tbuckley/cabot-search huggingface dataset:
Weekly docetaxel versus docetaxel/gemcitabine in elderly/poor performance status (PS) patients (pts) with stage IIIB/IV non-small cell lung cancer (NSCLC): Randomized phase III trial of the Minnie Pearl Cancer Research Network
Authors: F. A. Greco, D. R. Spigel, H. A. Burris, D. L. Shipley, C. Farley, J. Gandhi, G. A. Houston, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2007)

7534 Background: Standard treatment for pts with good PS stage IIIB/IV NSCLC currently includes a two-drug platinum-based chemotherapy regimen. Optimum treatment for elderly and/or poor PS pts is less well defined, with some studies showing comparable efficacy/decreased toxicity with single agent treatment. In this randomized phase III trial we compared single agent weekly docetaxel with the combination of docetaxel/gemcitabine. Methods: Between 8/01 and 3/06, 350 pts were enrolled from 39 sites. Eligibility: previously untreated stage IIIB/IV NSCLC; age = 65 years and/or ECOG PS2; measurable disease; no active CNS metastases; adequate kidney, liver, marrow function; informed consent. Pts were randomized to receive docetaxel (36 mg/m 2 IV days 1, 8, 15; repeated every 28 days) or docetaxel (30 mg/m 2 )/gemcitabine (800 mg/m 2 ) both given days 1, 8, 15 of a 28-day cycle. Pts were reevaluated after 8 weeks; responders continued treatment for 6 cycles or until disease progression. Accrual of 330 evaluable pts allowed detection of improvement in 1-year survival from 25% (expected with weekly docetaxel) to 40% (significance level 0.05, power 0.8). Results: Clinical features of pts receiving docetaxel/gemcitabine (n=174) vs. weekly docetaxel (n=171) were similar; 19% were ECOG PS2, and 38% were &gt; 75 years old. After a median follow-up of 22 months, there were no differences between docetaxel/gemcitabine vs weekly docetaxel in median survival (5.6 vs. 5.1 months; p=0.65) or 1-year survival (26% vs. 24%). TTP was prolonged with docetaxel/gemcitabine vs. docetaxel (4.8 months vs. 2.9 months; p=0.0004). Response rates: docetaxel/gemcitabine 25%; docetaxel 17%. Both regimens were well tolerated by most pts; grade 3/4 neutropenia, thrombocytopenia, and anemia were more frequent with docetaxel/gemcitabine. Conclusions: These two regimens have similar efficacy in these elderly/poor PS pts; weekly docetaxel produced less myelosuppression. However, these results in this relatively unselected community-based population emphasize the need for novel treatment approaches. No significant financial relationships to disclose.
Clonal Expansion of T/NK-Cells during Tyrosine Kinase Inhibitor Dasatinib Therapy
Authors: Satu Mustjoki, Marja Ekblom, T. Petteri Arstila, Ingunn Dybedal, PK Epling- Burnette, Felix Garzon, Tobias Gedde-Dahl, Sari Hernesniemi, Henrik Hjorth-Hansen, Martin Hoglund, Vesa Juvonen, Veli Kairisto, Panu Kovanen, Anna Kreutzman, Tuisku Laurinolli, Jane Liesveld, Ronald Paquette, Javier Pinilla, Auvo Rauhala, Neil Shah, Bengt Simonsson, Marjatta Sinisalo, Juan Luis Steegmann, Leif Stenke, Jukka Vakkila, Kimmo Porkka
Journal: Blood (2008)
&lt;italic&gt;Brief Communication:&lt;/italic&gt; Cytologic Changes Induced in Rat Liver Cells by ShortTerm Exposure to Chemical Substances&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Prince Masahito Hitachi, Kiyomi Yamada, Shozo Takayama
Journal: JNCI Journal of the National Cancer Institute (1975)

All the hepatocarcinogens administered to rats markedly increased the mitotic rate in the liver. Except for ɑ-benzene hexachloride and nitrosobutylurea, the nonhepatocarcinogens did not appreciably increase the mitotic rate. Cytogenetic analyses on the ploidy rate and chromosome abnormalities evidenced qualitative differences among mitotic liver cells in animals treated with hepatocarcinogens and nonhepatocarcinogens. The active cell proliferation and chromosome changes in liver cells observed after the administration of hepatocarcinogenic substances may have some relation to an essential process in hepatocarcinogenesis.
Radiotherapy-related fatigue in breast cancer patients
Authors: M. Rucinska, S. T. Langkjer
Journal: Journal of Clinical Oncology (2005)

8267 Background: Fatigue is a subjective experience, but may be defined as an unpleasant sensation of tiredness, weakness or lack of energy. Fatigue is one of the most prevalent and profound symptoms related to both malignancy and anti-neoplastic treatment that has been reported in 60% up to even 80% cancer patients. The aim of the study was to assess the level of fatigue during adjuvant postoperative radiotherapy of breast cancer patients. Methods: 32 patients (age 33–72 years, mean 56 years) with nonmetastatic breast cancer, who received radiotherapy after breast-conserving surgery (48Gy/24 fractions/5 weeks with residual mamma; 7 patients received boost 10Gy/5 fractions/1 week with tumor-bed) recruited between May and October 2004. Fatigue intensity was measured according to 10 visual analog scale before start of radiotherapy and once a week during radiotherapy and the last day of treatment. Results: Fatigue intensity increased gradually during radiotherapy (mean VAS before treatment was 1.13 and 2.25 in the last day of treatment). 25% of patients reported none fatigue during radiotherapy. Older patients (>60 years) estimated their fatigue in the last day of treatment on lower level than younger patients (1.45 vs 2.62). Patients with boost manifested a little higher fatigue level in comparison with other patients (2.71 vs 2.12). Smokers reported significantly more fatigue than non-smokers (4.20 vs 1.89). Fatigue level was associated with travelling time to hospital (if journey took 2 or more hours/day fatigue levels was 2.93 in VAS in the last day of treatment vs 1.56 if journej took <2 hours). The cancer localization (right or left breast), presence of lymph node metastasis, adjuvant chemotherapy and current use of hormontherapy were not correlated with fatigue. Conclusions: Fatigue increased during adjuvant radiotherapy of breast cancer patients after breast-conserving surgery. Fatigue was greater in young women, smoking patients and those who had a long travelling time to hospital. No significant financial relationships to disclose.
Effect of CCL2 on survival of breast cancer MDA-MB-231 cells via inhibition of apoptosis
Authors: A. S. Alva, Z. Varsos, H. Roca, K. Pienta
Journal: Journal of Clinical Oncology (2009)

e22176 Background: The cytokine CCL2 (Chemokine (C-C) motif ligand 2 or monocyte chemo attractant protein-1 MCP-1) has been shown to play an important role in breast cancer progression by promoting angiogenesis and migration. CCL2 is over-expressed by breast cancer cells as well as by macrophages and mesenchymal stem cells in the tumor micro-environment. We studied the effects of CCL2 and IL-6 on survival of breast cancer MDA-MB-231 cells. Methods: Cytokine expression including of CCL2 and IL- 6 were analyzed in supernatants from MDA-MB-231 cells using cytokine antibody array (Human Antibody Array 3; Ray Biotech, Inc). Serum starved MDA-MB-231 cells were treated with CCL2 (75 ng/mL) and IL-6 (100 ng/mL; both from Apollo Cytokine Research). Cell viability in response to treatment was analyzed at serial time points by cell proliferation assay WST-1 (Roche Applied Science). Protein expression of genes of interest was studied by Western blot. Results: In contrast to primary breast tumor cells, MDA-MB-231 cells express minimal CCL2 at baseline. MDA-MB-231 cells also exhibit low expression of IL-6. Stimulation of MDA-MB-231 cells with either exogenous CCL2 or exogenous IL-6 did not increase levels of the other cytokine. In MDA-MB-231 cells, CCL2, alone and in combination with IL-6, promotes survival in serum starved conditions. Treatment of MDA-MB-231 cells with CCL2 leads to survivin up-regulation beginning at 48 hours as determined by immunoblotting analysis. CCL2 in combination with IL-6 inhibits the cleavage of PARP, lamin and caspase3. Conclusions: There is minimal endogenous expression of CCL2 in MDA-MB-231 cells. CCL2 from the tumor micro-environment promotes survival of MDA-MB-231 cells associated with up-regulation of survivin. IL-6 may play a syngeristic role with CCL2 in promoting survival of MDA-MB-231 cells. We plan to explore the role of survivin up-regulation in protecting cells from cell death. Our findings raise the possibility of utilizing neutralizing antibodies against CCL2 in therapy of breast cancer. No significant financial relationships to disclose.
A pooled analysis of 11 NCCTG advanced stage non-small cell lung cancer (NSCLC) trials reveals the importance of baseline blood counts on clinical outcomes
Authors: S. J. Mandrekar, S. E. Schild, S. L. Hillman, N. R. Foster, A. A. Adjei, R. S. Marks, J. A. Mailliard, J. E. Krook, A. W. Maksymiuk, J. R. Jett
Journal: Journal of Clinical Oncology (2005)

7193 Background: An analysis of 11 advanced stage NSCLC trials was performed to examine the impact of several prognostic factors on survival, time to progression (TTP) and adverse events (AE). Methods: A pooled data set of 1031 patients from 11 trials was used for this analysis. Age, gender, performance status (PS), tumor stage, body mass index (BMI), creatinine clearance, hemoglobin levels (HgB), white blood cell counts (WBC) and platelet counts were tested for prognostic significance both univariately (Kaplan Meier and log-rank test) and multivariately (Cox Proportional Hazards Model). The impact of these factors on severe AE (CTC grade 3+) was also evaluated using multivariate Logistic Regression Methods: All models were stratified or adjusted for protocol, and analyses were carried out on the complete data available based on the selected covariates for the respective endpoints. Results: WBC and HgB were independent prognostic factors for survival and TTP. Patients with low HgB (M<13.2, F<11.5) and high WBC (M>10.2, F>10.6) had a significantly worse survival (Hazard Ratio, HR>1.4, p<0.001) and TTP (HR>1.3, p≤0.001). Patients with a high WBC count were at a significantly lower risk for heme grade3+ AE (Odds Ratio, OR=0.43, p<0.001). A high WBC count was associated with less severe AE but lower survival. Patients with PS>0, and BMI<18.5 had a significantly worse survival (HR≥1.7, p<0.001) and TTP (HR≥1.6, p<0.02). Stage IV patients had a significantly worse survival and TTP (HR>1.3, p<0.04). Patients with PS>0 were at a significantly higher risk for non-heme grade 3+ AE (OR>1.4, p<0.05), females were at a significantly higher risk for both heme and non-heme grade 3+ AE (OR>1.5, p<0.02) and patients >= 65 years of age were at a significantly higher risk for heme grade3+ AE (OR=1.9, p<0.001). Conclusions: In addition to the known prognostic factors of PS, BMI, and stage, the lab parameters of HgB and WBC should also be considered while designing or interpreting effects on clinical outcomes of patients with advanced NSCLC. No significant financial relationships to disclose.
Dasatinib 50 mg or 70 mg BID compared to 100 mg or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: One-year results of CA180034
Authors: N. P. Shah, D. W. Kim, H. M. Kantarjian, P. Rousselot, P. E. Dorlhiac-Llacer, J. H. Milone, E. Bleickardt, S. Francis, A. Hochhaus
Journal: Journal of Clinical Oncology (2007)

7004 Background: Previous data with dasatinib (SPRYCEL®), a short-acting oral multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, have shown the safety and efficacy of the 70 mg BID dose in CP-CML patients. Surprisingly, phase-I data (NEJM 2006;354:2531) demonstrated complete hematologic (CHR) and major cytogenetic responses (MCyR) among CP-CML patients at total daily doses (TDD) of 100 mg and 140 mg in both the BID and QD schedule, despite the achievement of only transient inhibition of BCR-ABL by dasatinib when administered once daily. Methods: Patients with CP-CML resistant or intolerant to imatinib were randomized to one of 4 dasatinib arms: 1) 100 mg QD; 2) 50 mg BID; 3) 140 mg QD; 4) 70 mg BID. In this randomized, prospective, open-label trial, the primary objective compared the CyR rate among the BID and QD arms. Secondary objectives included comparison of the CyR rate between TTDs of 100 and 140 mg and the safety among the 4 arms. Results: 662 patients were randomized from July 2005 to March 2006 and received treatment. Response rates, with a median duration of treatment of 8 months, are shown below. Duration of CyR and progression-free survival were similar across all 4 arms. There was significantly less grade (Gr) 3–4 neutropenia (P=0.035), thrombocytopenia (P=0.001), anemia (P=0.032), and pleural effusions (P=0.028) in the 100-mg QD arm compared to the other 3 arms combined. No differences were seen across the 4 arms in the rates of other adverse events. There were fewer interruptions and reductions and the least number of patients discontinuing treatment for drug-related toxicity in the 100-mg QD arm. Conclusions: Dasatinib 100 mg QD offers the most favorable benefit-risk ratio in CP-CML. This trial provides the first evidence that intermittent kinase inhibition can achieve deep clinical remissions and is associated with an improved safety profile. One-year follow-up on all subjects, molecular response rates, and BCR-ABL mutation data will be presented. [Table: see text] [Table: see text]
Efficacy and safety of 6-month depot leuprolide acetate for the treatment of prostate cancer: Results of a 48-week study.
Authors: J. Young, A. Spitz, L. Larsen, C. Mattia-Goldberg, J. Donnelly, K. Chwalisz
Journal: Journal of Clinical Oncology (2010)

e15042 Background: Leuprolide acetate is a synthetic analog of gonadotropin hormone-releasing hormone (GnRH-a) that reduces serum testosterone to castrate levels after continuous release administration, which results in suppression of tumor growth. This phase III, open-label, 48 week, multicenter study assessed efficacy and safety of leuprolide acetate 45 mg 6-month depot in 151 men with prostate cancer. Methods: Subjects with histologically-confirmed prostate cancer (NCI stage 2-4) received 2 IM injections of leuprolide acetate 45 mg 6-month depot administered 24 weeks apart. The primary efficacy endpoint was suppression of serum testosterone to ≤50 ng/dL from Week 4 through Week 48 using the Kaplan-Meier method for right-censored data. Results: Testosterone suppression was rapid and sustained through the 12 month treatment period. Overall, 93.7% of subjects met the primary endpoint of serum testosterone suppression to ≤50 ng/dL from Week 4 through Week 48. A transient initial increase in serum testosterone, a known flare effect of GnRH-a, was observed after the first study drug injection. By Week 4, mean testosterone concentration had decreased to 16.0 ng/dL. Suppression of testosterone was well maintained through each 24 week treatment interval (<11 ng/dL). 9 subjects were considered treatment failures: 1 failed to suppress by Day 32 and 8 escaped from testosterone suppression after Week 4. None of these escapes were associated with PSA increases and 5 were transient. After a slight initial increase in PSA, mean levels decreased to ≤2.9 ng/mL for the duration of the treatment period. The most common AEs reported in ≥10% of subjects were hot flush (58.3%), injection site pain (17.9%), and fatigue (11.9%). 2 subjects had SAEs considered possibly related to study drug (colonic pseudo-obstruction and angina pectoris), which resolved and the subjects were able to complete the study. Conclusions: The new 45 mg 6-month depot formulation achieved efficacy comparable to established leuprolide acetate depot formulations with suppression from Week 4 through Week 48 in 93.7% of subjects, resulted in no new safety signals, and will enhance convenience for patients by reducing the number of injections per year. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories GlaxoSmithKline, Pfizer, Solvay, Watson Pharmaceuticals
Fertility of females after treatment for childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS)
Authors: D. M. Green, T. Kawashima, W. M. Leisenring, M. Stovall, S. Donaldson, C. A. Sklar, J. Byrne, L. L. Robison
Journal: Journal of Clinical Oncology (2008)

10008 Background: Determine the proportion of female childhood cancer survivors with impaired fertility and evaluate impact of treatment on likelihood of pregnancy. Methods: 5,665 CCSS participants and 1,735 siblings were classified as surgically sterile for contraceptive purpose vs. non-contraceptive purpose, impaired fecundity (ongoing attempts to become pregnant for a period of one year without success or use of medication to help achieve a pregnancy), or fecund. Cox proportional hazard modeling was used to estimate the relative risk of pregnancy (RR) for survivors versus siblings, controlling for education level, marital status, age at primary diagnosis, race/ethnicity, smoking status and fecundity group. Additional models among survivors, examine the impact of treatment variables on pregnancy. Results: Survivors were 6–30 yrs from cancer diagnosis (mean-16.3 yrs) and 15–44 yrs of age at the time of study (mean-25.1 yrs). 516 (9.1%) survivors or their partners were surgically sterile, 415 (7.3%) had impaired fecundity and 4734 (83.6%) were fecund. Among fecund subjects, the RR for pregnancy was 0.9 (p=0.0004) for survivors compared to siblings. The RR was 0.8 (p=0.12) among subjects with impaired fecundity. Multivariate analysis demonstrated that ovarian RT dose ≤ 250 cGy with a pituitary RT dose > 4000 cGy (RR=0.4; p=0.0005) or ovarian RT dose > 250 with a pitutary RT dose ≤ 4000 cGy (RR= 0.3 p<0.0001) or a pituitary RT dose > 4000 cGy (RR=0.2; p=0.01) and increasing AAS (1st tertile RR=0.9; p=0.4); 2nd tertile RR= 0.8; p=0.04; 3rd tertile RR=0.8; p=0.04) were independently associated with impaired fertility. In the multivariate analysis, neither a history of oophoropexy nor prior treatment with cis-platinum, cytosine arabinoside, doxorubicin or vinblastine remained statistically significant. Conclusions: Female survivors of childhood cancer have impaired fertility due in part to ovarian RT dose and increasing AAS. No significant financial relationships to disclose.
Breast cancer survival in developing countries: The remainder disparities in health services access.
Authors: J. R. Cintra, M. R. Guerra, M. T. Bustamante-Teixeira, G. A. Silva, C. Domenge
Journal: Journal of Clinical Oncology (2010)

e12015 Background: The socioeconomic and demographic characteristics of specific populations may influence the global burden of diseases, including the behavior of the cancer, and are frequently associated to the observed differences in utilization of health services, mainly in developing countries. Methods: To understand how breast cancer survival may differ according to health services-related variables we investigated the 5-year breast cancer specific-survival (BCSS) among women diagnosed with invasive disease between 1998 and 2000 who were treated in southeastern region of Brazil, where the educational attainment, income and racial composition of the population of ∼1 million roughly mirror that of the nation. Kaplan-Meier method was used to calculate BCSS and Cox proportional hazard model was used to determine the role of these variables after adjusting for known prognostic factors. Results: 745 patients were studied with a median follow-up of 5.5 year; 94.5% showed interval time between disease diagnostic and first intervention (surgery or additional oncologic therapy) ≤ 12 weeks. The majority of patients (68.5%) were treated in public health services (SUS), and just 17.8% of non-white women were attended by private health insurance (PHI). SUS patients presented with more advanced disease than PHI patients (p < 0.002), situation also observed among non-white women in relation to the others race (p < 0.02). At 5 years BCSS was 86.0% for SUS patients vs 80.0% for PHI patients (p = 0.05); however, when adjusted for age, tumor size, number of nodes involved and city of residence this effect disappeared (p = 0.2). The main important independent prognostic factor was involvement nodal (HR = 4.0; 95%CI = 2.5-6.4). Conclusions: This study emphasizes the importance of the government health system (SUS) to ensure adequate oncologic treatment for great part of the Brazilian population. Nevertheless these results also suggest the existence of social inequalities in disease prevention and control in the studied region. In the settings of countries with limited resources, development and implementation of early detection programs, public awareness, and more pragmatic clinical and breast self examination are essential. No significant financial relationships to disclose.
A phase I study of XL281, a selective oral RAF kinase inhibitor, in patients (Pts) with advanced solid tumors
Authors: G. K. Schwartz, S. Robertson, A. Shen, E. Wang, L. Pace, H. Dials, D. Mendelson, P. Shannon, M. Gordon
Journal: Journal of Clinical Oncology (2009)

3513 Background: XL281 is a potent and selective inhibitor of wild type and mutant RAF kinases showing anti-tumor activity in multiple xenograft models. Mutations in KRAS or BRAF can activate the RAF/MEK/ERK pathway in human tumors and may promote sensitivity to RAF kinase inhibitors. Methods: Pts were enrolled in successive cohorts of XL281 orally once daily on a 28-day cycle. Tumor response was assessed per RECIST every 8 wks. Plasma pharmacokinetic and pharmacodynamic samples were collected. The maximum tolerated dose (MTD) was expanded to 10 pts each with colorectal (CRC), melanoma, papillary thyroid (PTC) and NSCLC. Pre- and post-dose tumor and surrogate tissues were obtained. Biomarker and genotype analyses of pathway genes were performed. Results: The dose escalation phase is complete; 30 pts were treated with XL281. DLTs of fatigue, nausea, vomiting, and diarrhea were observed at the MAD (225 mg). The MTD is 150 mg. The most common related AEs included Grade 1/2, fatigue (48%), diarrhea (35%), nausea (35%), vomiting (35%) and anorexia (30%). Three pts had related AEs ≥G3: hypokalemia, nausea, and vomiting. One pt with an ocular melanoma demonstrated a cPR of 4 mos duration. Twelve pts had SD (3 -17+ mos), including 2 with I 131 -refractory PTC harboring BRAF V600E mutations (15+ and 17+ mos). Nine of these pts had decreases in target lesions (5–29%), including a pt with KRAS mutant CRC on study for 20 wks with marked symptomatic improvement. At the MTD, paired biopsies from 4 pts (3 melanoma, 1 NSCLC) show an average 72 % decrease in pMEK, 68 % decrease in pERK, 24 % decrease in Ki67 (proliferation) and 64 % increase in TUNEL (apoptosis). Three of 6 evaluable pts in the MTD cohort show SD at first assessment, including 1 melanoma pt with a NRAS Q61R mutation who showed a 20% decrease in target lesions. Conclusions: XL281 was generally well tolerated and the MTD was established at 150 mg. One cPR occurred in an ocular melanoma subject, and clinical benefit (PR or SD) occurred in 43% (13/30) of pts in the dose-escalation phase. XL281 demonstrates biological activity by modulation of the RAF pathway in tumor and surrogate tissue, with decreases in cell proliferation and increases in apoptosis. [Table: see text]
Abstract 15979: Restoration of NADH/NAD Ratio Delays Pressure Overload-Induced Cardiac Dysfunction via Regulation of Mitochondrial Protein Acetylation and Permeability Transition
Authors: Chi Fung Lee, Lorena Garcia-Menendez, Georgios Karamanlidis, Rong Tian
Journal: Circulation (2013)

We previously showed that impaired mitochondrial function due to Complex I (C-I) deficiency (by cardiac-specific deletion of Ndufs4, KO) caused a higher NADH/NAD ratio, increased protein acetylatio...
90Yttrium Ibritumomab Tiuxetan as First Line Treatment for Follicular Lymphoma. First Results from an International Phase II Clinical Trial
Authors: Christian W. Scholz, Antonello Pinto, Werner Linkesch, Ola Linden, Andreas Viardot, Ulrich Keller, Georg Hess, Kristina Lerch, Ferdinando Frigeri, Manuela Arcamone, Bernd Frericks, Christiane Pott, Antonio Pezzutto
Journal: Blood (2010)