) for death in both patient subsets (no nephrectomy, HR=0.61 [95% CI, 0.41, 0.91]; nephrectomy, HR=0.84 [95% CI, 0.63, 1.11]). In both subsets, median PFS was longer when treated with TEMSR (no nephrectomy, HR=0.62 [95% CI, 0.43, 0.88]; nephrectomy, HR=0.72 [95% CI, 0.55, 0.93]). Nephrectomy status did not affect temsirolimus efficacy with respect to either OS (P=.20) or PFS (P=.47). Among non-nephrectomized patients, more patients treated with TEMSR showed reductions in primary kidney tumor size than did those treated with IFN (TEMSR, 37/64 [58%]; IFN, 18/59 [31%]). Conclusion: Temsirolimus benefits patients with advanced RCC and poor-prognostic features, regardless of nephrectomy status, and displays activity against primary kidney tumors. No Nephrectomy Nephrectomy IFN TEMSR IFN TEMSR Patients, n (%) 68 (33) 70 (33) 139 (67) 139 (67) Median OS, mo (95% CI) 6.2 (3.8, 8.8) 11.5 (8.5,14.5) 7.8 (6.2, 10.6) 10.4 (8.2, 13.0) OS HR, TEMSR:IFN (95% CI) - 0.61 (0.41, 0.91) - 0.84 (0.63, 1.11) Median PFS, mo (95% CI), independent assessment 2.0 (1.8, 4.3) 5.7 (3.9, 7.5) 3.5 (2.2, 4.3) 5.3 (3.8, 7.1) PFS HR, TEMSR:IFN (95% CI), independent assessment - 0.62 (0.43, 0.88) - 0.72 (0.55, 0.93) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Wyeth Wyeth Wyeth Wyeth
Impressive efficacy of isotretinoin and clindamycin in treatment of G2/G3 skin rash induced by erlotinib in advanced NSCLC: A pilot study.
Authors: P. Bidoli, D. L. Cortinovis, I. Colombo, A. Crippa, F. Cicchiello, F. Villa, M. E. Cazzaniga, G. Altomare
Journal: Journal of Clinical Oncology (2010)

e19551 Background: Oral tyrosine kinase inhibitors are useful in advanced NSCLC although compliance and efficacy are diminished by skin rash which develops in about 75% of patients. Skin rash is the main cause of dose reduction and therapy withdrawal, and is no specific treatment is available. Clindamycin modulates the chemotaxis of polymorphonucleocytes, while isotretinoin has favorable effects on cell proliferation and differentiation, and inflammatory mediators. We therefore assessed the efficacy of isotretinoin plus clindamycin in erlotinib-induced skin rash. Methods: We treated 56 patients with advanced NSCLC from April 2008 to September 2009 with erlotinib (150 mg/day) mainly as 2nd/3rd line therapy. Consenting patients who developed symptomatic cutaneous rash (G2/ G3) were started on clindamycin (450 mg/day days 1 to 10; 300 mg/day days 11 to 20) plus isotretinoin (20 mg/day days 11 to 20). Clinical examination with photographic documentation was performed on days 0, 15 and 30. Results: Thirty-one (53%) patients developed rash: 12 (20%) G2 and 8 (14%) G3. However only 7/20 (35%) consented to receive clindamycin plus isotretinoin after being informed of possible side effects of isotretinoin (particularly liver damage and photosensitivity) and lack of experience with the combination. The treatment was effective in 6 (86%) patients with resolution of rash to G1/G0; in the other patient (G3) it was also necessary reduce the erlotinib to 100 mg/day. Median time to rash resolution was 14 days (range 7-20) in these 7 patients. No adverse events associated with clindamycin plus isotretinoin were observed during the 20 days of treatment. Cutaneous rash (all grades) was related to erlotinib activity: 89% of patients with radiological response developed rash, while 52% of those with progressive disease did not develop rash. Conclusions: Isotretinoin plus clindamycin promises to be effective for managing erlotinib-induced skin rash, allowing maintenance of effective erlotinib dose in order to maximize clinical efficacy. A randomized phase II study, to further explore the efficacy of isotretinoin plus clindamycin, is planned. No significant financial relationships to disclose.
Response to EGFR inhibitors in fibroblast cell lines and its association with germline polymorphisms
Authors: W. Liu, R. C. Montenegro, W. Zhang, M. J. Ratain
Journal: Journal of Clinical Oncology (2006)

13167 Background: Only a small number of cancer patients benefit from therapy with EGFR inhibitors. It is therefore important to understand the mechanism of action of these drugs and to find predictive markers for drug response. Although somatic mutations and gene amplification have been correlated with the efficacy of EGFR-targeting therapy, cancer cells and/or patients with normal EGFR expression are also sensitive to these drugs. We then aim to further understand the mechanism underlying the predisposition to sensitivity to EGFR inhibitors in germline cells. Methods: We chose 70 human normal fibroblasts cell lines as an in vitro model. Cytotoxicity studies were performed on these cells using two EGFR inhibitors, gefitinib (G) and AG1478 (AG). Cells were incubated with serial concentrations of the drugs (10, 20, 40 and 60 μM for G and 5, 10, 15 and 20 μM for AG) dissolved in DMSO. Growth inhibition was measured by Alamar Blue. Three polymorphisms, −216G/T, R497K and intron 1 (CA) n , were genotyped in these cells. EGFR expression was measured with real-time PCR. Results: There was considerable variability in drug response in a dose-dependent manner among these cells. The two drugs behaved quite differently. The fibroblasts had a much more variable response to G (mean of coefficient of variance of survival rates under all 4 concentrations, 61%) when compared to the response to AG (26%). Drug response was not correlated with EGFR expression. A significant correlation was observed between the R497K polymorphism and the survival rate of cells treated with AG at 5 μM (p&lt;0.01) and 10 μM (p&lt;0.05) with higher growth inhibition in K allele-carriers. No correlation was observed between any of the three EGFR polymorphisms and G cytotoxicity. Conclusions: These observations suggest that the cytotoxic effects of G and AG are due to different mechanisms, and that other genes such as transporters may also contribute to drug response. The R497K polymorphism may be useful as a predictive marker for response to AG and/or similar agents. No significant financial relationships to disclose.
Immunological relevance of the tumor associated antigen (TAA) COA-1 in colorectal cancer (CRC)
Authors: D. C. Corsi, C. Maccalli, M. Ciaparrone, A. F. Scinto, G. Cucchiara, F. Belardelli, V. Zagonel
Journal: Journal of Clinical Oncology (2006)

13590 Background: Immunotherapy (IT) in CRC has often produced discouraging results. COA-1 is a new TAA recognized by CD4+ T cells from peripheral blood (PB) of a CRC pt; its immunogenic epitope is presented on the surface of tumor cells in association with DRβ1*1301 or *0402 HLA class II molecules. Our aim is verifying whether an immune response directed against COA-1 mediated by CD4+ T cells can be isolated from PB of CRC pts. To achieve a more efficient anti-tumor response a recognition of a specific antigen by both the CD4+ and CD8+ lymphocytes should be performed; so different epitopes deriving from the processing of the same antigen should be presented to the immune system in association with both class I and class II MHC molecules. We identified a list of COA-1 derived peptides with the calculated score for the binding to HLA-A2, the more common HLA class I molecule within the Caucasian population. A failure in generating COA-1 specific T cells was observed in stage I-II CRC pts. Methods: From Jan 04 to day PB samples from 36 CRC pts (14 stage III/ 22 stage IV) have been collected and the HLA typing has been performed. Pts. expressing HLA DRbβ*0402, HLA DRβ1*1301 or HLA-A2 have been selected to collect other blood drawns and verifying whether an immune response directed against COA-1 could be isolated from their PB. Results: 4 pts were positive for the expression of DRβ1*1301 and 2 for the expression of DRβ1*0402. PB lymphocytes have been in vitro stimulated with the COA-1 derived epitopes and tumor reactivity has been verified. An immune response directed to COA-1 was detected in the PB of these 6 pts; anti-COA-1 CD4+ T cells were in vitro isolated and their cytotoxicity measured by granzyme B release. 9 pts were positive for the expression of HLA-A2 and we are stimulating the lymphocytes isolated from these pts with 6 selected COA-1 derived peptides binding the HLA-A2. We observed specific CD8+ T cells for 2 peptides in 1 pt. Conclusions: Our data identify COA-1 like an immunogenic antigen that can evoke an anti-tumor immune response CD4+ mediated in CRC; the response correlates with disease progression. Experiments are ongoing to evaluate an immune response mediated by both CD4+ and CD8+ T cells. These results will determine whether COA-1 could be used for future protocols of IT in CRC. No significant financial relationships to disclose.
Central review of discordant samples for microarray based on ER, PR, and HER2 and local IHC/FISH assessment worldwide from 827 patients.
Authors: Jelle Wesseling, Corrado Tinterri, Anna Sapino, Fabrizio Zanconati, Martijn Lutke Holzik, Bichlien Nguyen, Kenneth B. Deck, Patrizia Querzoli, Tiziana Perin, C Giardina, Gerhard Seitz, Jean-Marc Guinebretiere, Julie Barone, Toru Watanabe, Femke De Snoo, Lisette Stork-Sloots, Pino Cusumano
Journal: Journal of Clinical Oncology (2012)

10554 Background: Differences in fixation and IHC and subjective interpretation can substantially affect the accuracy and reproducibility of estrogen receptor (ER), progesterone receptor (PR) and HER2 expression. The commercially available TargetPrint test measures the mRNA expression level of ER, PR and HER2 and is 98% concordant with centrally assessed ER as presented by Viale et al, SABCS 2011. This study compares results from the microarray-based TargetPrint with IHC and FISH (for HER2 IHC2+) generated by local standard procedures. Methods: Fresh tumor samples (core needle biopsies or surgical) were collected for 831 patients diagnosed with breast cancer stage I to IV (Feb 2008 - Jan 2011) from 22 hospitals from Europe, New Zealand, Japan and US. The results of the IHC/FISH assessments performed according to the local standards at the hospitals were compared to the quantitative gene expression readouts with TargetPrint. Discordant cases were centrally reviewed for IHC/FISH assessment. Results: Of the 831 samples, IHC assessment was unknown for 4 ER/ PR samples; HER2 was unknown for 12 samples. Comparison of IHC and gene expression read out by TargetPrint showed a concordance of 95% for ER; 83% for PR and 94% for HER2. In this study, 3% of all IHC ER positive samples were classified negative by microarray, and 11% of IHC PR positive samples were classified negative by microarray. For HER2, 4% of IHC/FISH HER2 positive samples were classified negative by microarray and 2% of IHC/FISH HER2 negative samples were classified positive by microarray. Most notably, all available 5 ER IHC negative/TargetPrint positive samples turned out to be positive with central re-assessment. HER2 IHC2+ samples with discordant classifications for TargetPrint and local assessment are currently being reviewed for FISH/SISH assessment. Conclusions: Microarray based readout of ER, PR and HER2 status using TargetPrint is fairly comparable to local IHC and FISH analysis in 827 analyzed samples in various hospitals worldwide. However, re-assessment of discordant cases –especially IHC ER-/TargetPrint ER+ cases- confirms TargetPrint to be a useful high quality second opinion for local IHC/FISH assessment.
Bottoms up! How top-down pitfalls ensnare speech perception researchers, too
Authors: Anne Cutler, Dennis Norris
Journal: Behavioral and Brain Sciences (2016)

Not only can the pitfalls that Firestone & Scholl (F&S) identify be generalised across multiple studies within the field of visual perception, but also they have general application outside the field wherever perceptual and cognitive processing are compared. We call attention to the widespread susceptibility of research on the perception of speech to versions of the same pitfalls.
Comorbidity and survival of esophageal carcinoma patients at a VA medical center.
Authors: F. Zhong, V. T. Chang, M. L. Gonzalez, A. Chodos, C. Abanonu, L. Duque, M. McPherson, B. Crump, J. Cogswell, B. Kasimis
Journal: Journal of Clinical Oncology (2010)

e14642 Background: This study is to analyze whether comorbidity indices predict survival in esophageal cancer patients (pts). Methods: In an IRB approved protocol, we reviewed the records of pts diagnosed with esophageal cancer at a VA Medical Center from 12/1/2003 to 11/30/2009. Comorbidity was assessed with four comorbidity indices, the Charlson Comorbidity Index (CMI), the Kaplan-Feinstein Index (KFI), the Cumulative Illness Rating Scale (CIRS), and VA Comorbidity Scale (VACS). Demographics, ECOG PS, stage, histology, grade, liver metastases (mets), dysphagia, weight loss, and hemoglobin (HGB) at diagnosis, alcohol or tobacco use, GERD, Barrett's esophagus, and first line treatment (Tx) were also reviewed. Statistical analysis was performed with SAS v9.2. Results: There were 44 patients with 29 (66%) Caucasian and 15 (34%) African American men. The median (M) age at diagnosis was 64.5 years (range 43-91). Median survival was 216 days (27-2163). 21 (47%) pts has localized disease (stage I/II), and 23 (53%) with advanced disease (stage III/IV). The M ECOG PS was 1.0 (0-4), CMI 4.1 (0.3-14.5), CIRS15 3.5 (0-6), CIRS16 6.0 (0-16), CIRS17 1.65 (0-3), CIRS18 0 (0-1), CIRS19 0 (0-2), KFI 2.0 (0-3), VACS 4.0 (1-12) and HGB 12.3 (8.4-16.3). Demographic features included alcohol use (60%), tobacco use (84%), dysphagia (75%), GERD (45%), and weight loss (64%). Histologies were squamous (43%) and adenocarcinoma (56%); 55% had poorly differentiated carcinoma and 25% had Barrett's. Eleven pts (25%) had liver mets. 65% pts received Tx. In univariate survival analysis, race, CIRS16, CIRS18, Barrett's, dysphagia, stage, histology, and Tx were significant in predicting survival. However, age, ECOG PS, CMI, CIRS15, CIRS17, CIRS19, KFI, VACS, alcohol, tobacco, GERD, weight loss, histology grade, liver mets and HGB were not significant for survival. In multivariate survival analyses, dysphagia (p < 0.039), treatment (p < 0.0023), and CIRS18 (p < 0.0442) were significant predictors. Conclusions: In this sample, dysphagia, treatment, and CIRS18 were independent predictors for survival in pts with esophageal cancer. Further analysis in a larger sample is needed. This was supported by the New Jersey Commission for Cancer Research 09-1133-CCR-EO. No significant financial relationships to disclose.