tbuckley/cabot-search huggingface dataset:
Can cetuximab specific IgE antibodies predict cetuximab-induced anaphylaxis?
Authors: B. Dupont, D. Mariotte, M. Galais, K. Bouhier, B. Le Mauff, J. Reimund, R. Gervais
Journal: Journal of Clinical Oncology (2010)

10548 Background: Cetuximab is increasingly used in treatment of cancer. Severe hypersensitivity reactions to cetuximab have been described with prevalences varying from 1.2% to 22% depending on geographical location. Recently, a study by Chung et al. (N Engl J Med 2008) reported that IgE specific for galactose-a-1,3-galactose are present before cetuximab therapy in the serum of most subjects who developed a hypersensitivity reaction (HR) to cetuximab. Therefore, the main objective of this retrospective analysis was to confirm that serum levels of this specific IgE were significatively higher in cetuximab-treated patients who developped a HR than in patients who do not (NHR). Methods: A total of 213 patients were treated by cetuximab in F. Baclesse Cancer Treatment Center of Caen between October 2005 and March 2009. Twenty one had a HR and 192 had none. Serum samples of 92 patients (14 in HR group and 78 in NHR group) could be retrospectively analysed. A control group included serum from 58 healthy blood donors. Anti-cetuximab IgE levels were measured using a home made enzyme-linked immunosorbent assay (ELISA). A technical cut-off value of 27 arbitrary units (AUE) of IgE was previously defined for positivity. HR and NHR groups were compared using Student t-test for quantitative values and using Chi-2 for qualitative values. Results: Nine point nine percent cetuximab-treated patients had a HR to the drug: NIH grade 2 (n = 6), grade 3 (n = 9) and grade 4 (n = 2). In 10/14 pretreatment samples of HR patients compared to 14/78 NHR patients, anti-cetuximab IgEs were detected (OR 11.43; IR 95% [33-41.8]). Levels of IgE were significantly higher in patients having a HR compared to the NHR patients: median 43.5 AUE, extremes (3-3,000) in HR group versus 4 AUE (3-250) in NHR group (p = 0.004). Considering only severe HRs (grade 3 or 4), sensitivity, specificity and NPV were 87.5, 79.8 and 98.5% respectively. Overall, anticetuximab IgE antibodies were found in 19/58 healthy controls samples in healthy controls compared to 24/92 in cetuximab-treated patients samples (p = 0.49). Conclusions: This work confirms that detection of anti-cetuximab IgEs may represent a valuable test for identifying patients likely to have a low risk of anaphylactic reaction to cetuximab. No significant financial relationships to disclose.
Guidelines for investigation of associations between insulin and cancer risk using prescription databases.
Authors: P. Boyle, I. Ford, J. F. Robertson, C. La Vecchia, P. Boffetta, P. Autier, C. A. Adebamowo, L. Vatten, T. Holford, J. Rosenstock
Journal: Journal of Clinical Oncology (2010)

e12061 Background: Analysis of associations between insulin and cancer risk using Prescription Databases and Cancer Registers is complicated and should only be undertaken with extreme caution and employing advanced statistical and epidemiological methodologies. Methods: Interaction between methodologists, diabetologists and oncologists is also critical. Failure to do so can result in unfortunate events with potential societal implications as could have happened following the recent publication of a flawed database analysis of the association between a long-acting insulin analogue and an increased risk of cancer. Such reports cause unnecessary confusion and concern among patients and their physicians. Results: Prescription Databases were not established with such analyses in mind, and cannot identify many critical limitations such as changes in insulin type during study observation (“switchers”). Notably, those who use more than one type of insulin simultaneously pose specific problems but restriction of the analysis to users of only one type of insulin during the study period is inappropriate and likely to introduce bias. There are outstanding issues surrounding how to deal with the entire issue of “dose” which requires further exploration by the biostatistical community (reliability of doses captured, defining doses at baseline or/and differences in dose exposure). Conclusions: It is possible to obtain clear information from Prescription Databases if (and only if) the study is designed adequately, key data are available including multiple confounders (age, body weight, diabetes duration glucose control, socioeconomic status, etc.) and the biostatistical analyses are predefined. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novo Nordisk, sanofi-aventis Novo Nordisk, sanofi-aventis sanofi-aventis
Association between c-myc amplification and other biologic features and prognosis in primary breast cancer.
Authors: E. Pietri, L. Medri, S. Bravaccini, E. Scarpi, A. Rocca, R. Maltoni, L. Cecconetto, S. Sarti, T. Ibrahim, D. Amadori
Journal: Journal of Clinical Oncology (2010)

673 Background: Amplification of c-myc is found in about 15% of breast cancers, half of which show HER2 coamplification. c-myc protein regulates cell proliferation, differentiation and apoptosis, but its prognostic impact remains controversial and varies on the basis of levels of cyclins and growth factors. Methods: c-myc amplification was retrospectively assessed in 67 consecutive HER2-amplified primary breast cancers (PBCs) and in 70 HER2-negative PBC controls using fluorescence in situ hybridization. We evaluated the correlation between c-myc and HER2 amplification, the association between c-myc amplification and pathological features such as estrogen receptors (ER), progesterone receptors (PgR), grade, tumor size, and lymph node metastasis, and the impact of c-myc and HER2 amplification on disease-free survival (DFS) and overall survival (OS). Correlations among qualitative variables were assessed using the chi-square test, while DFS and OS were estimated by the product-limit method and compared using the log- rank test. Results: c-myc amplification was present in 31 out of 67 (46%) HER2-amplified PBCs and in 15 out of 70 (21%) HER2-nonamplified PBCs (p > 0.002). It was significantly associated with high tumor grade (p < 0.0001), negative ER (p > 0.006) and PgR (p > 0.01), whereas no correlation was found with lymph node metastasis or tumor size. At a median follow up of 59 months, 5-year DFS was 71% (95%CI 55-86) in c-myc-amplified PBC and 80% (95%CI 71-89) in c-myc nonamplified PBC (p > 0.32). Five-year OS was 74% (95%CI 55-93) in c-myc-amplified PBC and 85% (95%CI 78-93) in c-myc nonamplified PBC (p > 0.39). Conclusions: C-myc amplification is associated with unfavorable biological features. We found an absolute, albeit not statistically significant, difference in DFS and OS of 9% and 11%, respectively, in favor of the group without c-myc amplification. Our results highlight the need for further investigation into the predictive role of c-myc in response to endocrine and anti-HER2 therapies, and also into its potential role as a therapeutic target. No significant financial relationships to disclose.
Bi-weekly administration of capecitabine + oxaliplatin (Xelox-2) in first-line treatment of advanced colorectal cancer (ACRC): A phase II study of the Gruppo Oncologico dell’Italia Meridionale (GOIM)
Authors: P. Fedele, G. Di Maggio, S. Leo, L. Nanni, F. Giuliani, M. Biglietto, V. Lorusso, S. Cinieri, G. Colucci, E. Maiello
Journal: Journal of Clinical Oncology (2009)

e15066 Introduction: FOLFOX regimen represents a standard first-line therapy for ACRC pts. Oral capecitabine (XEL) has been shown to be a convenient and well tolerated alternative to intravenous 5-fluorouracil (5-FU) in the treatment of ACRC. Experimental data demonstrated the synergism of XEL with Oxaliplatin (OHP), but the questions about the most appropriate dosage and schedule of capecitabine have not yet been completely resolved. Taking into account these data the GOIM started a phase II study to evaluate the activity and the toxicity of biweekly administration of XEL plus OHP (XELOX-2) in ACRC pts. Methods: Previously untreated pts with histological diagnosis of metastatic colorectal cancer, measurable disease, ECOG PS&lt;2, and age 18–75 yrs entered into this trial. The schedule of treatment was as follows: OHP at 100 mg/mq i.v. on days 1 and XEL at 2,000 mg/mq p.o. in two daily administrations from the 1 to the 7 day, every 2 weeks. RECIST and NCI criteria were employed to determine the activity and the toxicity of this regimen. Results: Fifty-one pts have been enrolled and up to now forty-seven are evaluable for activity and toxicity. The main characteristics of the entered pts were: sex (M/F) 38/13, median age 66,5 yrs (range 54–75 yrs), 28 (55%) single and 23 (45%) multiple site of disease. The main site of disease were liver in 38 pts (75%), lymph-nodes in 17 (33%), lung in 9 (18%). Two CR (4%) and 22 PR (47%), 13 SD (28%) and 10 PD (21%) were observed, with an overall response rate of 51% and a disease control rate (CR+PR+SD) of 79%. Median TTP was 5+ months (range 2–19). A total of 413 cycles were administered. In the evaluable pts the main toxicity rate (G1- 2 vs G3–4) were as follows: thrombocytopenia 51/6, anemia 42/0, neutropenia 15/0, nausea/vomiting 30/2, diarrhea 19/2, neurotoxicity 57/0 and asthenia 30/2. Only one pts presented G4 toxicity (diarrhea). Conclusions: These preliminary data show that the combination of XEL and OHP with a biweekly administration is active and well tolerated in ACRC pts. No significant financial relationships to disclose.
Activity of the mTOR inhibitor sirolimus and HDAC inhibitor vorinostat in heavily pretreated refractory Hodgkin lymphoma patients.
Authors: Filip Janku, Yasuhiro Oki, Gerald Steven Falchook, Vivek Subbiah, Aung Naing, Vivianne Marie Velez Bravo, David S. Hong, Jason R. Westin, Cesar Nunez, Luis Fayad, Sattva Swarup Neelapu, Larry W. Kwak, Elizabeth J. Shpall, Jennifer J. Wheler, Tamara Barnes, Winnie S. Liang, Bodour Salhia, Funda Meric-Bernstam, Razelle Kurzrock, Michelle A. Fanale
Journal: Journal of Clinical Oncology (2014)

8508 Background: Preclinical models suggested synergistic antineoplastic activity of HDAC and mTOR inhibitors in Hodgkin lymphoma by reducing the activity of AKT, mTOR and HDAC. Methods: We designed a phase I study to determine the safety of the mTOR inhibitor sirolimus (1mg-5mg PO daily q 28 days) and HDAC inhibitor vorinostat (100mg-400mg PO daily q 28 days) in advanced cancers with an expansion cohort at the recommended phase 2 dose (RP2D) of sirolimus 4mg and vorinostat 300mg for patients with refractory classical Hodgkin lymphoma. The expansion cohort included optional pre- and post-treatment tumor biopsies, peripheral blood mononuclear cells (PBMCs), plasma/serum collections for pharmacodynamic (PD) and pharmacokinetic (PK) endpoints. Upon identification of R2PD patients were allowed to be treated and registered off label if protocol spots were not available. Results: A total of 28 patients (men, n=15; women, n=13), median age 34 years, median of 6 prior therapies (including autologous SCT [n=23], autologous and allogeneic SCT [n=6]) were enrolled in dose escalation (n=1), RP2D (n=19) or registered off label (n=8). Per Cheson 2007 criteria the overall response rate was 57% with 9 CRs (32%) and 7 PRs (25%). At the median follow-up of 5.4 months, the median progression-free survival has not been reached. Also given successful induction of remissions 5 (18%) patients were referred for allogeneic SCT. Major grade 3-4 treatment-related toxicities included grade 3 thrombocytopenia (9 patients, 32%), grade 4 thrombocytopenia (8, 29%), grade 3 anemia (4, 14%), and grade 3 transaminitis (3, 11%). Treatment interruptions and/or dose modifications were needed in 19 (68%) patients. Ten (36%) patients had archival tissue available for targeted next-generation sequencing and one patient had a loss of TSC2, an abnormality that putatively activates mTOR (PR -56% for 8.4+ months). PD studies in pre- and post-treatment tumor biopsies, PBMCs and plasma as well as PK analysis are pending. Conclusions: The combination of sirolimus and vorinostat is well tolerated with encouraging activity in very heavily pretreated patients with Hodgkin lymphoma refractory to standard therapies. Clinical trial information: NCT01087554.
Combination therapy with sunitinib and bortezomib in adult patients with radioiodine refractory thyroid cancer.
Authors: R. D. Harvey, J. S. Kauh, S. S. Ramalingam, C. M. Lewis, Z. Chen, S. Lonial, I. C. Blount, D. M. Shin, F. R. Khuri, T. K. Owonikoko
Journal: Journal of Clinical Oncology (2010)

5589 Background: Thyroid cancer is the most common endocrine cancer worldwide and the fastest growing malignancy in the US. Therapeutic options remain limited for patients with radioiodine-refractory disease. Receptor kinase inhibitors have demonstrated promising clinical activity and survival impact. Combined inhibition of multiple signaling pathways is anticipated to result in improved efficacy and a delay in drug resistance. We therefore preferentially enrolled thyroid cancer patients in a phase I study of sunitinib (S) and bortezomib (B). Methods: Patients were treated in 6-week cycles with standard doses of S (37.5 mg or 50mg daily) and escalating doses of B (1 - 1.6mg/m2 weekly), both given for 4 weeks followed by a 2-week break. The primary objective was the determination of safety and tolerability; the secondary objective was efficacy outcome. Dose limiting toxicity (DLT) was evaluated during cycle 1, using NCI CTCAE version 3.0. Anatomic response was assessed by cross-sectional imaging at the end of every cycle and biochemical response, defined as ≥50% reduction in baseline thyroglobulin or calcitonin, was assessed after every 2 cycles. Results: Seven thyroid cancer patients were enrolled; median age - 67 years, M/F - 5/2, ECOG performance status 0-1 : 7 (100%); histology – medullary 2 (28%), papillary 3 (43%), Hurthle 2 (28%). Median number and range of cycles completed (4; 0-6); No DLT was encountered; grade ≥3 toxicities encountered were: thrombocytopenia 2 (29%); neutropenia 1 (14%); hypertension 1 (14%). Six patients were evaluable for response with 2 (33%) partial response and 4 (77%) stable disease; 1 patient is not yet evaluable. Three of five evaluable patients achieved biochemical response. Median progression free survival was 12 months but insufficient events for median overall survival estimation at data cutoff. Four patients remain on study, two progressed and one discontinued after 6 cycles for prolonged grade 3 neutropenia. Conclusions: The combination of S and B is well-tolerated and has promising efficacy in the treatment of thyroid carcinoma. These promising data support the need for randomized comparison of this combination to monotherapy with sunitinib. No significant financial relationships to disclose.
Induction of gemcitabine (GCB)-related genes by pemetrexed (MTA): Assessment of the best time interval between MTA and GCB administration
Authors: T. M. De Pas, R. Danesi, F. Toffalorio, A. Milani, E. Giovannetti, V. Mey, S. Nannizzi, G. Pelosi, M. Manzotti, F. de Braud
Journal: Journal of Clinical Oncology (2007)

14145 Background: Both MTA and GCB are active drugs in non-small cell lung cancer (NSCLC). Many molecular events induced by MTA support the synergic interaction between the two drugs and explain why the sequence MTA ? GCB is more active than GCB ? MTA. Of major interest, MTA induces the expression of deoxycytidine kinase (dCK), the rate-limiting enzyme of GCB activation, and of the human equilibrative nucleoside transporter-1 (hENT1), the key transporter for the intracellular penetration of GCB. Even if the optimal sequence is well established, no information on the best administration time between the two drugs is available. Methods: To evaluate if there is a reproducible timing of maximum dCK and hENT1 expression by MTA, we measured these targets in patients with advanced NSCLC after administration of MTA 500 mg/m 2 q2wks. All patients were not pre-treated with MTA or GCB. Gene-expression was measured in normal lymphocytes by quantitative real-time PCR (qRT-PCR), at various interval (up to 48 hrs) at each of the first 3 chemotherapy cycles. Results: Between September and December 2006, 8 out of the 19 planned patients were enrolled in the present study. At the time of this analysis, dosages from 63 samples / 9 cycles of chemotherapy are available. In all treatment cycles, qRT-PCR analysis revealed an increase of hENT1 and/or dCK genes at least in one time-point. With respect to gene expression levels at basal time, dCK increased both early (+1h: 3 out of 9 valuable cycles; + 4–6 hrs: 4 out of 9 cycles) and late (+ 24–48 hrs: 5 out of 9 cycles); hENT1 increased poorly at +1h (1 out of 6 valuable cycles) but consistently at + 4–6 hrs (5 out of 6 cycles) and late (+24–48 hrs: 6 out of 6 cycles). The increase of dCK and hENT1 gene expression was from + 15% to 285% and from 21% to + 380%, respectively. Conclusions: MTA induces GCB- related genes both at early and late time points with an inter-patients variability. The most rationale time interval between the two drugs administration will be valuated at the completion of the study. No significant financial relationships to disclose.
Association between lung cancer survival and pessimistic explanatory style
Authors: P. J. Novotny, R. Colligan, D. Szydlo, M. Clark, S. Rausch, J. Wampfler, J. A. Sloan, P. Yang
Journal: Journal of Clinical Oncology (2009)

6518 Background: Several studies have demonstrated the importance of pessimism in cardiovascular disease. However, this construct has not been well explored in oncology. Methods: This study examined the survival time of 534 adult who were diagnosed with lung cancer. These patients had completed the Minnesota Multiphasic Personality Inventory (MMPI) approximately 18.2 years prior to their lung cancer diagnosis. MMPI Optimism-Pessimism (PSM) scores were divided into high (60 or more) and low scores (less than 60), and log-rank tests and Kaplan-Meier curves were used to determine survival differences. Multivariate Cox models were used for assessing prognostic values of pessimism along with other known predictors for survival outcome. Results: At the time of diagnosis, patients were on average 67 years old, 48% were female, 85% had non-small cell lung cancer (NSCLC), 15% had small cell lung cancer (SCLC), 30% were stage I, 4% were stage II, 31% were stage III/Limited, and 35% were stage IV/Extensive. Patients who exhibited a non-pessimistic explanatory style survived approximately six months longer than patients classified as pessimists. Pessimists have significantly worse survival rates even after adjusting for other known prognostic variables. Conclusions: Among lung cancer patients, having a pessimistic explanatory style was related to surviving on average six months less compared to patients with a non-pessimistic explanatory style. [Table: see text] No significant financial relationships to disclose.
Clinical and biological significance of microRNA profiling in patients with myeloma
Authors: S. Adamia, H. Avet-Loiseau, S. B. Amin, P. Moreau, S. S. Minvielle, S. Treon, C. Li, K. C. Anderson, N. Munshi
Journal: Journal of Clinical Oncology (2009)

8539 MicroRNA, a small endogenous RNA regulating specific expressed gene function has been implicated in normal biological processes as well as in malignant transformation. Here we have investigated the role of microRNAs in multiple myeloma (MM) biology, and their influence on prognosis and clinical outcome. We evaluated profiles of 384 microRNAs in CD138+ MM cells from 79 patients with MM, 11 cell lines and 9 healthy donors using qRT-PCR based microRNA array. We detected significant modulation of expression of 61 microRNAs in myeloma cells compared to normal plasma cells. Unsupervised hierarchical clustering of filtered matured microRNAs, identified two major groups within the MM population (groups A and group B). Group A clustered with MM cell lines, indicating more aggressive course of disease. Within B group, second degree node, group B2, clustered with normal plasma cells indicating indolent course. The unsupervised clustering of all MM samples showed consistent change in miR-146b, -140, -145, -125a, -151, -223, -155, let-7f, indicative of a role of these microRNA in myelomagenesis; while supervised analysis of samples within groups A and B identified modulated expression of different sets of miRNAs. In group A miR585 and let-7f were upregulated 8–12 fold; in group B, all differentially expressed microRNAs were downregulated (p&lt;0.001) compared to normal plasma cells. These modulated miRNAs target critical signaling molecules such as HOX9, c-myc, Bcl-2, SHP1 and SHP2. We further analyzed the effect of microRNA on clinical outcome. We have observed significantly superior event free and overall survival of patients in group B compared to patients ingroup A (2 yr estimated EFS 79% versus 54% respectively; p=0.05; and 2 yr estimated OS 94% versus 70% respectively; p =0.017). Functional analysis by modulating miRNAs 585, 155 and let-7f showed change in levels of predicted genes with consequent biological effect on growth and apoptosis in MM cell line. Taken together, this data identifies miRNAs as critical modulators of gene expression and signaling pathways and provides potential novel targets in MM to both understand biological behavior and for therapeutic application. No significant financial relationships to disclose.
Code status documentation in the outpatient electronic medical records of patients with metastatic cancer
Authors: J. Greer, J. Temel, S. Admane, J. Solis, T. Lynch, W. Pirl
Journal: Journal of Clinical Oncology (2009)

9576 Background: Advanced care planning is an essential component of cancer care for patients with incurable malignancies. However, the extent to which clinicians clearly document end-of-life care discussions and code status preferences in ambulatory medical records is unknown. The goal of the study was to investigate the rate of code status documentation in the electronic longitudinal medical record (LMR) of patients with metastatic cancers. Methods: We conducted a retrospective review of outpatient medical records of 2498 patients with metastatic solid tumors seen at an academic cancer center from 10/1/06 through 2/29/08. An electronic database was used to gather information on patient demographics, cancer type, and visits to the cancer center. The sample consisted of patients with metastatic breast, colorectal, non-colorectal gastrointestinal (GI), bladder/kidney, ovarian, prostate, and lung cancers. For the study endpoints, we queried the LMR to determine completion and designation of code status, which could be documented as follows: full code, do not resuscitate (DNR)/do not intubate (DNI), or DNR/DNI with specific resuscitation requests. Multiple logistic regression was used to identify independent predictors of code status completion and resuscitation preference. Results: Among the 2498 patients, 508 (20.3%) had a documented code status. Code status was documented more frequently in patients with metastatic non-colorectal GI (193/609, 31.7%) and lung (179/583, 30.7%) cancers compared to patients with genitourinary malignancies (bladder/kidney [4/89, 4.5%], ovarian [4/93, 4.3%] and prostate [7/365, 1.9%] cancers). Independent predictors of having documented code status included cancer type and a greater number of visits to the cancer center. Younger patients and black patients were less likely to be designated as DNR/DNI. Conclusions: Despite the incurable nature of metastatic cancers, a minority of patients had a code status documented in the outpatient medical record. Given the importance of advanced care planning for those with terminal illness, interventions are needed to encourage discussion and documentation of end-of-life care preferences in patients with advanced cancer. No significant financial relationships to disclose.