tbuckley/cabot-search huggingface dataset:
Telomerase interference in combination with docetaxel therapy for maximal prostate cancer inhibition: In vitro data for a novel therapeutic approach
Authors: D. Sahu, T. Xu, R. Lau, L. Xue, A. Goldkorn
Journal: Journal of Clinical Oncology (2009)

e14596 Background: Metastatic castration-resistant prostate cancer (mCRPC) carries a median survival of 18 months with standard docetaxel based therapies. Telomerase interference (TI) is a promising novel therapeutic strategy that exploits the high telomerase activity in cancer cells by introducing a mutated telomerase RNA (MT-Ter) that encodes toxic telomeres and rapidly induces apoptosis. We investigated whether TI can be combined with docetaxel therapy to achieve greater growth inhibition in mCRPC. Methods: PC3 and DU145 mCRPC cell lines were treated with docetaxel in the presence of TI or vector control. TI was accomplished by concurrent lentiviral expression of 2 constructs: telomerase RNA with an altered template region (MT-Ter) and siRNA targeting wild-type telomerase RNA (anti-Ter siRNA). Telomere length and telomerase activity were assessed using RT-PCR and TRAP, respectively. Proliferation, apoptosis, and DNA damage were quantified using MTS, TUNEL, and 53bp1 staining, respectively. Statistical significance was calculated using a 2-sided t-test. Results: Docetaxel (10nM) induced 22% inhibition (p=0.01) of PC3 proliferation in the presence of vector control and 41% inhibition (p=0.001) in the presence of TI (results were similar in DU145 cells). This near-doubling of efficacy was attributable to an independent inhibitory effect (17% inhibition, p=0.04) from TI treatment alone, which occurred without change in bulk telomere length or telomerase activity. TI alone generated increased numbers of DNA damage foci (7/cell vs. 2/cell with vector control) while docetaxel alone did not generate significant increases in DNA damage. Both TI and docetaxel induced a marked increase in the rate of apoptosis. Conclusions: Docetaxel and TI each exerted a pro-apoptotic effect which, when combined, produced an additive inhibition of mCRPC proliferation. TI-mediated apoptosis ensued from DNA damage, consistent with its known telomeric-uncapping effect, while docetaxel-induced apoptosis was not associated with direct DNA damage, also consistent with known docetaxel mechanisms of action. These findings underscore the therapeutic promise of combining standard agents with TI to improve efficacy and reduce toxicity. No significant financial relationships to disclose.
Benefit of cytostatic therapy in 3rd and following line in metastatic breast cancer
Authors: A. Dieing, G. Georgieva, P. Schmid, A. C. Regierer, N. Ehlers, B. Flath, K. Possinger
Journal: Journal of Clinical Oncology (2005)

742 Background: A variety of cytostatic substances are effective in the treatment of metastatic breast cancer. Most substances have been evaluated in clinical studies as first- or second-line therapy, and occasionally as third-line therapy. However, patients (pts.) with progressive disease after second line therapy and good performance status might receive further treatment. Known pathomechanisms and clinical experience support the assumption that tumors which progress during chemotherapy are more likely to be resistant to following therapies, but clinical studies are not available. The aim of this retrospective study was, to evaluate the effect of third- to seventh-line cytostatic therapy. Methods: 120 patients with metastatic breast cancer with at least three cytostatic therapies from 1991 to 2004 were included. Median age at first diagnosis of breast cancer was 51 years (27–76), 64% of the tumors were hormone receptor positive. 58% of the patients had received (neo-) adjuvant cytostatic therapy. Therapies were evaluated with respect to response, time to treatment failure (TTF) and toxicity WHO III° and IV°. Results: Of 120 patients, 120 received three, 99 four, 63 five, 31 six and 21 seven consecutive cytostatic regimens. Mainly used cytostatic substances were (descending frequency): anthracyclines, taxanes, vinca alcaloids, alkylating agents, capecitabine or 5-fluoruracil, gemcitabine and trastuzumab. Response rates, TTF and toxicity rates are shown in table 1. Conclusions: Clinical benefit for patients with metastatic breast cancer is possible even after several preceding cytostatic therapies. High grade toxicity is rare. Thus, further therapy for those patients can be acceptable in individual situations. No significant financial relationships to disclose.
A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, ifosfamide (VIP) plus stem cell support in males with poor prognosis germ cell cancer (GCC): An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974).
Authors: G. Daugaard, I. A. Skoneczna, N. Aass, R. De Wit, M. De Santis, H. Dumez, S. Marreaud, L. Collette, C. Bokemeyer, H. Schmoll
Journal: Journal of Clinical Oncology (2010)

4512 Background: To compare the efficacy of one cycle standard dose VIP plus three cycles high-dose VIP followed by stem cell infusion to four cycles standard BEP in previously untreated patients with poor prognosis GCC. Methods: Patients with poor prognosis GCC were randomly assigned to receive either BEP regimen or VIP followed by high-dose chemotherapy with peripheral stem-cell supp ort (HD-CT arm). Patients assigned to HD-CT-arm received one 21-day cycle of VIP (cisplatin 20 mg/m2 i.v. days 1-5), etoposide 75 mg/m2 i.v. days 1-5 and ifosfamide 1200 mg/m2 i.v. days 1-5. followed by three 21-day cycles of high-dose VIP: Cisplatin 20 mg/m2 i.v. days 1-5, etoposide 300 mg/m2 i.v. days 1-5 and ifosfamide 2400 mg/m2 i.v. days 1-5). To show a 15% improvement in 1-year failure-free survival at 2-sided 5% significance (Logrank) and 80% power, the study aimed to recruit 222 patients but closed with 137, due to slow accrual. Results: 131 patients were included in this analysis. All 66 patients assigned to BEP started treatment. Of 65 patients allocated HD-CT 62 (95.4%) received that treatment. The approximate dose intensity in the BEP and the HD-CT arm was 97.7% and 89.3%, respectively.The complete response rates in the HD-CT and in the BEP- arm did not differ: (ITT) 44.6% vs 33.3% (p=0.18). There was overall no difference in failure-free survival between the two treatment arms (Logrank P=0.057, 66 events). At one year the failure-free survival rate was 48% (95% CI 35.5-59.5) after BEP and 66.1% (95% CI 53.1-76.2) after HD-CT with a difference of 18.1% (SD=7.3%), (P=0.035). At 2 years it was 44.8% (95% CI 32.5-56.4) after BEP and 58.2% after HD-CT(95%CI 48.0-71.9); but this 16.3% (SD 7.5%) difference was not statistically significant (P=0.060). Overall survival did not differ between the two groups (Logrank P>0.1, 47 deaths). Toxicity was more severe in pts on HD-CT. Conclusions: This study could not demonstrate that high-dose chemotherapy plus autologous stem cell support given as part of first-line therapy improves outcome in patients with po or prognosis GCC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck, MSD, Roche AstraZeneca, Merck, Roche Merck, Roche
The Myelofibrosis Symptom Burden (MF-SB): An International Phenotypic Cluster Analysis of 329 Patients
Authors: Holly Lynn Geyer, Amylou C. Dueck, Robyn M. Emanuel, Jean-Jacques Kiladjian, Stefanie Slot, Sonja Zweegman, Peter Boekhorst, Suzan Commandeur, Harry C Schouten, Federico Sackmann, Ana Kerguelen Fuentes, Dolores Hernandez-Maraver, Heike Pahl, Martin Griesshammer, Frank Stegelmann, Konstanze Doehner, Françoise Boyer, Gabriel Etienne, Jean-Christophe Lanotto, Dana Ranta, Lydia Roy, Jean-Yves Cahn, Claire N Harrison, Deepti H Radia, Pablo J. Muxi, Norman I. Maldonado, Carlos Besses, Francisco Cervantes, Peter Johansson, Giovanni Barosi, Alessandro M. Vannucchi, Francesco Passamonti, Bjorn Andreasson, Maria L Ferarri, Alessandro Rambaldi, Jan Samuelsson, Gunnar Birgegard, Zhijian Xiao, Yue Zhang, Xiujuan Sun, Junqing Xu, Robert Peter Gale, Ayalew Tefferi, Peihong Zhang, Thomas Lehmann, Andreas Reiter, Karin Bonatz, Ruben A. Mesa
Journal: Blood (2012)
An open label, randomized phase II trial of primary systemic therapy with exemestane (EXE 25 mg/d) plus epirubicin (EPI, 20 vs 30 mg/m<sup>2</sup> q1w × 8–12) in breast cancer: An interim analysis of the German Neoadjuvant Aromasin Initiative (GENARI-3)
Authors: C. J. Wolf, G. Raab, W. Eiermann, I. Grammatikakis
Journal: Journal of Clinical Oncology (2004)

826 Background: This randomized phase II trial explores the efficacy of EXE, a steroidal aromatase inactivator, in combination with lower doses of EPI, a topoisomerase-II targeted anthracycline, as an alternative presurgical therapy (PST) option for women who may not be eligible for more toxic primary chemotherapy regimens. Methods: Age: ≥ 50 years, postmenopausal hormone receptor (HR) + /−, primary tumors T2, 3, 4a-c, Nx, M0, ECOG PS 0–2. All patients (pts) obtained continuous EXE and were randomized to either 20 mg/m2 (A) or 30 mg/m2 (B) EPI q1w × 8–12. Endpoints (1st/2nd): pathological complete remissions (pCR), rate of breast conserving surgery (BCS), and grade/frequency of toxicity. Results: A total of 23 pts (12 in arm A, 11 in B) with median age of 68 (53–77) and tumor status T2 were enrolled. 28 patients are still under therapy and will be applicable for final analysis at the time of this presentation. All pts were HR+ and were evaluable for toxicity. Four patients (n=3: 20 mg/m2; n=1: 30 mg/m2) had reduced numbers of cycles [5(n=2), 6(n=1), 11(n=1)] after dose delay due to grade (G) 2 toxicity (NCI-CTC): leukopenia (n=2), infection (n=2) or G 3 toxicity: infection (n=1). One patient withdrew consent for pre-operative staging and surgery (arm B, no DLT). Efficacy (22 pts): Clinical responses were as follows: (A/B): clinical partial responses, n= 9/7; clinical stable disease, n= 3/3. Pathological tumor response (A/B): ypT0 (pCR), n=0/1, ypT1a, n=1/0; ypT1c, n=6/2; ypT2, n=4/5; ypT3, n=1/2. BCS: n=19/3. Conclusions: The interim results for 23 of 60 patients suggest good therapeutic efficacy and excellent tolerability of combined EXE and EPI . It has to be shown wether this treatment offers additional benefit for women with hormone- receptor positive breast cancer, who showed lower response to primary chemotherapy when compared to receptor- negative patients. In addition this supports the concept of combination PST as an alternative to hormonal PST in postmenopausal patients. No significant financial relationships to disclose.
Bronchial-associated lymphoid tissue (BALT) lymphoma: a retrospective analysis
Authors: S. Steffanoni, G. Pruneri, L. Spaggiari, L. Preda, D. Laszlo, L. Calabrese, E. Zucca, S. Bassi, G. Martinelli
Journal: Journal of Clinical Oncology (2006)

17547 Background: Systemic CT in BALT lymphoma is the accepted therapy for those pts where surgery isn’t radical or possible. There is not a standard systemic treatment for this uncommon lymphoma however its indolent behavior and the relative asymptomatic outcome, allows on systemic therapy delay and may justify the use of less toxic CT agents. Methods: Here we reported our experience on 19 pts (10 men and 9 women) with biopsy-proven BALT lymphoma, median age was 61 yrs; 8 pts presented a symptomatic disease at diagnosis. 15 pts had a localized pulmonary disease (stage IE); 4 pts had stage IVE disease for peripheral blood and bone marrow involvement (3 pts) and gastric involvement (1 pt). Of 16 pts valuable for response, 3 pts received radical surgery (1 wedge resection and 2 lobectomy) as definitive treatment and 13 pts received systemic treatment (Chl containing regimen in 6, Rituximab ± Chl in 6; CVP regimen in 1) because of symptomatic disease or relapse after major surgery. Results: 6/13 pts achieved CR: 5/6 are still alive and disease free: 1 pt in CR died for other causes. 3 pts in asymptomatic PR don’t need further therapy while the additional 4 pts in PR need subsequent treatment because of symptomatic progression after a median TTP of 40 months. With a median follow up of 39 months, the OS and RFS observed are 85% and 63% respectively. Hematology and non-hematology toxicity was in general mild: transient G3 neutropenia occurred in only two pts; no pt discontinued the treatment because of treatment-related toxicity and no toxic death was recorded. Conclusions: Our analysis seem to confirm that surgery could be considered as unique treatment only for minority of pts with BALT lymphoma. Systemic chemotherapy with Chl containing regimen may achieve a clinical control of disease with about 50% of CR as well as other reported with more aggressive CT regimen. A larger retrospective analysis on pathological figure and clinical outcome is planned on behalf of IELSG. No significant financial relationships to disclose.
Effects of ascites on perioperative and postoperative outcome in epithelial ovarian cancer
Authors: A. P. Novetsky, T. L. Pua, J. P. Curtin
Journal: Journal of Clinical Oncology (2009)

e16567 Background: A third of epithelial ovarian cancer (EOC) patients (pts) present with ascites at the time of diagnosis. Though not universally accepted, ascites has been reported to be a poor prognostic factor. Our purpose is to study the effects of ascites on the peri and postoperative outcome in EOC patients undergoing cytoreductive surgery. Methods: 172 EOC pts were retrospectively evaluated to determine the prognostic significance of ascites. Pts were divided into two groups based on the presence of ascites defined in pre-operative CT scans as A, none/small, versus B, moderate/ large. Influence of ascites on peri- and post-operative characteristics such as estimated blood loss (EBL), rates of optimal cytoreduction, intensive care unit (ICU) admission, minor complications (infection, ileus/bowel obstruction, transfusion, wound separation, DVT/PE), major complications (death or readmission within 30 days) and length of hospital stay (LOS) were analyzed using Chi Square, multivariate linear and cox regression, where appropriate. Results: There was no significant difference in EBL between the two groups (p = 0.27). Pts in A were more likely to be optimally cytoreduced compared to B (96% vs 61%, p &lt; 0.001). After controlling for stage, women in B were more likely to be admitted to the ICU, (OR 3.03 (95% CI: 1.05–8.71). The rates of major complication was higher for B (3% vs 10%) though this did not reach statistical significance (p = 0.06). Overall minor complications were greater for B than in A (64% vs 26%, p &lt; 0.0001). After controlling for stage, LOS was 2.9 days longer in B (p = 0.02). 21 women received at least 3 cycles of neoadjuvant chemotherapy prior to cytoreduction. EBL, LOS and major complications were no different than those undergoing primary cytoreduction then adjuvant chemotherapy. Conclusions: Optimal management of EOC pts with ascites is uncertain. Pts with ascites are more likely to be suboptimally cytoreduced, have increased rates of complications and consume more healthcare resources (ICU admission and longer LOS). Though our numbers are small, patients who received neoadjuvant chemotherapy do not have any difference in peri-post operative characteristics, but were all optimally cytoreduced. No significant financial relationships to disclose.
Outcome to erlotinib in non-small cell lung cancer (NSCLC) patients (p) according to the presence of the EGFR T790M mutation and BRCA1 mRNA expression levels in pretreatment biopsies.
Authors: R. Rosell, M. A. Molina, C. Costa, M. Taron, J. Bertran-Alamillo, C. Mayo, S. Benlloch, T. Moran, F. Cardenal, R. Porta
Journal: Journal of Clinical Oncology (2010)

7514 Background: The initial pr esence of double EGFR mutations (L858R or exon 19 deletion plus T790M) has been detected in the absence of drug selection and could explain the selection of the T790M mutation as the single drug-resistance mutation during therapy with gefitinib or erlotinib. Experimental evidence shows that the disruption of BRCA1 enhances erlotinib-mediated cytotoxicity. Methods: Pretreatment biopsi es from129 erlotinib-treated NSCLC p with EGFR mutations were re- examined for the presence of the T790M mutation using laser microdissection followed by TaqMan assay in the pr esence of a peptide-nucleic acid clamp. BRCA1 mRNA expression was examined by quantitative PCR. Results: Double mutations were found in 45 p (35%), with no differences between p with and those without T790M in characteristics or initial r esponse to erlotinib (63.6% vs 72.3%, respectively). Median progression-free survival (PFS) was 12 months (m) in p with T790M and 18 m in p without T790M (p = 0.05). PFS was 27 m in p with low BRCA1, 18 m in p with intermediate BRCA1 and 10 m in p with high BRCA1. PFS was also 27 m for p with T790M and low BRCA1, while it dropped to 3 m for p with T790M and intermediate or high BRCA1. The multivariate analysis showed an association between poor PFS and T790M (HR, 3.96; p = 0.001), male sex (HR, 3.18; p = 0.01), brain metastases (HR, 4.55; p = 0.006), intermediate BRCA1 (HR, 4.36; p = 0.008), and high BRCA1 (HR, 5.81; p = 0.001). Conclusions: The high frequency of pretreatment double mutations concurs with a previous report (Mah eswaran et al. NEJM 2008). The strong influence of T790M and BRCA1 levels on erlotinib outcome can lead to novel personalized treatment strategies. No significant financial relationships to disclose.
Information needs and preferences of women with adjuvant and metastatic breast cancer (BC): Results of a survey in Germany
Authors: G. Oskay-Oezcelik, J. Sehouli, H. J. Hindenburg, W. Lehmacher, R. Mirz, M. Kaufmann, M. Bamberg, W. Lichtenegger, D. Wallwiener, F. Overkamp, K. Diedrich
Journal: Journal of Clinical Oncology (2005)

6096 Background: An increasing number of breast cancer patients in western countries are accessing the Internet for medical information. Little is known about to why breast cancer patients access the Internet. The following study was condcuted to explore the information needs and preferences of patients with special focus on doctor-patient communication. Methods: During an eight months period of time, a questionnaire consisting of 62 questions was developed and validated in a phase-I study and was addressed both via internet (homepage) and via a print-version to breast cancer patients. Results: A total of 617 patients (pts), 552 online version and 65 by print version, were eligible. Pts who took part in the survey via the internet had a median age of 47 years; those used the print version, 53 years. 65% of the pts didn’t have distant metastases. There were no significant differences in the answers between pts with adjuvant and metastatic BC. The most relevant source of information concerning treatment was the physician (84%) followed by the internet (55%). Looking for alternative therapies beside the regular treatment was the most frequent reason for using the internet. Asking the pts what information refering their disease and therapy are of major importance to themthe responses were: do I receive the right therapy? (89%); How many patients with my disease my physician is treating? (46%); Can I participate in a trial? (46%). The most frequently mentioned recommendations to optimize the management were: more alternative therapies should be offered (54%); physicians should invest more time for explanations (51%); communication between all involved physicians should be improved (39%). 94% of all pts demand an independent advice cancer centre and 97% of all pts require more information of the impact of treatment on the everyday life. Conclusions: This study confirms an unspoilt trust of patients in their doctors and underlines the need to give patients with breast cancer all details on treatment options. (Supported by ESSEX Pharma Germany) This study underlines the need to give patients with breast cancer all details on treatment options and cancer managements. (Supported bei ESSEX Pharma Germany) No significant financial relationships to disclose.
A phase II study of gemcitabine (GEM) given at fixed-dose rate (FDR) infusion, low-dose cisplatin (CDDP), and bevacizumab (BEV) for metastatic adenocarcinoma of the pancreas (PanCa): Update with completion of study accrual
Authors: A. H. Ko, E. Dito, B. Schillinger, A. P. Venook, E. K. Bergsland, D. Wong, J. Allen, M. A. Tempero
Journal: Journal of Clinical Oncology (2007)

4548 Background: The objectives of this study are to determine safety and efficacy in pts with metastatic PanCa treated with a novel combination consisting of FDR GEM, low-dose CDDP, and BEV. We present here updated results on the full 53-pt study cohort. Methods: Chemotherapy-naive pts with histologically confirmed PanCa and documented extrapancreatic metastases received GEM 1,000 mg/m 2 at FDR infusion (10 mg/m 2 /min), CDDP 20 mg/m 2 , and BEV 10 mg/kg, all administered on dd 1 and 15 of a 28-dd cycle. Pts were monitored by CT scans every 2 cycles and monthly serum CA19–9 measurements. Results: 53 pts (24M,29F; median age 60 y.o. [range 39–85]; ECOG PS 0–1) were enrolled betw 6/2004 and 9/2006 (med f/u, 513 dd; range, 93–885). 16 pts remain alive, with 9 still undergoing study rx. Pts received a median of 4.75 cycles of rx (range, 0.5–20). 29 pts discontinued study rx 2o to progressive dz (med # of cycles, 5; range, 0.5–20); 9 pts 2o to rx-assoc toxicity; 4 pts 2o to plateau in response with cumulative asthenia (after 8–12 cycles); and 2 pts 2o to prolonged rx delay from bowel obstruction. Major events include 2 bowel perforations, one associated with placement of a duodenal stent; 4 major GI bleeds; 7 DVT/PE; 1 stroke-like sxs; and 3 cardiac events (MI x 1, arrhythmias x 2). 4 pts (7.5%) developed grade 3/4 HTN. Gr 3/4 hematologic toxicities inc. neutropenia in 4 pts (7.5%) and thrombocytopenia in 1 pt (2.9%). 16 pts (20%) required dose reduction in gemcitabine during study rx and 4 required holding of cisplatin. There were 3 deaths potentially assoc with rx. 12 pts (22.6%) have had an unconfirmed response (1 CR, 11 PR) and 26 pts (49.1%) have had stable dz for &gt;2 cycles, for an overall dz control rate of 71.7%. 20 of 35 pts (57.1%) with elev baseline CA19–9 levels (&gt;2X ULN) had &gt;50% biomarker decline during rx. Median TTP is 6.2 months. Median overall survival is 8.0 months with an est. 1-yr survival rate of 40%. Conclusions: The addition of BEV to FDR GEM/low-dose CDDP shows promising efficacy, particularly in TTP and 1-yr survival rate, with manageable toxicity. Further efforts are ongoing to identify which pts are most likely to benefit from BEV-based rx. [Table: see text]