tbuckley/cabot-search huggingface dataset:
Single versus tandem high dose chemotherapy (HDC) with hematopoietic stem cell support in patients with chemosensitive metastatic breast cancer (BC) –results from a multicenter phase III trial
Authors: U. A. Nitz, N. Kroeger, M. Frick, S. Mohrmann, B. Metzner, Y. Ko, E. Berdel, C. Ziske, H. G. Bender, A. Zander
Journal: Journal of Clinical Oncology (2004)

6665 Background: Optimal HDC strategy in breast cancer remains to be defined. This phase III trial evaluates the role of the number of HDC cycles. Methods: From 2/97 to 6/01 we randomised 187 patients to single or to tandem HDC. Patients were eligible if they were hormone refractory and achieved complete or partial remission after 4 to 6 cycles of standard induction chemotherapy. Patients were stratified according to remission status and localisation of metastases (bone or visceral). HDC consisted of once or twice STAMP V with cyclophosphamide, carboplatinum and thiotepa (6000/800/500 mg/m2) the tandem given at an interval of 35 days.Pts. (single/tandem): mean age 45.7/45.1 yrs, prior adjuvant chemotherapy 41%/40%, ER +: 49%/43%, mean recurrence-free interval: 45.4/37.9 months. 11% of patients had isolated bone metastases. Induction chemotherapy consisted in 51% /48 % of a combination of anthracylines and taxanes. 14 % of patients in the single and 43 % of patients in the tandem-HDC arm did not receive the planned treatment. Results: Toxicity data were reported earlier (Proc ASCO 17:141a,1997). Treatment related mortality was 3,6 %. After exclusion of drop outs CR rates are 46% in the tandem and 33% in the single HDC arm. With a median follow-up of 24 months the intent to treat analysis shows progression-free survival rates of 36%/43% after two years and 6%/12% after three years (p=0.055) in favour of the tandem. Overall survival rates were 55% and 48% after two and 18% and 21% at five years with a median overall survival of 29.4 versus 23.5 months (p =0.46) Conclusions: Tandem STAMP V induces higher complete remission rates and non significantly higher progression-free survival rates. Overall survival is not affected. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Angem
T<sub>reg</sub> depletion with denileukin difititox (DD) enhances lymphocytosis and eosinphilia in patients treated with high-dose IL-2 (HDIL-2) for metastatic renal cell cancer (MRCC)
Authors: A. Gidron, J. Eklund, B. Mortone, A. W. Rademaker, C. Goolsby, T. Kuzel
Journal: Journal of Clinical Oncology (2006)

14627 Background: CD4 + CD25 + T cells (T reg ) play a suppressive role in immune regulation. DD is an IL-2 receptor specific cytotoxin. We postulated depletion of T reg with DD may enhance immune effector cell populations during HDIL-2 tx, including eosinophilia which was reported to be involved in immune response to neoplasm (Mattes et al. J Exp Med 197: 387, 2003). Methods: Seven pts (5 male, median age 58 yrs) with MRCC were tx’d with HDIL-2 and DD in different schedules to determine safety and effect on immune response as manifested by changes in T reg , lymphocyte, and peak eosinophil counts. Pts were tx’d with IL-2 600,000 IU/kg Q8H on days (d) 1–5 and 15–19. Three (group A) and 2 (group B) pts were given 6 and 9 ug/kg daily on d 8–10 respectively, while 2 (group C) pts received 9 ug/kg of DD on d -4- -2. Four (group D) pts with metastatic melanoma who received HDIL-2 as above but without DD were included as controls. Flow cytometry was done on days -4, 1,8,10,15 for group C and on days 1, 8, 10, 15, 22 for groups A, B, and D. CBC was obtained within 24 hours of flow cytometry. Results: After DD T reg increased in group A (mean change in absolute T-reg count of 16%) and decreased in groups B and C (34.5 and 20% respectively) compared to baseline. Group C trended toward a greater lymphocytosis at day 8 compared to all other groups (mean increase of 8.6 vs. 3.3 K/ul p = 0.059). A higher peak level of eosinophilia was noted in group C compared with groups A, B and D combined (mean increase of 9.9 vs. 3.0 k/ul p = 0.03). Group C demonstrated a higher mean % change in absolute number of CD8+ T-cells between onset of therapy and Day 8 compared to groups A, B, D combined (increase of 1095% vs. 496% respectively, p = 0.35). Toxicity was similar to that expected with HDIL-2. Conclusions: Administration of DD in conjunction with HDIL-2 was associated with a decrease in T reg that may be schedule and dose dependent. The results suggest an enhanced immune stimulatory effect as manifested by lymphocytosis and peak eosinophilia and CD8 + T-cells in group C. Despite small pt numbers, results suggest that pre-treatment with DD may confer an advantage. It is too early to know if laboratory results correlate to clinical benefit. [Table: see text]
Abstract 183: A Genomewide Screen to Identify Novel NFAT Regulators
Authors: Majorie Maillet, N Scott Blair, Jeffery D Molkentin
Journal: Circulation Research (2012)

NFAT (Nuclear Factor of Activated T cells) transcriptions factors are directly activated by the Ca2+ activated serine-threonine protein phosphatase calcineurin. Following dephosphorylation, NFAT factors translocate to the nucleus. They share a Rel/NFkB homology DNA binding domain that functions in concert with other transcription factors such as AP-1, GATA4, NFkB, MEF2, CREB, Myc, and IRF-1 to alter the expression of genes involved in tissue and cellular differentiation as well as adaptation to extracellular stimuli. Although the fundamental aspects of how NFAT factors are regulated by phosphorylation and dephosphorylation, as well as some interacting factors, have been described; much remains to be understood about the function of these factors in cardiac myocytes and other cell types. To identify potential new NFAT regulators that could influence nuclear shuttling or its trans-activating properties, we performed a genome wide screen with a NFAT-dependent luciferase reporter and a library of cDNA expression plasmids. Roughly 20,000 cDNA expression plasmids from the Mammalian Genome Collection were individually co-transfected with a NFAT-luciferase reporter in a human immortalized cell line in 384-well plates. Approximately 2% of the genes of the library gave a positive result, including well-known NFAT partners, calcium sensitive genes and transcriptions factors. Among them, twenty potential NFAT activators were selected and NFAT-Luciferase activation was validated in a secondary screen which normalized for transfection efficiency and cell number. The results of the screen will be presented along with functional characterization of the more interesting interacting NFAT co-activators.
Accelerated BEP for metastatic germ cell tumors: Combined analysis of Australian and U.K. phase I/II trials.
Authors: Peter S. Grimison, Mark D. Chatfield, Danish Mazhar, Guy C. Toner, John D. Chester, Martin R. Stockler, Daniel P. Stark, Damien B. Thomson, Jonathan Shamash, Michael Friedlander, Jeff White, Val Gebski, James Wason, Amy L Boland, Yvonne L. Rimmer, Angus McDonald, Howard Gurney, Mark Rosenthal, Nimit Singhal, Michael V. Williams
Journal: Journal of Clinical Oncology (2012)

4531 Background: Standard chemotherapy for advanced germ cell tumors is 3-weekly BEP (bleomycin, etoposide, cisplatin). 5-year overall survival is &gt; 90% in good risk disease, but only ~80% in intermediate and ~ 60% in poor risk disease. Accelerated versions of standard regimens have proven more effective in other malignancies. We aimed to determine tolerability and activity of accelerated (2-weekly) BEP by combining data from two single arm, multi-center, phase I/II trials. Methods: The UK trial (n=16) included patients with intermediate and poor risk metastatic germ cell tumours. The Australian trial (n=45) also included patients with radiologically measurable good risk disease. BEP chemotherapy was repeated every 2 weeks for 4 cycles (3 cycles for good risk). The Australian and UK regimens differed for cisplatin (20mg/m 2 D1-5; 50mg/m 2 D1-2), etoposide (100mg/m 2 D1-5; 165mg/m 2 D1-3), bleomycin (30kIU weekly x 12 or 9; 30kIU at 4-6 day intervals x 12), and pegylated G-CSF (6mg D6; 6mg D4) respectively. Primary endpoint for combined analysis was 2-year progression-free survival. Results: 61 patients were enrolled from 2004-09 (UK) and 2008-10 (Australia). 17 had poor risk, 28 intermediate risk, 16 good risk disease. Median follow-up is 27 months (range 6 to 81). Adverse events are presented in the table. 45 of 61 patients (74%) achieved a complete response to chemotherapy +/- surgery (9 of 17 poor risk (53%), 20 of 28 intermediate risk (71%), 16 of 16 good risk disease (100%)). 11 of 61 patients have relapsed. 2 patients have died of disease (both intermediate risk). 2 year overall survival is 98%. 2 year progression-free survival is 65% for poor risk, 86% for intermediate risk, and 92% for good risk disease. Conclusions: Efficacy data are promising, particularly for intermediate and poor risk disease. Adverse events appear comparable to standard BEP. These results provide the rationale for an international trial randomised trial comparing accelerated and standard versions of BEP. [Table: see text]
Changes in gene expression profiling due to primary chemotherapy in patients with locally advanced breast cancer
Authors: J. Hannemann, H. M. Oosterkamp, C. A. J. Bosch, C. Loo, A. Witteveen, A. Velds, E. J. T. H. Rutgers, S. Rodenhuis, M. Van de Vijver
Journal: Journal of Clinical Oncology (2004)

502 Introduction: It is currently not possible to predict sensitivity of locally advanced breast cancer (LABC) to specific drugs. This study was designed to identify gene expression patterns in LABC that can predict response to neoadjuvant therapy with Adriamycine (60 mg/m2) and Cyclophosphamide (600 mg/m2) (AC); or Adriamycine (50 mg/m2) and Docetaxel (75 mg/m2) (AD). Methods: We started a phase III trial for patients with locally advanced breast cancer, randomizing between 6 courses of AC or 6 courses AD. Total RNA was isolated from a 14 G core needle biopsy obtained before treatment. All patients underwent surgery after completing chemotherapy. RNA was isolated from any remaining tumor. Amplified mRNA was hybridized on human 18k cDNA microarrays (NKI microarray facility). Supervised and unsupervised classifications were used to analyze differences between gene expression before and after treatment and to correlate expression profiles with response to the chemotherapy. Results: 62 patients with LABC have been randomized in the study. Good quality RNA from tissue with more than 50% tumor cells was obtained from 46 biopsies and from 18 tumors after chemotherapy. Data from 49 patients were included in the analysis: 25 from the AC arm, 24 from the AD arm. Using two-dimensional unsupervised hierarchical clustering, the tumor and biopsy clustered together in almost all cases when no response to chemotherapy was observed. When partial or complete remission was observed, the untreated biopsy specimens and the tumors after treatment clustered together more closely than the specimen obtained from individual patients before and after treatment. Using 9-fold cross-validation on the whole dataset containing 46 biopsies before and 18 specimen after treatment, an optimal number of 30 genes could be identified to distinguish between specimen before and after treatment with an average performance of 91%. Discussion: When breast carcinomas do not respond to neoadjuvant chemotherapy, there are no large alterations in the gene expression pattern. When tumors respond, a gene expression pattern of 30 genes distinguishes tumors before and after therapy. No significant financial relationships to disclose.
Randomized 2 × 2 Trial Evaluating Hormonal Treatment and the Duration of Chemotherapy in Node-Positive Breast Cancer Patients: An Update Based on 10 Years’ Follow-Up
Authors: W. Sauerbrei, G. Bastert, H. Bojar, C. Beyerle, R. L. A. Neumann, C. Schmoor, M. Schumacher
Journal: Journal of Clinical Oncology (2000)

PURPOSE: In 1984, the German Breast Cancer Study Group started a multicenter randomized trial to compare six versus three cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) starting perioperatively and to investigate the additional effect of tamoxifen as adjuvant treatment in node-positive breast cancer patients treated with mastectomy. PATIENTS AND METHODS: From 1984 to 1989, 473 patients were randomized from 41 institutions. After a median follow-up of approximately 10 years for overall survival (OS) and 9 years for event-free survival (EFS), the treatment groups were compared with respect to OS and EFS. Results based on a median follow-up of 56 months have been published earlier. RESULTS: Estimated cumulative locoregional incidence rate after 10 years was 19.9%; the corresponding rate of distant recurrences was 41.3%. Concerning duration of chemotherapy, we did not find any difference between six and three cycles of CMF (EFS: relative risk [RR] in multivariate analysis = 0.95; 95% confidence interval [CI], 0.74 to 1.21 OS: RR = 0.90; 95% CI, = 0.69 to 1.18). Treatment with tamoxifen resulted in an improvement in outcome (EFS: RR = 0.81; 95% CI, 0.61 to 1.07, OS: RR = 0.74; 95% CI, 0.55 to 1.0) although it proved not significant. Number of positive lymph nodes and progesterone receptor were the dominant prognostic factors. CONCLUSION: In this study, we observed some tendency in favor of hormonal treatment, which is in agreement with the literature. Concerning duration of chemotherapy, the results of this study provide further evidence that a reduction to three cycles of CMF is possible without increasing the risk of recurrence or death. For a definitive conclusion, however, further investigations are required.
The influence of the interval between IORT during breast-conserving surgery and external beam radiotherapy (EBRT) on late toxicity
Authors: G. Welzel, E. Blank, U. Kraus-Tiefenbacher, A. Keller, F. Vorodi, C. Herskind, O. Tome, M. Sütterlin, F. K. Wenz
Journal: Journal of Clinical Oncology (2008)

630 Background: Intraoperative radiotherapy (IORT) during breast-conserving surgery is increasingly used. When given as a boost, the sequencing of IORT, systemic therapy and external beam radiotherapy (EBRT) may be of importance as to local tumor control and normal tissue damage. We analyzed the influence of the interval between IORT and EBRT on the development of late toxicity in breast cancer patients receiving IORT as a boost before EBRT to the whole breast. Methods: Forty-eight patients (62.7 ± 9.1 yrs) were followed for a median of 36 months (minimum 30 months) after IORT and EBRT. The IORT boost was given with 50 kV x-rays (INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany) delivering 20 Gy at the applicator surface and was followed by 46 - 50 Gy EBRT with a median interval of 36 days (14 - 197). Toxicity was assessed with the modified LENT SOMA score. Results: Thirty patients had no higher grade chronic toxicity. Of the 18 patients with chronic higher grade toxicity, 12 patients developed a higher grade fibrosis (II - III), 3 patients teleangiectasia, 1 breast edema grade II, 6 retraction, 4 hyperpigmentation and 5 pain (grade II - III). The median interval between IORT and EBRT was significantly shorter in these patients (n = 18) compared to the 30 patients without chronic higher grade toxicity (29.5 d vs. 39.5 d, p = 0.023, Mann-Whitney U test). Conclusions: Starting EBRT about 5 - 6 weeks after IORT appears safe. A shorter interval between IORT and EBRT was associated with an increased frequency of chronic late toxicity. No significant financial relationships to disclose.
Breast cancers with stem cell-like features delineate endocrine responsiveness
Authors: A. Rody, T. Karn, C. Solbach, R. Gaetje, R. Diallo, M. Gehrmann, G. von Minckwitz, S. Loibl, U. Holtrich, M. Kaufmann
Journal: Journal of Clinical Oncology (2007)

10517 Background: Endocrine responsiveness is one of the most important characteristics of breast cancer. The negative association between expression of the estrogen receptor (ER) and proliferation detected in normal breast is frequently lost in breast cancers leading to receptor independent growth and poor patients’ prognosis. Methods: Microarray analysis of 171 breast cancer samples allowed the discrimination of a KIT + tumor group by using a set of genes coregulated with the “stem cell factor” receptor KIT. Validation was performed on three independent datasets encompassing 637 samples. Furthermore the response to endocrine treatment only was analyzed in a dataset of 700 patients. Results: KIT + tumors are transcriptionally related to proposed mammary stem cells. Two types of KIT + tumors were identified which are characterized by their positive and negative ER status, respectively. The inverse link of ER expression and proliferation is perfectly conserved within the KIT + tumor groups, while it is uncoupled among half of the KIT-Low ER positive tumors. Those “uncoupled” ER positive tumors with altered ER response are characterized by a prognosis inferior to the ER negative cancers despite an apparent positive ER status (hazard ratio for disease recurrence, 2.07; 95% CI 1.53–2.81; P&lt;0.001). Moreover, the 5 and 10 year survival rates of lymph node negative “uncoupled” tumors are even worse than those of lymph node positive “normal” ER positive cancers. While all ER positive patients seem to profit from endocrine treatment the relative benefit was reduced in uncoupled tumors (21.2 % vs. 31.7 %). Conclusions: The classification of breast cancers according to this biologically based model identified clinical relevant tumor groups whose further characterization will have important implications. Moreover, since the ability to recognize malfunctions in ER pathways largely depends on an appropriate reference system, the KIT + tumors could allow a dissection of estrogen responsiveness giving crucial insights for prediction of response to endocrine therapy. No significant financial relationships to disclose.
Prognostic role of serum levels of hTERT, VEGF, and EGFR in metastatic colorectal cancer
Authors: R. Sirera, C. Camps, A. Blasco, A. Cabrera, M. Safont, V. Iranzo, D. Cayuela, C. Caballero, M. Gil, J. Lorca
Journal: Journal of Clinical Oncology (2008)

15075 Background: Serum hTERT levels have been demonstrated as prognostic markers in several malignancies. VEGF is the most important angiogenic factor and EGFR is an oncogen with prognostic implications in cancer. Our objective was to analyze the prognostic role of serum concentrations of hTERT, VEGF and EGFR in metastatic colorectal patients and their association with other clinical variables. Methods: Retrospective analysis with 55 patients diagnosed of colorrectal carcinoma stages II-IV diagnosed between 2001 and 2005. Blood samples were collected before any clinical intervention. Concentration levels of VEGF and EGFR were determined by a sandwich quantitative ELISA. Serum free DNA was isolated by using Qiagen affinity columns and hTERT levels were assessed by RT-PCR using a Taqman assay. Results: Median age was 70 years; 60% males; 8% stage II, 56% stage IIIB and 36% IV; 62% curative and 38% palliative surgery; 58% not presented metastasis. Median hTERT levels increased significantly with stage: II, 298 ng/ml; III, 545; III, 1460; p=0.048. hTERT values differ significantly between those patients that received curative surgery versus those with palliative: 492 ng/ml vs 1224, p=0.042. EGFR, VEGFR and hTERT serum levels were not correlated with pre-operative CEA levels, presence of anaemia or metastasis or relapse after surgery. Splitting the cohort in two groups attending to median levels of serum EGFR, VEGFR and hTERT, time to progression and overall survival curves were not significantly different. Conclusions: hTERT levels, but not EGFR and VEGF increase significantly with disease severity or stage. We have not found any other correlation between these molecular mediators and any patient's clinical characteristics. No significant financial relationships to disclose.
Treatment Patterns in Patients (Pts) with Metastatic Castration-Resistant Prostate Cancer (Mcrpc) Previously Treated with Docetaxel (Doc)-Based Chemotherapy (Ctx): Proxima
Authors: H. Akaza, G. Procopio, C. Pripatnanont, G. Facchini, S. Fava, D. Wheatley, K.C. Leung, M. Butt, A. Silva, L. Castillo, G. Fountzilas, S. Hitier, E.B. Ecstein-Fraisse, S. Bensfia, M. Özgüroğlu
Journal: Annals of Oncology (2014)
Therapy of renal cell carcinoma with interleukin-2 and lymphokine-activated killer cells: phase II experience with a hybrid bolus and continuous infusion interleukin-2 regimen.
Authors: D R Parkinson, R I Fisher, A A Rayner, E Paietta, K A Margolin, G R Weiss, J W Mier, M Sznol, E R Gaynor, M H Bar
Journal: Journal of Clinical Oncology (1990)

Forty-seven patients with metastatic or unresectable renal cell carcinoma were treated with interleukin-2 (IL-2) and lymphokine-activated killer (LAK)-cell therapy, using a hybrid IL-2 regimen. IL-2 was administered initially by intravenous bolus (10(5) U/kg [Cetus Corp, Emeryville, CA] every 8 hours for 3 days) during the priming phase, and subsequently by continuous infusion (3 x 10(6) U/m2 for 6 days); during this second treatment period, in vitro-generated LAK cells were administered. Despite selection of patients for good performance status (PS) (29, PS 0; 18, PS 1) prior nephrectomy (43 of the 47 patients), and low tumor burden, the response rate was low (two complete [CRs] and two partial responses [PRs], for an overall objective response rate of 9%). Toxicity was comparable to that experienced with the high-dose bolus regimen. These results suggest that the dose and schedule of IL-2 administration may influence the likelihood of response to IL-2 in renal cell carcinoma.
The impact of recurrence score (RS) performed on pretreatment (Tx) core biopsies (CB) in predicting response to neoadjuvant chemotherapy (NCT) in patients (Pts) with ER+ breast cancer (BC).
Authors: Atilla Soran, Kandace P. McGuire, Gretchen Ahrendt, Marguerite Bonaventura, Priscilla F. McAuliffe, Emilia Diego, Merida Serrano, Ronald Johnson
Journal: Journal of Clinical Oncology (2013)

63 Background: The Oncotype DX 21-gene assay is beneficial in predicting disease-free survival and local regional relapse in hormone receptor BC. The ability of the assay to predict response of primary BC to NCT is less well studied. We hypothesize a (+) association exists between the RS result on pre-Tx CB and % tumor response (%TR) after NCT on final pathology. Methods: Pre-Tx RS was measured on paraffin-embedded CB from 60 pts with ER+ Her2(-) BC who then received NCT and for whom post-Tx pathology was available. %TR is calculated as 100 x (pre-Tx size – post-Tx size)/pre-Tx size. Pre-Tx tumor size was determined using imaging measurements selected in the following preferential order: MRI, US or mammogram. Post-Tx tumor size was calculated as the product of: maximum dimension of tumor-bed/fibrosis and % change in cellularity (compared with pre-therapy biopsy). Partial response (PR) is defined as ≥50% reduction in TR. Results: Mean pre-Tx tumor sizewas 4.8 (range 1-23) cm. 83% of pts were clinically lymph node (-). Nottingham Score was &gt;6 in 93%. Breast conserving surgery was performed in 17 (28%) pts. Median RS was 20 (range 3-69). Median %TR was 42 (range 0-97)%. There were no pCRs. PR was observed in 43% of pts. No association was found between %TR and pre-NCT tumor size, age, Nottingham score or node status (p&gt;0.05). No association for the RS as a continuous or categorical variable with %TR (p&gt;0.05) was seen. There is a non-significant (p=0.07) trend toward increased response to NCT with increasing RS. Response to NCT improved as values of ER (p=0.02) and HER2 (p=0.007), by RT-PCR as reported with the RS, decreased. Conclusions: In the subset of patients with ER+ BC, where NCT was recommended to affect tumor downstaging, RS did not successfully discriminate pts that would respond to NCT as measured by %TR. While there was a trend toward better response with higher scores, the result was nonsignificant. The use of this genetic assay to discriminate between NCT and hormonal therapy requires further study. [Table: see text]