tbuckley/cabot-search huggingface dataset:
Standardization of EGFR FISH in colorectal cancer: Results of an international, interlaboratory reproducibility ring study.
Authors: A. Sartore-Bianchi, S. Fieuws, S. Veronese, M. Moroni, N. Personeni, M. Frattini, V. Torri, F. Cappuzzo, S. Vander Borght, V. Martin, M. Skokan, A. Santoro, M. Gambacorta, S. Tejpar, M. Varella-Garcia, S. Siena
Journal: Journal of Clinical Oncology (2011)

3597 Background: Epidermal growth factor receptor (EGFR) gene copy number (GCN) evaluated by fluorescence in situ hybridization (FISH) has been shown to discriminate among KRAS wild type patients those with better outcome to EGFR-targeted therapy in metastatic colorectal cancer (CRC), further enhancing selection of patients. Nevertheless, enumeration of gene copies in CRC is challenging and the lack of analytical standardisation has limited incorporation of the test into the clinical practice. Methods: A ring study was designed in order to assess EGFR FISH inter-laboratory consensus among 5 pathology reference centres located in Belgium, Italy, Switzerland, and United States. A set of 12 CRC samples circulated among laboratories and samples were scored according to commonly agreed guidelines. Reproducibility was quantified using the standard error of measurement (SEM). Results: A SEM of 0.865 and a within-subject coefficient of variation (WSCV) of 26.8% for mean EGFR gene per nuclei and a SEM of 0.235 and a WSCV of 19.4% for the mean EGFR gene/CEP7 ratio were observed, indicating low level of agreement. Measurement of the fraction of cells displaying chromosome 7 polysomy within tumor specimens was also performed, showing WSCV of 46.6%, 34.0% and 51.0% for % of cells displaying ≤2, ≥3 and ≥4 EGFR signals, respectively. Among different slides of the same specimen, the WSCV was 6.1% for mean EGFR gene per nuclei and 3.9% for mean of EGFR gene/CEP7 ratios and 10.5%, 12.4% and 24.0% for the % of cells displaying ≤2, ≥3 and ≥4 EGFR signals, respectively. Conclusions: Molecular diagnosis of EGFR GCN by FISH varied largely among experienced international pathology centres, with fluctuations covering the whole range of proposed cut-offs of predictive usefulness from literature. Definition of a detailed scoring system and implementation of a comprehensive training program for molecular diagnostic laboratories are therefore necessary before including the test into clinical practice as a standard assay for predicting outcome to EGFR-targeted therapies in metastatic CRC.
Therapeutic potential of antisense Bcl-2 as a chemosensitizer for patients with gastric carcinoma
Authors: R. Kim, M. Emi, K. Tanabe, T. Toge
Journal: Journal of Clinical Oncology (2005)

4050 Background: Bcl-2 confers resistance to apoptosis, thereby reducing the effectiveness of chemotherapy. We performed a preclinical evaluation of antisense (AS) Bcl-2 as an enhancer of the chemotherapeutic effect in the treatment of gastric carcinoma. Methods: AS Bcl-2 was used with 18-mer phosphorothiated oligonucleotides in the MKN-45 gastric carcinoma cell line. Drug sensitivity in vitro was evaluated by the MTT assay, and antitumor effect in vivo was evaluated by the nude mouse xenograft. Apoptosis was determined with TUNEL assay. AS Bcl-2 in vitro was treated with lipofectin, whereas it was administered intraperitoneally for 6 consecutive days twice in q2wks in vivo. Anticancer drugs were administered intraperitoneally four times in qwk. Results: Bcl-2 was downregulated to 60% of initial value after the treatment with 1.0 μM of AS Bcl-2 compared to the controls of random and mismatched ODNs. Drug sensitivity to doxorubicin (DOX), cisplatin (CDDP), and paclitaxel (TXL) was increased three- to four-fold when used in combination with AS Bcl-2, which was determined with IC50 values in comparison with the control. Increased drug sensitivity was associated with apoptosis, increasing in Bax, Poly (ADP-ribose) polymerase and decreasing in phosphorylated Akt. The antitumor effect of CDDP and TXL in vivo was significantly enhanced in combination with AS Bcl-2. Downregulation of Bcl-2 was observed at day 4 after the treatment with AS Bcl-2. AS Bcl-2 ODNs induced splenomegaly in association with increased serum IL-12, CD80 and CD83 expression, which was attenuated by methylation of the CpG motifs of AS Bcl-2, however, methylated CpG failed to negate the increased antitumor effect of AS Bcl-2. Conclusions: Combination treatment with AS Bcl-2 and anticancer drugs, including CDDP and TXL, may be a new strategy for enhancing the chemotherapeutic effect in the treatment of gastric carcinoma. No significant financial relationships to disclose.
Reactivation of the tumor suppressor RASSF1A by selective depletion of DNA methyltransferase 1 (DNMT1) by MG98 sensitizes renal cancer cells to interferon (IFN)-induced apoptosis
Authors: F. J. Reu, R. K. Maitra, D. R. Rempinski, S. I. Bae, N. Beaulieu, A. R. Macleod, E. C. Borden
Journal: Journal of Clinical Oncology (2005)

9541 Background: Epigenetic mechanisms may underlie resistance of renal cell carcinoma (RCC) to therapies including IFNs. RASSF1A is the tumor suppressor gene most frequently silenced by DNA methylation in renal cancer. Functions in mitosis control and apoptosis have been described. Methods: To inhibit maintenance of DNA methylation ACHN human renal cancer cells were treated with the DNMT1 selective phosphorothioate antisense inhibitor MG98 (DNMT1 AS) before exposure to IFNs. Flow cytometric TUNEL analysis and immunoblotting for caspase 3 cleavage were used to measure apoptosis. DNA demethylation was assessed by methylation specific PCR (MSP). Role of RASSF1A was examined by siRNA and lentiviral expression with selection of clones expressing physiologic levels, as determined by comparison on immunoblots to levels achieved by DNA demethylation. Results: Although ACHN cells were resistant to apoptosis induction by IFN-a2 or -β even at 500 U/ml (<5% TUNEL positive), MG98 (DNMT1 AS), but not mismatch oligonucleotide (DNMT1 MM) pretreatment led to apoptosis with only 50 U/ml IFN-a2 or -β (25–50% and 50–80% TUNEL positive, respectively). MG98 (DNMT1 AS) pretreatment alone did not result in apoptosis (<5% TUNEL positive) but decreased DNMT1 protein to undetectable levels, demethylated RASSF1A promoter region, and reactivated RASSF1A protein expression. RASSF1A siRNA transfection following demethylating treatment reduced IFN-induced apoptosis from 57% with control siRNA to 32% (TUNEL). Lentiviral stable expression of RASSF1A levels achievable by DNA demethylation overcame resistance of ACHN cells to IFN-induced apoptosis while empty virus did not sensitize (about 60% and 5% TUNEL positive, respectively, after 50 U/ml IFN-β). Untreated lentiviral clones had no increase in apoptosis (<5% TUNEL positive). Conclusions: DNA demethylation induced by MG98 treatment may enhance antitumor effect of IFNs in RCC at least in part by reactivation of RASSF1A. These results support the ongoing phase II clinical trial of IFN-a2 and MG98 in RCC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MethylGene MethylGene
Follow up of a multicenter phase II study of sequential paclitaxel and S-1 (TXL/S1) as postoperative adjuvant chemotherapy for gastric cancer (GC)
Authors: A. Tsuburaya, N. Murata, M. Kimura, Y. Ueda, M. Takahashi, S. Yoshino, M. Takagi, S. Morita, J. Sakamoto
Journal: Journal of Clinical Oncology (2007)

15084 Background: Of patients who undergo R0 resection for GC with serosal invasion (T3–4), more than half recur mainly in the peritoneum, while TXL and S1 exhibited efficacy for diffuse type and peritoneal metastases in the phase II studies. Primary analysis of the sequential chemotherapy with TXL/S1 had shown its safety and tolerability, its survival benefit is being tested in a large phase III study (the SAMIT trial) with oral fluoropyrimidines as controls. The analysis for survival of this preceding phase II study is performed. Methods: Eligibility criteria included histologically proven GC; sT3–4; sN0–2; M0 (except peritoneal cytology: CY); post D2–3 gastrectomy and R0–1; ECOG PS 0–1; and 20–80 years old. On postoperative day 14 to 56, patients received 3 courses of weekly TXL (80mg/m 2 on day 1, 8 for the 1 st course and on day 1, 8, 15 for the 2 nd and 3 rd courses, repeated every 3 or 4 weeks) followed by 4 courses of S1 (80mg/m 2 daily for 2 weeks, repeated every 3 weeks). The primary endpoints were % of patients who completed all 7 courses (compliance) to see whether the lower 95% confidence limit of compliance was greater than 69% and incidence of severe toxicities and the secondary endpoints were 3-year survival and toxicities. Results: 50 patients were accrued from May 2003 to March 2004. The median age was 63 (range 34–74); male/female: 34/16; pT2/T3/T4: 1/44/5; CY0/CY1: 4/46; f-stage2/3a/3b/4: 12/15/16/7. The overall compliance was 84%. Median follow up time was 1063 days for survivors (694–1332) and 1030 days for all. Three-year DFS were 64.6% for all, 66.1% for CY0 and 50.0% for CY1. Conclusions: Sequential TXL/S1 may serve as an active adjuvant for gastric cancer patients especially who are at high risk for peritoneal spread. No significant financial relationships to disclose.
Prognostic factors for survival in patients with metastatic renal cell carcinoma (mRCC) treated with antiangiogenic therapies: Overall results of a large experience.
Authors: G. Procopio, E. Verzoni, R. Iacovelli, F. Mattana, V. Guadalupi, L. Mariani, S. Stagni, R. Salvioni, R. Buzzoni
Journal: Journal of Clinical Oncology (2011)

e15026 Background: While the most important prognostic factors for mRCC have been evaluated in the cytokines era, only limited data and evidences are available to correlate and validate the role of prognostic factors with the use of targeted therapies (TT).(Heng 2009). This study was performed to assess the role of prognostic factors in mRCC treated with TT. Methods: From Dec 2004 to Jun 2010 baseline characteristics and outcomes of 310 consecutive patients affected by mRCC and receiving TT were collected from the database of Fondazione IRCCS Istituto Nazionale Tumori of Milan, Italy. The main characteristics of patients were: ECOG PS 0/1/2 168(54%)/123 (40%)/19(6%); sex M/F 229 (74%)/81 (26%); clear-cell histology 268 (86%)/non clear-cell 42 (14%); previous nephrectomy 273 (88%); Fuhrman grade 1/2/3/4 15 (6%)/93 (34%)/118 (44%)/43 (16%).The Fuhrman grade was unspecified in 41 pts (13%). According to Motzer criteria 100 cases (32%) were classified as low risk, 146 (47%) as intermediate risk and 64 (21%) as poor prognosis. One hundred sixty three (53%) patients received only one TT while 113 (36%), 30 (10%) and 4 (1%) received 2, 3 and 4 TT, respectively. Overall 233 (75%) patients received sorafenib, 172 (55%) sunitinib, 32 (10%) a bevacizumab regimen and 20 (7%) other TT. The uni- and multi-variate analyses were done by Cox proportional hazard regression analysis. Results: After a median follow-up of 37 months, 179 patients (57%) had died. The median overall survival (OS) was 22 months and the 5- year OS was 23.4% (95% CI:16.7-30.0). The Motzer criteria were validated as prognostic factors in the uni- and multi-variate analysis (p<001). The median and 5-year OS was 43 months and 42.8% in low risk patients, 21 months and 15.9% in the intermediate risk and 8 months in poor risk. In the univariate analysis nephrectomy, ECOG PS, number of sites of disease and Fuhrman grade were independent prognostic factors of outcome (p<001). Conclusions: The Motzer criteria were validated in patients with mRCC receiving TT. ECOG PS, nephrectomy, Fuhrman grade and number of sites of disease are independent prognostic factors of outcome.
Effects of the sequential administration of GEMOX followed by FOLFIRI in cholangiocarcinoma.
Authors: Sihem Sebbagh, Chantal Dreyer, Armand De Gramont, Olivia Hentic, Pascal Hammel, Eric Raymond, Sandrine J. Faivre
Journal: Journal of Clinical Oncology (2014)

348 Background: Advanced cholangiocarcinoma are benefiting from platinum-based therapy (Valle et al, NEJM) but no validated option is available as second line systemic therapy. Methods: Objective : Explore the effect of 2 consecutive lines of chemotherapy in patients with cholangiocarcinoma fitted to receive sequential administration of received gemcitabine and oxaliplatin (GEMOX) followed by FOLFIRI. A retrospective study was conducted among patients who received GEMOX in first line followed by FOLFIRI in second line from January 2005 and September 2013 at Beaujon hospital (France). Overall survival, progression free survival and prognostic factors were determined by the Kaplan-Meier method and univariate analysis. Results: Thirty-four patients were included in the cohort. Eighteen patients (53%) presented intrahepatic cholangiocarcinoma (ICC) and 16 (47%) presented extrahepatic cholangiocarcinoma (ECC). At diagnosis, tumors were localized in 4 patients (12%), locally advanced in 13 patients (38%) and metastatic in 17 patients (50%). Among 10 patients with prior surgery, 7 received GEMOX adjuvant chemotherapy. The median overall survival time was 20.6 months in all patients and 17.1 months in patients who received GEMOX followed by FOLFIRI in the advanced setting. The median first line progression-free survival (PFS) was 5.7 months with a median number of 8 cycles of GEMOX. The median second line PFS was 2.9 months with a median number of 5 cycles of FOLFIRI. Patients who received &gt;8 cycles of GEMOX in first line survived longer than those who received ≤ 8 cycles (23.1 vs 15.1 months; hazard ratio (HR) 5.22, P=0.009). The PFS of second line FOLFIRI was not different in patients who received more than 8 cycles of GEMOX (HR=1.72 P=0.26). Univariate analysis showed no correlation between age, sex, localization of primary, stage, and surgery with overall survival. No severe toxicity was reported related to GEMOX-FOLFIRI sequential combination in this study. Conclusions: Sequential administration of GEMOX followed by FOLFIRI is feasible for fitted patients with cholangiocarcinomas, yielding overall survival over 1 year.
Use of performance data to drive process change and improve patient wait time for chemotherapy treatment.
Authors: Ben De Mendonca, Carlo DeAngelis, Flay Charbonneau, Tiffany Leung, Maureen E. Trudeau
Journal: Journal of Clinical Oncology (2012)

223 Background: The Odette Cancer Centre (OCC) manages more than 24,000 chemotherapy visits annually. The delivery process is complex and patients have significant wait times for treatment. The OCC was faced with improving this process with no data infrastructure to support continuous quality improvement. Methods: An electronic scheduling manager, Chemotherapy Appointment Reservation Manager (CHARM) was designed that includes workflow communication between pharmacy and nursing. A multidisciplinary team created a value stream map of the process. Rate limiting steps and key milestones in the delivery process were identified. CHARM timestamps stages in the chemotherapy process, from nurse approval to pharmacy verification, medication processing and medications received on the chemotherapy unit. Extracted data was used to create a weekly report to monitor key performance indicators (KPIs). Results: An analysis of six months of data led to the establishment of KPIs and targets. Our baseline targets were established as pharmacy turnaround time (AR) &lt; 1 hour, pharmacy verification (HP)&lt; 13 minutes, medication processing (PR) &lt;45 minutes and chemotherapy ready (CR) +/- 30 minutes of the patient appointment time. Since April 2012, KPIs have been reported. Over a four month period (81 clinic days and 5,920 appointments) the median AR time was 1:02 (hh:min), HP was 00:12 and PR was 00:43. The KPI targets were met AR 46%, HP 52% and PR 51% and CR 29% of the time. The data infrastructure now drives the quality improvement initiatives. An early strategy implemented queuing theory, to process orders by appointment rather than approval time, resulting in no change in median AR time, but a decrease of seven minutes AR range. Conclusions: Quality improvement is hinged on measurement and evaluation. The OCC has successfully implemented a continuous quality improvement data infrastructure that monitors quality of ambulatory chemotherapy delivery. These data describe pharmacy and nursing processes. Further work to improve the delivery process and data infrastrucutre is ongoing.
Influence of First-Line Regimens on the Outcomes of High-Dose Chemotherapy with Autologous Hematopoietic Stem-Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma.
Authors: Bimalangshu R. Dey, Benjamin Cox, A. Jo Chien, Martin Caron, Steven L. McAfee, Christine Colby, Thomas R. Spitzer
Journal: Blood (2004)
Gefitinib in the adjuvant treatment of hepatocellular carcinoma: A pilot study by the Singapore hepatocellular carcinoma consortium.
Authors: G. Lopes, C. K. Ho, K. H. Liau, A. Chung, P. Cheow, A. Y. Chang
Journal: Journal of Clinical Oncology (2010)

TPS210 Background: The epidermal growth factor receptor (EGFR) pathway may play an important role in the pathogenesis of hepatocellular carcinoma (HCC) as it is expressed in 75% of patients' tumors in contrast to 30% of normal hepatocytes. Gefitinib, an oral tyrosine kinase inhibitor that targets the EGFR, is approved for the treatment of lung cancer in Asia. We intended to study the feasibility of gefitinib in the adjuvant treatment of patients with HCC and to identify prognostic and predictive biomarkers. Methods: We designed a multicenter pilot study. Patients with a clinical diagnosis of potentially resectable hepatocellular carcinoma who are willing to give informed consent prior to surgery and who have adequate end-organ function are eligible for screening. Patients with macroscopically resected disease (at least R1 resection or better) and pathologically confirmed hepatocellular carcinoma are eligible for adjuvant therapy. Treatment consists of gefitinib 250 mg orally daily for 6 months. Primary endpoints are to assess the feasibility of conducting a larger randomized trial and correlative studies. We aim to study selected genetic and/or protein markers as prognostic and predictive factors. These include: EGFR, p-EGFR, MEK, ARK in tumor tissues; serum insulin growth factor I/II, insulin growth factor binding protein-3, VEGF, PDGF, AFP, and PIVKAII; and hyper-methylation of tumor suppressor genes SOCS-1, GSTP, APC, p16, and p53 from the specimen at resection. Secondary endpoints are progression-free survival, toxicity and overall survival. Sample size is 40 eligible patients. Sixty-seven patients have been approached to participate. Forty-five consented and enrolled in the trial. Fifteen patients were ineligible (due to diagnosis other than HCC, 4 patients; poor post-operative recovery, 4 patients; unresectable disease, 3 patients; withdrawal of consent, 2 patients; 1 patient was diagnosed with bladder cancer and another developed metastatic disease before adjuvant treatment started). Thirty patients have started adjuvant treatment with gefitinib. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca
Features of relapsed disease in lymphocyte predominant Hodgkin’s disease patients
Authors: A. Liberati, P. Cerroni, R. Zanotti, M. Spina, S. Viviani, G. Cervetti, C. Stelitano, P. Ferrara, M. Merluzzi, U. Vitolo
Journal: Journal of Clinical Oncology (2005)

6688 Background: There is little information in the literature regarding the natural history of lymphocyte-predominant (LP) Hodgkin’s disease (HD) mainly at the time of relapse. The objectives of our group were to investigate: time to recurrence, anatomical and histological patterns of first and second recurrences, and response to therapy of relapsing disease in patients with LP-HD. Methods: All available clinical data were collected in Perugia, but some specific information is still pending. A central pathology review was performed in 188 cases and in the remaining 423 cases was performed, ongoing, by single institutional pathologists, but a centralized review was planned in selected cases as required by local experts. Results: Relapse was documented(32,6mths from diagnosis)in 131/611 cases. In 45 patients data was not complete at the time of writing. LP-HD was confirmed in 41/58 patients who were biopsied at the relapsing site. Classical (6) or unclassifiable (3) HD or diffuse large B cell lymphoma (8) was diagnosed in the other 17 cases. In the 41 LP-HD patients the site of relapse was nodal in 40 or both nodal and extranodal in 1. The clinical stage in the 32 pts with complete data was I in 17, II in 7 and III in 8. A CR to radiotherapy alone was documented in 7/7 pts and in 13/13 patients treated with combined radio-chemotherapy. Fourteen CR and 3 NR were documented in 17/19 evaluable cases, who received chemotherapy alone. At 2nd relapse, a new histological examination was performed in 10/23 cases. LP-HD was confirmed in 7 patients. Four CR and 2 PR were obtained in 4 patients treated with chemotherapy alone and in 2with chemo- radiotherapy. No information was available in the 7th patient. Conclusions: The present analysis indicates that patients with relapsing LP-HD have a favorable clinical pattern of disease and a good response to salvage treatment. No significant financial relationships to disclose.
KRAS testing of mCRC patients in a community-based oncology setting.
Authors: Gebra Cuyun Carter, Pamela Landsman-Blumberg, Barbara H Johnson, Robert Sedgley, Veena Shankaran
Journal: Journal of Clinical Oncology (2013)

364 Background: In late 2008, treatment guidelines were updated to recommend KRAS testing for patients at diagnosis (Dx) of metastatic colorectal cancer (mCRC). This study explored KRAS testing rates over time and compared characteristics of those mCRC patients who were tested and those not tested in a community-based setting. Methods: Patients ≥18 years old, with a mCRC Dx between 1/1/2008 - 12/31/2011, no other primary cancer, and 2+ outpatient visits were selected from the ACORN Data Warehouse (Memphis, TN). Text mining of progress notes and random forests modeling predicted if KRAS testing was done. If tested, test date and result were abstracted from charts. The proportions of those tested overall and at Dx (pre and ≤ 60 days post-mCRC Dx) were calculated by year. Chi-square and t-tests were used to compare demographic and cancer characteristics at Dx and clinical history of those tested and not. Results: Among 1,363 patients identified, 47.5% (n=648) were KRAS tested. Overall 48.1% were KRAS WT, 42.3% KRAS mutant, and 9.6% unknown. Proportion of eligible patients who underwent KRAS testing in pre-2008, 2008, 2009, 2010, and 2011 was 5.8%, 15.9%, 29.1%, 26.9%, and 28.0% respectively. Of those tested, 6.2% were tested at Dx pre-2008 and 27.4%, 65.4%, 73.2%, and 78.4% were at Dx in 2008, 2009, 2010, and 2011 respectively. KRAS tested patients were younger (59.5% vs. 51.5% &lt;65 years, p=0.004), had more baseline comorbid conditions (3.7±4.0 vs. 2.7±3.4, p&lt;0.001), were more likely to have bone (12.1% vs. 8.5%), lung (36.6% vs. 26.2%) and liver (73.5% vs. 66.2%) metastases, were less likely to have peritoneal (3.7% vs. 10.1%) metastases (all p&lt;0.05), and had poorer performance status (PS) (ECOG &gt;1: 41.9% vs. 34.0%, p=0.042). No significant differences were found by cancer location (colon, rectum, both), if the cancer was newly diagnosed or a recurrence, or in tumor histologic grade. Conclusions: While KRAS testing increased in 2008-2009 corresponding to changes in treatment guidelines and anti-EGFR product labels, the majority of patients were not tested. The proportion tested at diagnosis continued to increase annually from 2008-2011. Patients with greater comorbidities and poorer PS are more likely to undergo KRAS testing than healthier patients.