tbuckley/cabot-search huggingface dataset:
MultiChip: A new diagnostic tool to perform gene expression analysis and CNV in one array.
Authors: J. Laes, P. Godard, L. Gatto, J. Detiffe, L. Alexandre
Journal: Journal of Clinical Oncology (2010)

e21031 Background: In the routine diagnostic of cancers, the monitoring of the transcriptome and the chromosomal abnormalities becomes nowadays a huge challenge. Indeed, blooming of high throughput technologies based on microarray has led to a plethora of signatures related either to expression of peculiar genes or based on chromosomal abnormalities. At present, no dedicated tool is available to monitor, in routine, those biomarkers in a single integrated array. Here, we present the first microarray able to analyze, in a single process, the expression of the genes and the copy number variation (CNV). Methods: Based on the Affymetrix technology, we developed a unique custom microarray targeting breast cancer. This GeneChip of 220 000 probes targets the genes allowing the discrimination of the molecular classes of breast cancer (ER+, ER-, HER2, luminal, basal, p53_associated, GGI) and genes related to hypoxia, plaxitacel resistance, tamoxifen resistance. This GeneChip also contains the most affected chromosomal regions in breast cancer (17p13, 17q11-12, 11q22-24). We developed and validated a 3 days protocol of labeling which allows, from 500 ng of total RNA and 250 ng of Genomic DNA, the analysis of the expression of those genes and the CNV analysis in order to provide oncologists with unique integrated information. Results: We performed classical Affymetrix experiments from 500 ng of total RNA on the HU 133 Plus 2.0 on 20 tumor samples and the normal diploid MAQC RefA. We also performed CNV analyses (on the Affymetrix SNP 6.0) from several DNAs either normal diploid or where chromosomal abnormalities were previously detected. Those results have been compared to those provided by our MultiChip. We observed more than 99% of correlation for the analysis of expression and all the CNV previously identified have been validated. No false positive or false negative results have been found. Conclusions: Thanks to this protocol, custom arrays based on the Affymetrix technology can be now build and used in the routine process to analyze biomarkers based on either expression or CNV in one experiment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration DNA Vision
A phase I study of doxorubicin-loaded anti-EGFR immunoliposomes in patients with advanced solid tumors.
Authors: C. Mamot, R. Ritschard, B. Vogel, T. Dieterle, L. Bubendorf, C. Hilker, S. Deuster, R. Herrmann, C. Rochlitz
Journal: Journal of Clinical Oncology (2011)

3029 Background: Immunoliposomes (ILs) combine antibody-mediated tumor recognition with liposomal delivery and, when designed for target cell internalization, provide intracellular drug release in order to increase specificity and efficacy of the encapsulated drug. In animal studies we have shown the ILs approach to be active and promising when targeting the epidermal growth factor receptor (EGFR). Methods: ILs were modularly manufactured under GMP conditions with Fab' fragments from MAb C225 (cetuximab), covalently linked to pegylated liposomes containing doxorubicin (PLD). This first in man single-center phase I clinical trial of anti-EGFR ILs-dox was designed for patients (pts) with various solid tumors, overexpressing EGFR (DAKO EGFR pharmDx-test). ILs-dox was administered i.v. q 4 weeks at a doxorubicin (dox) dose of 5, 10, 20, 30, 40, 50 and 60 mg/m2, 3 pts per dose level, for a maximum of 6 cycles. In addition to weekly safety monitoring, echocardiography was performed q 2 cycles, and pharmacokinetic assessments during cycle 1. The primary objective of this study was the establishment of MTD; secondary objectives included PK, tumor response, and time-to-progression. Results: After failure of standard treatments 26 pts were included between January 2007 and May 2010. Median age was 62 years, WHO PS-0 in 3, PS-1 in 19 and PS-2 in 4 pts. Most common histologies included pancreatic, H&N, colorectal and urothelial cancer. Two cases of neutropenia, defined as a dose limiting toxicity, occurred on dose level 7 (= 60 mg dox/m2). On all lower doses the compound was very well tolerated, e.g. skin toxicity grade 1 in 2 pts, no hand-foot-syndrome, no alopecia, no cardio-toxicity, no cumulative toxicity. Therefore, 50 mg dox/m2 was defined as the maximum recommended dose for further phase II development. Best response to treatment included 1 CR, 1 PR and 8 SD lasting 2-12 mo (median 5.75 mo). Mean total dox half-life was calculated to be 31.0 h (+/- 7.6 h) and for the attached monoclonal antibody fragment of C225 17.7 h (+/- 4.3 h), respectively. Conclusions: Anti-EGFR dox-loaded ILs are safe and well tolerated up to 50 mg dox/m2. Clear evidence of clinical activity was observed warranting further evaluation in phase II trials.
Cetuximab with irinotecan/folinic acid/5-FU as first-line treatment in advanced gastric cancer: A nonrandomized multicenter AIO phase II study
Authors: S. Kanzler, T. Trarbach, T. Seufferlein, S. Kubicka, F. Lordick, M. Geissler, S. Daum, P. R. Galle, M. Moehler
Journal: Journal of Clinical Oncology (2009)

4534 Background: Cetuximab has demonstrated high efficacy in combination with irinotecan-based therapies in metastatic colorectal cancer and irinotecan/folinic acid/5-FU (IF) may be an effective alternative to cisplatin-based regimens in advanced gastric cancer. We therefore conducted a phase II AIO study to evaluate the tolerability and efficacy of cetuximab combined with IF as first-line treatment in patients with advanced gastric cancer. Methods: Patients (pts) were eligible with untreated adenocarcinoma of the stomach or oesophagogastric junction, with ECOG performance status (PS) &lt; 2, measurable lesions and adequate organ functions. Pts received weekly cetuximab (first dose 400 mg/m 2 , subsequent doses 250 mg/m 2 ) combined with chemotherapy consisting of irinotecan (80 mg/m 2 ) plus 24 hours continuous infusion of sodium folinic acid (Na-FA: 200 mg/m 2 ) and 5-FU (1500 mg/m 2 ) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle. Treatment was continued until tumor progression and tumor assessments were performed every 2nd cycle. Results: Between Aug 2006 and Sep 2007, 49 pts were enrolled: 71% were males, median age was 63 years (range 33–77), median PS was 0 (65% pts), and 69% of pts and 31% of pts had gastric and oesophagogastric junction carcinomas, respectively. The median treatment time was 15.2 weeks (range 1.1–69.1). Grade 3/4 toxicities were diarrhoea (17% pts), skin reactions (13% pts), anorexia (9% pts), anaemia and fatigue (7%pts), allergic reactions, leucopoenia and neutropenia (4% pts each). Among 48 response-evaluable pts, the overall response rate (CR + PR) was 42% (CR 4%/PR 38%) and the tumour control rate was 73%. Median progression-free and overall survival times were 8.5 months (36.6 weeks; 95% CI 30.1; 48.1) and 16.6 months (71.1 weeks; 95% CI 50; 93.4), respectively. Conclusions: Cetuximab plus IF was well tolerated and encouraging survival data were observed. Cetuximab combined with chemotherapy in advanced or metastatic gastric cancer is under further investigation in an ongoing phase III trial. No significant financial relationships to disclose.
A phase Ib trial of ARQ 501, a selective checkpoint activator, in combination with docetaxel in patients with advanced solid tumors
Authors: C. Li, J. Nemunaitis, N. Senzer, G. Edelman, S. Glasner, G. Dombal, A. Dovholuk, C. Cunningham
Journal: Journal of Clinical Oncology (2006)

13053 Background: ARQ 501 is a DNA damage checkpoint activator. It directly activates DNA damage response pathways without inducing primary DNA damage, resulting in selective apoptosis in a broad range of cancer cells. The cell death pathway of ARQ 501 is mediated by E2F1, and is independent of p53. In preclinical models, ARQ 501 demonstrates potent anticancer activity with a high therapeutic index. In these models, the addition of a variety of cytotoxic agents, including docetaxel, greatly enhances the anti-tumor activity of ARQ 501. Therefore, clinical investigation of this combination is warranted. Methods: Phase 1b dose escalation study in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), pharmacokinetics, and preliminary antitumor activity of ARQ 501 in combination with docetaxel. Two schedules have been investigated. In one, ARQ 501 was administered for 5 consecutive days with a single docetaxel infusion at 50 to 100 mg/m 2 given on day 3. In the other, a single dose of ARQ 501 was given in combination with a single docetaxel infusion on day 1. Both schedules were repeated every 3 weeks. Pharmacokinetic data were collected during study weeks 1 and 4 and tumor evaluations performed every 6 weeks. Results: To date, the first ARQ 501 treatment schedule has been given to 9 evaluable patients, and the second to 7 patients with a wide variety of tumor types. The combination is well tolerated and exhibits favorable, apparently linear, pharmacokinetics. ARQ 501 does not alter docetaxel pharmacokinetic parameters in patients. The most common grade 3 and 4 adverse events are neutropenia (4.9%) and anemia (4.4%). Of the 16 patients receiving at least 8 weeks of treatment, 12 have achieved a response of stable disease or better, including four responses (2 unconfirmed PRs based on RECIST, and 2 responses based on CA-125 decreases). Conclusions: The combination of ARQ 501 with docetaxel demonstrates clinical tolerability, favorable pharmacokinetics, and signs of antitumor activity. Further dose escalation is ongoing to determine a recommended phase II regimen. [Table: see text]
Prostate-specific antigen doubling times are similar in patients with recurrence after radical prostatectomy or radiotherapy: a novel analysis.
Authors: B D Leibman, O Dillioglugil, P T Scardino, F Abbas, E Rogers, R D Wolfinger, M W Kattan
Journal: Journal of Clinical Oncology (1998)

Some investigators have analyzed the rate of growth of prostate cancer that has recurred after definitive radiotherapy or radical prostatectomy using serum prostate-specific antigen (PSA) doubling times (DT). We examined all PSA values in recurrent patients to determine the pattern and rate of increase in PSA after radiation therapy and radical prostatectomy.Charts of 96 recurrent radical prostatectomy patients (mean age, 62.8 years; range, 47 to 76) and 42 recurrent radiation therapy patients (mean age, 67.2 years; range, 52 to 83) were reviewed. All available PSA values between the date of operation/radiation treatment and last follow-up evaluation or the initiation of second-line therapy are included. Rate of PSA DT was not assumed to be constant over time; it was instead allowed to vary. We use a piecewise linear random-coefficients model in time for log (PSA), which allowed different mean models for both treatments.The PSA DT in the first year after radiation therapy was--1.17 years, which reflects the continuous decline in PSA in the average patients during the first year after radiotherapy despite eventual biochemical progression. In contrast, the PSA DT in the radical prostatectomy group was 0.66 in the first year. In year 2, after radiation therapy, the PSA DT was lengthy at 1.82 years, significantly longer (P = .0025) than in the radical prostatectomy group (0.76 years). After year 2, there were no significant differences between the two groups (P > .05).A piecewise linear random-coefficients model enables interval analysis of PSA DT. While the PSA DT after radiation therapy and radical prostatectomy are different in the first 2 years, the rate of increase in PSA appears to be similar in the two groups after year 2, which suggests the rate of growth of cancers that recur after radiation therapy and radical prostatectomy is similar.
Safety of omacetaxine mepesuccinate (OM) subcutaneous (SQ) injection for the treatment of chronic myeloid leukemia (CML) patients (pts) resistant or intolerant to tyrosine kinase inhibitors (TKIs): Analysis of two phase II studies.
Authors: J. H. Lipton, M. Wetzler, F. Nicolini, M. Baccarani, M. R. Baer, T. Masszi, D. Cram, A. Benichou, N. Nanda, J. E. Cortes
Journal: Journal of Clinical Oncology (2010)

6568 Background: OM is a first-in-class cetaxine with demonstrated clinical activity as a single agent in CML. OM inhibits production of short-lived proteins involved in cancer cell survival via a mechanism of action independent of BCR-ABL binding. Methods: Safety data from two long-term phase II studies (CML-202 and CML-203) of OM in 170 CML pts from all disease phases (chronic [CP], accelerated, and blast) who were resistant to or intolerant of TKIs are summarized. CML-202 included 81 pts (median age 58 years; CML duration 54 months) with T315I mutation who had failed imatinib. CML-203 included 89 pts (median age 57 years; duration of CML of 73 months) who had failed ≥ 2 TKIs. The median follow-up time of the combined studies (CML-202/CML-203) was 5.3 months (range 0.2-39) across all phases (CP 8.9 months [range 0.2-39]). Results: Of the 170 pts, 80% had at least one grade 3/4 treatment-emergent adverse event (TEAE). Grade 3/4 TEAEs for all pts and for CP pts (n = 93) were mainly myelosuppression: thrombocytopenia 49% and 62%, neutropenia 34% and 47%, and anemia 30% and 38%, respectively. Ten percent of CP pts had episodes of neutropenic fever and 4% had hemorrhagic complications. Across all phase patients, non-hematologic grade 3/4 TEAEs were uncommon overall, including respiratory 5%, musculoskeletal 9%, gastrointestinal 14%, and infections 14%. Among CP pts, grade 3/4 myelosuppression was more common in the initial cycles of treatment and was managed by reducing the number of days of drug administration in subsequent cycles. At cycle 1 (n = 93), the incidence of grade 3/4 myelosuppression was thrombocytopenia 24%, neutropenia 25%, and anemia 14%; by cycle 6 (n = 42), corresponding rates were 12%, 10%, and 10%, respectively. Conclusions: These results suggest that OM can be safely administered with a favorable toxicity profile. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ChemGenex ChemGenex ChemGenex ChemGenex
Small bowel adenocarcinoma and associated malignancies
Authors: S. Ahmed, R. K. Shahid, A. Sami, I. Ahmad, S. Yadav, D. Mirchandani, D. Popkin, K. Haider
Journal: Journal of Clinical Oncology (2005)

4088 Background: Small bowel (SB) tumors are uncommon and comprise only 1–5% of gastrointestinal cancers. In the Western countries, adenocarcinoma is the most common SB tumor and represents about 28–47% of all malignant SB tumors. Limited data is available about second malignancies in SB adenocarcinoma. Our experience of second malignancies in patients with SB adenocarcinoma in a Canadian province is presented here. Methods: Patients with SB adenocarcinoma and a second malignancy diagnosed since 1958 were identified by using Saskatchewan Cancer Registry. Patients with colo-rectal cancer with extension to the SB or with metastatic adenocarcinoma to SB were excluded. Results: Twenty-two patients with SB cancer and a second cancer were identified. The median age was 73 yrs (17–81) and M: F was 1:1. 7/17 (41%) patients had smoking history and 11/14 (79%) patients had history of alcohol intake. Family history was available in 16 patients and 8/16 (50%) patients had at least 1 (1–3) first degree relative with cancer. Seventy-seven percent patients had localized disease at the time of diagnosis. Sites of involvement were as follows: Duodenum 36%, Ileum 36%, and Jejunum 27%. All except 1 patient underwent curative or palliative resection of the tumor. None had received adjuvant therapy. The median time from the diagnosis of SB adenocarcinoma to a second malignancy was 8. 5 years (0–30). Six patients had ≥1 second cancer. In 32% patients, SB adenocarcinoma was the first cancer diagnosed. Median number of second cancers was 1 (1–4) and a total of 31 second cancers were diagnosed. The frequency of second cancers were as follows: Colon cancer 45%, breast cancer 23%, prostate cancer 13%, lung cancer 6%, rectal cancer 3%, thyroid cancer 3%, cervical cancer 3%, and ovarian cancer 3%. Median follow up period was 12.5 yrs (1–36). 24% with localized SB cancer had recurrence of the disease after curative resection. Median survival from the time of diagnosis of SB adneocarcinoma was 4 yrs (0.1–29).15 patients died during follow up period. 60% patients died of small bowel cancer and 27% died of second cancer. Conclusions: An association was noted between SB adenocarcinoma and colo-rectal cancer. Moreover, a long latency period was found between SB adenocarcinoma and a second cancer. No significant financial relationships to disclose.
Evaluation of the relationship between early hemoglobin rise during epoetin alfa treatment and improved patient-reported quality of life
Authors: J. Fastenau, P. Lefebvre, M. S. Duh, S. Buteau, R. S. McKenzie, C. T. Piech
Journal: Journal of Clinical Oncology (2004)

8124 Background: Previous research has confirmed epoetin alfa (EPO) improves quality of life (QoL) in patients with chemotherapy-related anemia. This analysis evaluates the association between an early hemoglobin (Hb) rise during EPO treatment and patient-reported QoL. Methods: Data from two EPO trials were used (Study 1: N=2,964; Study 2: N=2,289). EPO regimens were: Study 1: 40,000U once weekly; Study 2: 10,000U thrice weekly. Treatment duration for both trials was 16 weeks. Patients were at least 18 years old, had a baseline Hb of less than or equal to 11 g/dL, and received concomitant chemotherapy. Early Hb rise was defined as Hb change at week 4 of EPO therapy independent of transfusion. Change in QoL was measured at week 8 and end of study (EOS) by the Linear Analog Scale Assessment and Functional Assessment of Cancer Therapy -Anemia and Fatigue. Multivariate analyses were conducted to isolate the effect of early Hb rise on change in QoL while controlling for the following covariates: baseline QoL, change in Hb after week 4, age, gender, tumor type, baseline Eastern Cooperative Oncology Group (available for Study 1) score, tumor response, and receipt of platinum chemotherapy. Results: Mean change in Hb (g/dL) observed at week 4 were similar across studies ([On-treatment; week 4, Study 1:1.0, Study 2: 1.2]; [Intent-to-treat; week 4, Study 1: 0.8, Study 2: 0.9]). Multivariate analyses revealed a significant association between early Hb rise and change in QoL at both week 8 and EOS, consistently observed across all QoL parameters, patient populations, and studies (all p< 0.0001). Furthermore, the magnitude of early Hb rise effect on QoL was similar for the on-treatment and intent-to-treat populations. Other covariates consistently observed to be associated with QoL change included: baseline QoL score and tumor response. Conclusions: Early Hb rise during epoetin alfa treatment is significantly associated with improved patient reported QoL. Traditional EOS efficacy measures may not reflect the early benefits of EPO therapy. An erythropoietin that provides an early and sustained Hb rise would be clinically most desirable. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ortho Biotech Products, L.P. Ortho Biotech Products, L.P. Ortho Biotech Products, L.P.
Abstract 19611: An Examination of Survival by Sex in the HVAD BTT and CAP Trials
Authors: Edwin C McGee, Keith Aaronson, Emma J Birks, Steven W Boyce, William G Cotts, Samer S Najjar, Francis D Pagani, David Hathaway, Mary V Jacoski, Kevin B Najarian, Mark S Slaughter
Journal: Circulation (2012)

Background: The HeartWare ® Ventricular Assist System (HVAD) is a novel design, continuous flow, centrifugal pump. The ADVANCE Bridge to Transplant Trial (BTT) was a multi-center, prospective trial that used an external contemporaneous control group from the Inter-Agency Registry for Mechanically Assisted Circulatory Support (INTERMACS) to compare the HVAD Pump with commercially available left ventricular assist devices (LVAD). Methods: Baseline characteristics, adverse events and subsequent survival were compared for men and women in the combined BTT and Continued Access Protocol trials (CAP). Survival was evaluated by Kaplan-Meier and proportional-hazards methodologies. Results: In the combined BTT and CAP study (N=332), 236 men and 96 women received an HVAD pump. At baseline, men had larger BSA (2.13+0.26 versus 1.80+0.25, P &lt;0.001), more frequent history of hypertension (61.9% versus 49.5%, P =0.048) and more ischemic cardiomyopathy (45.3% versus 15.6%, P &lt;0.001). Kaplan-Meier analysis revealed no significant difference in survival at 180 days (91.5%, men; 89.6%, women) and 1-year (84.1%, men; 84.3%, women). Furthermore, a Cox proportional hazards model indicated no statistically significant gender effect on survival when controlling baseline BSA. A review of adverse events revealed similar rates between men and women who received an HVAD. Conclusion: As expected, heart failure etiology differed between men and women in this BTT cohort. However, these data suggest that gender was not a factor for survival in men and women receiving the HeartWare System, and the survival data in women compares very favorably to data reported using contemporary LVADs.
Abstract 17883: Racial and Insurance disparities in Paroxysmal Supraventricular Tachycardia Ablation
Authors: Nileshkumar J Patel, Achint Patel, Neil Patel, Shantanu Solanki, Abhishek Deshmukh, Grishma Dhaduk, Sohilkumar Manvar, Shilpkumar Arora, Nilay Patel, Apurva O Badheka, Marcin Kowalski, Hakan Paydak, Juan F Viles Gonzalez, Robert J Myerburg, Raul D Mitrani
Journal: Circulation (2014)

Objective: To identify racial and/or health insurance disparities in the population undergoing ablation for paroxysmal supraventricular tachycardia(PSVT). Method: We identified adult patients (pts) admitted with principle diagnosis of PSVT by ICD 9 code 427.0 who had catheter ablation (ICD 9 code - 37.34), using the Nationwide Inpatient Sample (2000-2011). We stratified patients by race (White, Black, Hispanic, and other minority racial groups)and insurance status, and a hierarchical mixed effect multivariate model was created to identify independent predictors of PSVT ablation. Results: 64,564(20.2%) patients underwent ablation out of 319,579 patients admitted for PSVT during the period of 2000-2011. In absolute numbers, the majority of ablations were performed in Whites (58.7%) and patients with Medicare (56.3%) or private insurance (30.1%). After adjusting for confounding factors, the odds of having ablation were lower in Black pts (compare to White), and Medicare, Medicaid, and Uninsured pts (compare to private insurance) (see table). Other predictors of lower rate of ablations were: older age and female patients while odds of receiving ablation were higher for elective admissions and in teaching hospitals (p&lt;0.001 for all comparisons). Conclusion: In a population of pts admitted for PSVT, those without private insurance and Black pts were less like to be treated with catheter ablation; and, this disparity persisted from 2000-2011. Since catheter ablation for PSVT is generally considered a curative procedure, future studies are needed to identify the factors that lead to these disparities of care.