tbuckley/cabot-search huggingface dataset:
NEAT-A: Accelerated sequential epirubicin followed by CMF using pegfilgrastim is a feasible regimen for delivering dose dense chemotherapy in early breast cancer
Authors: D. Rea, S. J. Bowden, L. Gross, C. J. Poole, L. Hiller, R. K. Agrawal, K. F. McAdam, H. M. Earl, S. Anwar
Journal: Journal of Clinical Oncology (2007)

11001 Background: E-CMF [epirubicin (E) x 4 cycles every (q) 21 days (d), followed by classical CMF x 4 cycles q 28d] is established as highly effective adjuvant chemotherapy for early breast cancer (BC), reducing mortality by 30% compared with CMF alone [Poole NEJM 2006]. However, dose dense anthracycline-taxane schedules, accelerated with GCSF support, have been shown to be superior to conventional regimens [Citron JCO 2003, Burnell SABCS 2006]. Exploration of accelerated E-CMF is therefore of considerable interest. Methods: A non-randomised, multicenter trial was designed to explore the feasibility and tolerability of accelerated E-CMF chemotherapy for women with early BC. The primary endpoint was delivered dose intensity (DDI). The accrual target was 40 patients (pts). Pts were treated with 4 cycles E (100mg/m 2 ) q 14d, with Pegfilgrastim (PF) (6mg sc) d2, followed by 4 cycles of Cyclophosphamide, Methotrexate, and 5-Fluorouracil (600/40/600mg/m 2 ) administered intravenously d1 + 8, with PF d9, q 21d. Results: 44 pts were enrolled. Complete dose information from 40 pts and toxicity data from 336 cycles (44 pts) has been analysed. Median DDI was 96.7% of target. Delays of &gt;2 d were recorded for 8% of cycles. Dose reductions were recorded in 4% of cycles. 90% of pts received &gt;85% intended total dose and 85% of pts received &gt;85% intended DDI. Percentage grade 2 and 3/4 toxicity reported per cycle were respectively: fatigue 34/12; all infections 7/4; emesis 19/4; bone pain 18/4; diarrhoea 7/3; dyspnoea 20/3; febrile neutropenia not applicable (na)/2; mucositis 12/0.3; and phlebitis 29/na. Hospitalisation occurred in 10% of cycles. One pt developed endocarditis in association with repeated line infections, and a further pt experienced severe delayed phlebitis requiring surgical intervention. Conclusions: Accelerated E-CMF with PF is feasible achieving high DDI in a majority of pts. Non-haematological toxicity was responsible for the majority of hospital admissions which were more frequent than anticipated. Relative efficacy of this regimen requires phase III evaluation. We have also completed a second study of accelerated E-CMF where 6 cycles of intensified CMF (800/50/600mg/m 2 ) was delivered at 14 d intervals. No significant financial relationships to disclose.
Multidisciplinary Approach to Wilms' Tumor: 10 Years Experience of NCI, Egypt
Authors: I. Sidhom, H. Hussien, M. Kotb, G. Anwer, S. Aboul Naga, M. Amin, E. Ebied, H. Ahmed
Journal: Journal of Clinical Oncology (2004)

8544 Background: This is a retrospective study of 140 nephroblastoma patients newly diagnosed and treated at the National Cancer Institute between January 1991 and December 2000. The aim was to report results of combined modality treatment and to investigate the impact of biopsy, presence of blastema and preoperative chemotherapy on outcome Methods: Chemotherapy consisted of Vincristine 1.5mg/m2 and Actinomycin-D 45μg/kg for stage I and stage II favorable. Doxorubicin 40mg/m2 was added in alternation with Actinomycin-D to stage II unfavorable and stages III-V. Duration of therapy was 6 months for stage I and stage II favorable, 12 months for stages II unfavorable, III-V favorable and 18 months for stages III-V unfavorable. Rhabdoid tumors were given Etoposide 150mg/m2×3days and Carboplatin 500mg/m2 day1 alternating with Ifosfamide 1800mg/m2×5days and Doxorubicin 75mg/m2 day1. Postoperative radiotherapy was given to tumor-bed (10–27Gy) in stage II unfavorable, stages III-V and to metastatic lung site (12Gy). Preoperative chemotherapy was employed in massive or bilateral tumors or presence of metastases Results: Using NWTS staging system 21.4%, 36.4%, 20.7%, 15.7% and 5.7% were stages I-V respectively. Histology was favorable (FH) in 93 (67%) patients [31/93 showed blastema] and unfavorable (UH) in 46 (33%). Preoperative chemotherapy resulted in down staging of 30/54 (55.6%) patients to stages I and II, of which only 4 relapsed. Local recurrence was reported in 4/32 patients (12.5%) with core biopsy, 0/15 fine needle biopsy and 10/93 (10.75%) without biopsy. With median follow up of 63 months, overall 5-year survival and disease free survival (DFS) were 72.3±4% and 69±3.9% respectively. For FH, 5-year DFS was 78.2±4.3% [stages I-V being 92%, 74.3%, 74%, 60%, 80%] and 51.4±7.9% for UH (p= .0007, log rank test) [stages I-V being 75%, 72.7%, 63.6%, 8.3%, 33.3%] Within FH, 5-year DFS was 76.6% for blastema versus 83.3% for non blastema (p= .46, log rank) Conclusions: This study suggests that biopsy and down staging after preoperative chemotherapy did not lead to increased risk of recurrence. Presence of blastema had adverse impact on outcome; however it needs to be studied on larger scale No significant financial relationships to disclose.
In vitro and in vivo antitumor activity of the maytansinoid immunoconjugate BB-10901 (huN901-DM1) on CD56+multiple myeloma cells.
Authors: P Tassone, A Gozzini, VS Goldmacher, MA Shammas, R Shringarpure, L Catley, T Hayashi, T Hideshima, D Chauhan, KC Anderson, N Munshi
Journal: Blood (2003)
Barriers to clinical development in oncology: The impact of new thinking around non-inferiority
Authors: K. Carroll, R. Milsted
Journal: Journal of Clinical Oncology (2004)

6082 Background: While it is hoped that novel, biologically targeted anticancer agents will offer significant advantages over standard therapies in terms of improved tolerability, they may not always demonstrate increased efficacy. Therefore, active-control, non-inferiority trials to compare the new agent with a standard agent are likely to be necessary, the conventional aim being to show no clinically relevant loss of efficacy. Methods: Rothmann et al (Stat Med 2003; 22: 239–64) recently described non-inferiority sample size and data analysis methods, which are increasingly being used by regulators in the USA and Europe. We illustrate the impact of Rothmann's approach on trial size and, thus, development of novel anticancer agents. Results: For example, if a standard treatment was previously shown to double survival (eg hazard ratio=0.5, p=0.02), and the goal for a new, better-tolerated therapy is to retain at least half of this effect, a conventional sample size calculation shows that a total of 350 deaths is required to provide 90% power at the 1-sided, 2.5% significance level. Applying Rothmann's method increases the number of deaths required, and so sample size, by almost 9-fold to 3082 deaths, which would result in impractical trials in many settings. Conclusions: As shown, use of Rothmann's method has enormous consequences. We suggest the first purpose of non-inferiority trials should be to prove that a new agent would have been better than placebo, had placebo been included. The second purpose should be to estimate (indirectly) the size of the effect of the new agent relative to placebo. Both aims are achievable with Rothmann's approach, with some small modifications. This philosophy does not require prespecification of a percentage effect retention (although the result can be displayed as the likely fraction of standard effect retained) and concentrates on estimating the degree of benefit over placebo. Fisher et al (Am Heart J 2001; 141: 26–32) describe a related approach in patients at risk of ischaemic events. This approach focuses on absolute rather then relative efficacy, and, in future, may be a more appropriate model to apply to trials of oncology agents. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca AstraZeneca AstraZeneca
Study of a decision tool for chemotherapy in the aging population
Authors: M. B. Dabrow, D. E. Galinsky, J. Moore, T. Li
Journal: Journal of Clinical Oncology (2008)

20665 Background: Cancer is a disease of aging. In those over 70 years of age chronologic age does not necessarily reflect physiologic age. The efficacy of chemotherapy in the elderly is equivalent to younger populations. Identification of those over 70 who are likely to tolerate treatment is crucial. By modifying the Comprehensive Geriatric Assessment for cancer patients we hope to develop a tool for all medical oncology practices to select patients likely to tolerate/benefit from chemotherapy. Methods: An Oncology-Geriatric Assessment was developed by geriatricians and medical oncologists. This instrument included 1) Folstein Mini-mental examination, 2) Beck depression inventory, 3) mini-nutritional assessment, 4) FACIT-F and 5) FAS test. Baseline and subsequent scores were assessed in patients seen at an adult outpatient chemotherapy unit. Patients were 70 years of age or older and provided responses without assistance. Repeat evaluations were done after 2 or 3 cycles of treatment. Evaluations were performed by oncology nurses. Cox proportional hazard models were used in both univariate and multivariate analyses to look for statistically significant predictors of better survival. Results: 33 patients participated in the trial. Age range 70–90 years old, median = 78. The number of evaluations ranged from 1 (9 patients) to 8 (1 patient), median number of evaluations = 2. Most common diagnosis: lung cancer (13 patients). Univariate analysis showed a significant p value for prediction of survival for the functional, physical well being and additional sections of the FACIT-F, the mini-nutritional assessment and the Beck depression index. Multivariate analysis showed that higher scores in the functional section of the FACIT-F (p=.0021; HR=0.84; 95% CI (0.76–0.94) and the S portion of the FAS test (p=.0396; HR=0.84; 95% CI (0.80–0.99) were both significantly associated with better survival. Conclusions: The Oncology-Geriatric Assessment can be performed in a general oncology practice, administered by oncology nurses and applied to common diagnoses. Function, physical well-being and additional portions of the FACIT-F, the mini-nutritional assessment and the Beck depression index should be used in future studies. A larger study evaluating an intervention to improve tolerance is planned. No significant financial relationships to disclose.
Primary resistance to docetaxel-based chemotherapy in metastatic breast cancer patients correlates with a high frequency of BRCA1 mutations
Authors: P. J. Wysocki, K. Korski, K. Lamperska, J. Zaluski, A. Mackiewicz
Journal: Journal of Clinical Oncology (2008)

1079 Background: Docetaxel is a member of taxoid antineoplastic agents which are routinely used in the treatment of high-risk or metastatic breast cancer. A recent study has demonstrated that a low response rate to taxane-based neoadjuvant chemotherapy is associated with BRCA1 mutations. Therefore, we have analyzed the frequency of BRCA1 mutations in a population of metastatic, docetaxel-refractory patients. Methods: From a group of 175 metastatic breast cancer patients treated with docetaxel-based therapy 19 treatment-refractory patients were selected. DNA isolated from blood or paraffin-embedded tissues was screened for 3 founder mutations common (>80%) in Polish population. Additionally, the frequency of BRCA1 mutations was correlated with a particular phenotype of breast cancer cells. Results: BRCA1 mutations were found in 5/19 of patients (26.3%), and were only detected in 5 of 7 patients with triple-negative breast cancer (71%; p<0.002). Conclusions: Our study indicates that administration of taxanes, especially docetaxel to metastatic BRCA1 breast cancer patients requires consideration. Moreover, BRCA1 testing in triple-negative breast cancer patients resistant to docetaxel- based treatment may help to identify families with germinal mutations without history of hereditary breast cancer. No significant financial relationships to disclose.
‘(De-)sensitization’ vs. ‘Uncoupling’: what drives cardiomyopathies in the thin filament? Reply
Authors: Steven Marston, Andrew Messer, Maria Papadaki
Journal: Cardiovascular Research (2015)

Dr Hwang's recent letter concerning our paper raises some very interesting points about the molecular mechanism of familial cardiomyopathy (HCM and DCM) due to mutations in the proteins of the thin filament and the key role of troponin.

In principle, such mutations could cause defects in force generation or force transmission, but so far all the mutations in thin filament proteins that have been investigated in detail indicate abnormal force production linked to abnormal Ca2+ regulation. Troponin, in concert with tropomyosin and actin, comprises the Ca2+-dependent switch of muscle, and the properties of this switch are modulated by PKA phosphorylating troponin I (TnI); therefore, troponin abnormalities are likely to play a central role in cardiomyopathies. The case has been made that HCM-causing mutations increase myofilament Ca2+ sensitivity, and this is sufficient to trigger the symptoms of HCM. On the other hand, DCM-causing mutations uncouple the normal relationship between Ca2+ sensitivity and PKA-dependent phosphorylation of TnI, and this has been shown to blunt responses to adrenergic stimulation and predispose the heart to systolic dysfunction under stress.1,2

Our recently published work highlights the importance of troponin still more, since we have demonstrated that small molecule Ca2+ sensitizers (EMD57033 and Bepridil) can mimic the uncoupling effect of mutations, …
Rituximab Therapy for Autoimmune Hemolytic Anemia and Immune Thrombocytopenia: A Belgian Registry.
Authors: Daan Dierickx, Philippe Mineur, Agnes Triffet, Alain Kentos, Carine Keppens, Pascal Pierre, Alina Ferster, Dominique Boulet, Christiane Vermylen, Bernard Deprijk, Yves Beghin, Marie-France Dresse, Khalil Kargar, Greet Bries, Gregor Verhoef, Andre Delannoy
Journal: Blood (2007)
Thymidylate synthase and MDR1 mRNA levels predict response to chemotherapy with S-1 in metastatic colorectal cancer
Authors: I. Fujita, K. Hayashi, K. Uchida, H. Kuramochi, K. Kudo, S. Miyakura, M. Yamamoto, K. Takasaki
Journal: Journal of Clinical Oncology (2006)

13107 Background: To test the hypotheses of whether the relative mRNA expression of the thymidylate synthase (TS) gene and multidrug resistance 1 (MDR1) gene are associated with response to chemotherapy with S-1 in metastatic colorectal cancer. Methods: Eighteen patients with progressive stage IV CRC were treated with S-1 twice daily (BSA = 1.5 m 2 , 60 mg/day) for 28 days, followed by a 2-week period rest. cDNA was derived from frozen tumor specimens to determine TS and MDR1 mRNA expression relative to the internal reference gene GAPDH using fluorescence-based, real-time reverse transcriptase polymerase chain reaction (Taqman) system. Results: The median TS gene expression level from 18 CRC tumors was 0.94 × 10(−3) (minimum expression, 0.15 × 10(−3); maximum expression, 8.0 × 10(−3)), and the median MDR1 gene expression level was 7.75 × 10(−3) (minimum, 0.83; maximum, 41.5 × 10(−3)). The gene expression cutoff values for chemotherapy nonresponse were 1.0 x 10(-3) for TS and 10.0 × 10(−3) for MDR1. The response rate for patients with TS &lt; or = 1.0 × 10(−3) (10 of 18 patients) was 60% (6/10), compared with 0% (0/8) for patients with TS greater than 1.0 × 10(−3) (P = 0.013). Patients with MDR1 expression &lt; or = 10.0 × 10(−3) (13 of 18 patients) had a response rate of 46% (6/13), compared with 0% (0/5) for patients with MDR1 expression greater than 10.0 × 10(−3) (P = 0.11). Regarding the combination of TS and MDR1 Expression, low TS and MDR1 expression levels were detected in 8 (44%) of the patients, and 10 patients (56%) had a high TS and/or MDR1 expression level. The response rate was 75% (6/8) for the low TS and MDR1 expressors and 0% (0/10) for the high TS and/or MDR1 expressors (P = 0.001). Conclusions: These data suggest that intratumoral TS and MDR1 mRNA expression levels are independent predictive markers of response to S-1 chemotherapy in metastatic colorectal cancer. No significant financial relationships to disclose.
An open label phase I dose escalation study of ADH-1 in combination with chemotherapy in subjects with N-Cadherin expressing solid tumors
Authors: R. N. Raju, C. Alemany, M. Basche, L. E. Garbo, D. A. Richards, D. A. Smith, J. J. Stephenson, R. Norris, M. Lawton, W. Peters, C. R. Becerra
Journal: Journal of Clinical Oncology (2008)

14529 Background: Malignant transformation and invasive capacity is highly correlated with the expression on tumor cells of N-cadherin (N- cad), a cell signaling and adhesion molecule. ADH-1, a cyclic pentapeptide (CHAVC), is a functional inhibitor of N-cad, and produces apoptosis and tumor vascular disruption in preclinical models. We report results from a phase 1, multicenter, dose-escalation study of ADH-1 in combination with either 1) carboplatin (C) or 2) docetaxel (T) or 3) capecitabine (CAPE) in subjects with N-cad positive, advanced solid tumors. Methods: 35 patients whose tumors expressed N-cad by IHC and had advanced solid tumors with measurable disease (per RECIST criteria) for which treatment with either C, T, or CAPE was appropriate were enrolled. Most patients were heavily pre-treated (57% had received at least 5 previous antineoplastic agents). A 3+3 rule of dose escalation was used to determine the maximum tolerated dose (MTD). ADH-1 dose levels were 1.0 gm, 2.0 gm and 4.0 gm in succeeding cohorts. C was concurrently administered at a dose of AUC 5 on day 1 of each 28 day cycle with ADH-1 administrations on days 1, 8, 15, and 22. 75 mg/m^2 of T was concurrently administered on day 1 of each 21 day cycle with ADH-1 administrations on days 1, 8, and 15. 1000 mg/m^2 of CAPE was administered po bid on days 1–14 of each 21 day cycle with ADH-1 administrations on days 1, 8, and 15. Results: 10 patients have been enrolled on the C arm (6 - 1gm, 4 - 2gm), 11 on the T arm (3 - 1 gm, 3 - 2gm, 5 - 4gm), and 14 (3 - 1gm, 6 - 2gm, 5 - 4gm) on the CAPE arm. The MTD of T in combination with ADH-1 is 2.0 gm. The MTD for the CAPE and C arms has not, as yet, been reached. 2 partial responses (CAPE arm) and 4 stable diseases that lasted at least 2 cycles (3 on T arm and 1 on CAPE arm) were documented. The DLTs consisted of grade 4 febrile neutropenia, grade 3 mucositis, grade 2 and 3 nausea/vomiting, grade 3 thrombocytopenia, and grade 3 hand/foot syndrome. No pharmacokinetic data were collected during this study. Conclusions: ADH-1 was generally well tolerated and there was some evidence of antitumor activity in heavily pretreated patients in combination with docetaxel and capecitabine. The DLT of ADH-1 in combination with docetaxel was myelosuppression. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Adherex Adherex Adherex Technologies Adherex Technologies Adherex Technologies
Randomized placebo-controlled trial (RCT) of erlotinib for prevention of oral cancer (EPOC).
Authors: William Nassib William, Vassiliki Papadimitrakopoulou, J. Jack Lee, Li Mao, Heather Lin, Ann M. Gillenwater, Jack W Martin, Ezra E.W. Cohen, Mark W. Lingen, Jay Boyle, Dong Moon Shin, Nadarajah Vigneswaran, Nancy Shinn, Jeffrey Myers, Adel K. El-Naggar, Scott Michael Lippman
Journal: Journal of Clinical Oncology (2014)

6007 Background: Loss of heterozygosity (LOH) profiles predict oral cancer (OC) risk in patients (pts) with oral premalignant lesions (OPL). We conducted a randomized, multi-center, double-blind, placebo-controlled, personalized medicine trial of the EGFR inhibitor erlotinib in pts with OPLs defined as high risk by molecular criteria. Our primary hypothesis was that erlotinib would improve oral cancer-free survival (OCFS) in the high-risk, LOH+ population. Methods: Pts with histological evidence of an OPL (with or without a prior history of invasive OC) underwent LOH profiling at 3p14, 9p21, 4q, 8p, 11p, 13q, 17p. LOH+ pts were defined as those with prior OC and LOH at 3p14 and/or 9p21; or those without prior OC and LOH at 3p14 and/or 9p21 plus an additional chromosomal site. LOH- pts received no treatment. LOH+ pts were stratified by history of OC, then randomized (1:1) to erlotinib 150 mg po daily for 12 months or placebo and were assessed every 3-6 months for development of invasive OC. Primary endpoint was OCFS in the intent-to-treat (ITT) population. With a planned sample size of 150, the study had 85% power to detect a hazard ratio (HR) of 0.47 with a 5% 2-sided type I error rate (stratified logrank). Results: Of 375 pts evaluated for LOH, 254 were LOH+, of which 150 were randomized to erlotinib (N=75) or placebo (N=75). After a median follow up of 2.9 years, 44/179 LOH+ pts not randomized or randomized to placebo developed OC, versus 15/121 LOH- pts (HR=2.1, 95% CI 1.2-3.8, p=0.01). Among the randomized, LOH+, ITT population, 18/75 (24%) placebo-treated pts developed OC versus 22/75 (29%) erlotinib-treated pts. The HR for OCFS was 1.2 (95% CI 0.7-2.3, p=0.51) in the ITT population, 0.6 (95% CI 0.2-1.7) in 66 pts without prior OC, and 1.9 (95% CI 0.9-4.2) in 84 pts with prior OC (p=0.08 for interaction). Dose reductions were implemented in 34/75 and 1/75 erlotinib and placebo-treated pts, respectively, mostly due to expected, low-grade toxicities. Conclusions: EPOC is the first personalized RCT in cancer prevention and prospectively confirmed LOH as an OC risk marker. Erlotinib did not reduce OCFS in this high-risk population, although the trend of reduced OCFS in pts without prior OC suggests that the timing of this intervention may be important. Clinical trial information: NCT00402779.