tbuckley/cabot-search huggingface dataset:
Phase II trial of combination of bortezomib and rituximab in relapsed and/or refractory Waldenstrom macroglobulinemia
Authors: I. M. Ghobrial, J. Matous, S. Padmanabhan, A. Badros, S. Chuma, R. Leduc, M. Rourke, J. Kunsman, B. Harris, D. Warren, P. Richardson
Journal: Journal of Clinical Oncology (2009)

8535 Background: This phase II study aimed to determine safety and activity of weekly bortezomib in combination with rituximab in patients with relapsed/refractory Waldenstrom macroglobulinemia (WM). Methods: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. NCI CTCAE v3.0 was used for toxicity assessment. All patients received bortezomib IV weekly at 1.6mg/m2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m2 at days 1, 8, 15, 22, on cycles 1 and 4. Results: 37 pts (26 men and 11 women, median age 62 years, range 42 - 73) have been treated to date. The median number of lines of prior treatment was 3 (range 1 - 5). All patients had received prior rituximab and 5 pts received prior bortezomib. The median IgM at baseline was 3540 mg/dL (range 700-10,800). The median follow up is 12 months (range 5 - 26 months). Thirty-five pts are evaluable for response. Complete remission and near complete remission occurred in 2 (6%), partial remission in 17 (48%), and minimal response in 10 (29%). Progressive disease occurred in 1 (3%) and stable disease occurred in 5 (14%). Most patients achieved response rapidly within 3 months of therapy (2–7 months). Rituximab flare occurred only in 6 patients (20%). At 24 months of follow up, 8/35 pts have shown relapsed disease. The median time to progression and duration of response has not been reached. Patients tolerated therapy well without significant toxicities: grade 3 peripheral neuropathy occurred in only 2 pts. Grade 1 and 2 neuropathy occurred in 10 pts (26%). Other grade 3 and 4 toxicities included neutropenia in 5 patients, and anemia and thrombocytopenia in 4 patients. Grade 5 pneumonia and viral infection occurred in 1 patient who was within the first cycle of therapy and did not receive herpes zoster prophylaxis. Attributable toxicities otherwise proved manageable with appropriate supportive care and the combination was generally well tolerated. Conclusions: The combination of weekly bortezomib and rituximab has been well tolerated and demonstrates encouraging activity, with CR+ PR + MR in 83% of evaluable patients with relapsed WM. No significant peripheral neuropathy has been observed to date with this regimen. [Table: see text]
Assessment Of Early Cytogenetic Response By 3 Months Versus &gt;3-6 Months Or No Response By 6 Months As a Predictor Of Long-Term Clinical Outcomes In a Phase 1/2 Study Of Bosutinib In Chronic Phase CML
Authors: Jorge E. Cortes, H. Jean Khoury, Andreas Hochhaus, Jane F Apperley, Stephen G. O'Brien, Eric Leip, Kathleen Turnbull, Maureen G. Conlan, Hagop M. Kantarjian, Tim H. Brümmendorf
Journal: Blood (2013)
Abstract 14468: Carolic Restriction Ameliorates Cardiac Steatosis by Activation of Autophagy via Cyclic AMP/AMPK/PKA Axis
Authors: Akio Monji, Yasuko K Bando, Morihiko Aoyama, Toko Mitsui, Toshimasa Shigeta, Toyoaki Murohara
Journal: Circulation (2012)

[INTRODUCTION] Cardiac steatosis promotes cardiac remodeling and impair cardiac function due to myocardial lipid accumulation and lipotoxic injury in animals and patients with metabolic disorder. I...
Prognosis related to Ki67 in early breast cancer.
Authors: R. Gerson, F. Alban, A. Villalobos, A. Serrano
Journal: Journal of Clinical Oncology (2010)

e11085 Background: Breast cancer (BC) is the most common tumor in Mexican women. Ki67 is a nuclear antigen considered as a proliferation marker with potential prognostic significance in BC survival. Our objectives are determine the prognosis and correlation between Ki67 and prognostic factors in BC patients (pts). Methods: From January 2000 to December 2008, patients (pts) > 18 yrs old with invasive BC, I to IIB, ductal or lobular, treated with surgery were included. Pts with in situ or inflammatory BC or neoadjuvant chemotherapy were excluded. Age, tumor size, lymph node status, Ki-67, HER2, ER, PR, p53, angiogenesis, adjuvant therapy, recurrence and overall survival were registered. Pts were divided into four groups according to Ki67 levels: 1) Ki67 < 5%, 2) 6 to 20%, 3) 21 to 50%, and 4) > 51%. Descriptive statistical methods and X2, ANOVA tests were applied. Results: 132 pts analyzed. Groups 1 to 4 were integrated by 23 pts (17.4%), 49 (37.1%), 39 (29.5%) and 21 (15.9%); median age 49, 48, 51 and 48 yrs (p > 0.05), respectively. Conservative surgery 56.4%, 30.6%, 25.6% y 42.9%, respectively. In each group, adjuvant chemotherapy was indicated in 82.6%, 83.6%, 89.7% and 90.4%; radiation 47.8%, 36.7%, 43.5% and 42.8%; hormonal therapy 65.2%, 71.4%, 50.9% and 38%. Chemotherapy based in anthracyclines in 36.8%, 34.1%, 31.4% and 31.5%, anthracyclines and taxanes in 57.8%, 53.6%, 62.8% and 68.5%. Ki67 was associated to tumor size > 2 cm (p = 0.02), negative ER (p = 0.000), negative p53 (p= 0.048). A tendency was detected for relationship to negative PR (p = 0.06) and hypodiploid DNA (p = 0.071). We noted higher frequency of triple negative immunophenotype in the groups with greater expression of Ki67 (8.7%, 10.2%, 10.2% y 28.5%) (p > 0.05). In each group, median follow-up time was 49, 37, 41 y 48 mos, (p > 0.05). Recurrence was observed in 18 pts (13.6%), of them 0, 5, 7 y 6 in the groups 1 to 4, respectively. Systemic was more frequent than local recurrence (66.6% vs. 27.4%). Median time to recurrence was 27, 39 and 60 mos in the groups 2 to 4. There were 0, 2 (4%), 4 (10.2%) and 3 (14.2%) deaths in each group, median overall survival 49, 25.5, 38.5 y 36 mos, respectively. Conclusions: High cellular proliferation through Ki67 (> 51%) was related to poor prognostic factors in BC. No significant financial relationships to disclose.
Presurgical sunitinib malate and androgen ablation in patients with localized prostate cancer at high risk for recurrence
Authors: A. J. Zurita, J. F. Ward, J. C. Araujo, C. A. Pettaway, L. L. Pisters, P. Dieringer, P. Troncoso, C. J. Logothetis
Journal: Journal of Clinical Oncology (2008)

16004 Background: Presurgical androgen deprivation therapy (ADT) does not improve long-term outcomes in patients (pts) with high- risk localized prostate cancer (PCa). Sunitinib malate (SU) is an oral inhibitor of the tyrosine kinases of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET. Since the VEGF and PDGF signaling pathways have been implicated in angiogenesis and PCa progression, and ADT results in endothelial cell apoptosis in the prostate by a VEGF-mediated mechanism, we hypothesized that combined treatment with SU might improve the efficacy of ADT in this pt population. Methods: Pts with no radiological evidence of metastases and either PCa ≥ clinical (c)T3 disease or Gleason score (GS) 8–10 or serum prostate-specific antigen (PSA) ≥ 20 ng/mL or cT2b-c and GS 7 and PSA ≥10 ng/mL (AJCC, 1992), receive i.m. leuprolide and oral SU for three 30-day cycles followed by surgery. SU is administered continuously at 37.5 mg daily (25 mg daily in the initial 6 pts). The primary endpoint of this phase II trial is rate of pathologic complete response (pCR). Secondary endpoints include safety and time to PSA progression. Unresectable pelvic nodal disease, confirmed post-operative PSA ≥ 0.2 ng/mL, or administration of post-operative radiation or ADT, define treatment failure. Results: Forty-four pts have been enrolled, completing accrual, with a median age of 58 years (range 47–72); 34 Caucasian, 5 African-American, 4 Hispanic, and 1 Indian. High-risk criteria included cT3 (24/44), GS 8–10 (30/44), PSA ≥ 20 ng/mL (16/44). Two men were ineligible or declined therapy. Thirty-three pts have completed 3 months on treatment; no toxicity-related discontinuations or grade 4 toxicities have been observed. Grade 3 toxicities included hypertension (8), hand- foot syndrome (2), mucositis (2), fatigue (2), neutropenia (6), and hepatic (1). Thirty pts have completed surgery to date with no unexpected surgical complications. One pt experienced a pCR, while 3/30 (10%) have met the definition for treatment failure. Conclusions: The preoperative combination of SU and ADT appears to be safe and well tolerated in pts with high-risk primary PCa. One complete remission has been observed thus far. Ongoing analysis will allow us to determine if this strategy is worthy of further development. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology Pfizer Oncology
Abstract OT2-3-04: A PILOT PHASE II STUDY TO EVALUATE THE IMPACT OF DENOSUMAB ON DISSEMINATED TUMOR CELLS (DTC) IN PATIENTS WITH EARLY STAGE BREAST CANCER (ESBC)
Authors: J Li, HS Rugo
Journal: Cancer Research (2012)

Abstract Background: Bone is the most common site of metastases in breast cancer (BC). The detection of keratin + cells (DTC) in bone marrow (BM) has been shown to correlate with an increased risk of disease recurrence. Receptor activator of nuclear factor kappa b (RANK) is critical to bone turnover. Pre-clinical studies have shown that the ligand to RANK (RANKL) can induce metastases of RANK-expressed tumor cells, and that treatment with a RANKL inhibitor can reduce BC metastases. Our previous study suggests that higher RANK expression in tumor at the time of diagnosis correlates with worse recurrent free survival (RFS). Denosumab, a humanized RANKL inhibitor, has been approved in patients (pts) with osteoporosis and metastatic BC to bone. Trial design: We designed a nonrandomized, open label phase II pilot study evaluating the impact of denosumab on DTCs in pts with ESBC and DTCs following (neo) adjuvant chemotherapy. A total of 45 pts will be enrolled; treatment (Rx) consists of denosumab by subcutaneous injection monthly for 6 months, then every 12 weeks for 6 months for a total of one year. BMA will be repeated at 6 and 12 mo; samples will be evaluated for DTC and for specific gene expression. Eligibility criteria: Eligible pts have completed adjuvant chemotherapy and at least 3 months (mo) of hormonal Rx as indicated, and have &amp;gt;10 DTC on screening bone marrow aspiration by immunomagnetic enrichment + flow cytometry (IE/FC). Specific aims: The primary efficacy endpoint is the reduction of DTC/ml from &amp;gt;10DTC/ml to ≤ 10DTC/ml at 6 mo and one year, and the feasibility of denosumab use in this setting. Secondary and exploratory endpoints are to evaluate the correlation of DTC at each time point with BC recurrence, and to analyze gene expression of markers related to bone destruction and inflammation in sorted DTC. Statistical methods: A total of 45 pts will be enrolled. Based on results from a previous trial testing zoledronic acid in a group of pts with similar eligibility, we expect to have evaluable BMA on 37 (82%) at 1 year. With standard Rx we expect 5% or fewer will have counts ≤10 DTC/ml at 1 year. Using STATA routine sample size (SAMPSI: sample size and power for means and proportions), as long as 20% of pts in treated group become DTC-negative, we will have 89% power to detect this degree of efficacy. These calculations are based on an “exact” test of the proportion of successes; those with reductions to ≤10DTC/ml in sample sizes of 37 based on one-sided testing at a 5% level of significance. We will compare the DTC/ml at 6 and 12 mo to baseline to evaluate reduction in counts. Present accrual and target accrual: trial will be open in July, 2012 with target accrual of 45 pts. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-3-04.
Oncogenicity of the R-35 Rat Mammary Tumor Virus2
Authors: Arthur E. Bogden, William R. Cobb, Mumtaz Ahmed, Sharon Alex, Marcus M. Mason
Journal: JNCI Journal of the National Cancer Institute (1974)

R-35 mammary tumor virus (R-35MTV), a C-type rat virus originally isolated from the R-35 mammary adenocarcinoma, was inoculated subcutaneously (sc) into neonatal Sprague-Dawley-derived GFRC:SPF(SD) females and males to determine its oncogenic potential in the species of origin. During a 20-month observation period, overall mammary tumor incidence in the R-35MTVinoculated female population was 29.5%; it was 18.5% in uninoculated controls. Although benign tumor incidence in both populations was similar, malignant tumor incidence in the virus-inoculated group (10.8%) was 6 times greater than in controls (1.8%). Malignant tumors, all mammary carcinomas or adenocarcinomas, also appeared earlier (4-5 months) in virus-treated than in control (9–13 months) animals. Estrogen imbalance, induced by sc implantation of 17β-estradiol pellets, resulted in a mammary tumor incidence of 35% in virus-treated animals during a 13- month observation period, whereas no tumors were detected in the control group during that time. Of 8 tumors examined from animals given virus, all were found positive for R-35MTV antigen and 3 for C-type particles by electron microscopy. Five primary tumors from controls were negative for both R-35MTV antigens and C-type particles. None of the 315 virus-inoculated and 247 control animals, of either sex, developed leukemia. Though morphologically it is a C-type particle, R-35MTV given neonatally seemed associated with an increased incidence of mammary neoplasms of epithelial rather than of connective tissue origin.
DNA-Guided Precision Medicine for Cancer: A Case of Irrational Exuberance?
Authors: Emile E. Voest, Rene Bernards
Journal: Cancer Discovery (2016)

Abstract Summary: Precision treatment with targeted cancer drugs requires the selection of patients who are most likely to benefit from a given therapy. We argue here that the use of a combination of both DNA and transcriptome analyses will significantly improve drug response prediction. Cancer Discov; 6(2); 130–2. ©2016 AACR.
Correlation of target kinase genotype with clinical activity of imatinib mesylate (IM) in patients with metastatic GI stromal tumors (GISTs) expressing KIT (KIT+)
Authors: M. C. Heinrich, J. S. Shoemaker, C. L. Corless, D. Hollis, G. D. Demetri, M. M. Bertagnolli, J. A. Fletcher
Journal: Journal of Clinical Oncology (2005)

7 Background: Most GISTs express constitutively activated mutant isoforms of the KIT or PDGFRA tyrosine kinases that are therapeutic targets for IM (Gleevec). The relationship between mutations in these two kinases and IM activity was examined in a group of patients (pts) treated with IM for advanced KIT+ GIST as part of a randomized phase III study comparing 400 vs. 800 mg daily doses (CALGB 150105/SWOG S0033). Methods: Pre-treatment GIST samples from 324 pts were examined for baseline mutations of KIT or PDGFRA. Results: For the 324 eligible pts with a confirmed diagnosis of KIT+ GIST, we found KIT mutations in 280 pts (86.4%) and PDGFRA mutations in 3 pts (1%) for an overall mutation frequency of 87.3%. Pts whose tumor expressed an exon 11 KIT mutant isoform were more likely to have a objective response (OR) to IM therapy (OR=67%) than pts whose tumor expressed a KIT exon 9 mutant isoform (OR=40%) or had no kinase mutations (OR=39% p=0.0022). There was no significant effect of IM dose on the likelihood of clinical response among pts with KIT exon 11 mutant, exon 9 mutant, or no mutation GISTs. Among patients with exon 11 mutations, there was no significant difference in clinical response between patients whose tumors had point mutations versus deletions. In a multivariate analysis, KIT exon 11 genotype was the single best predictor of objective response. Pts with a KIT exon 11 mutant tumor had a significantly longer median TTF (576 days) than pts whose tumor expressed either an exon 9 KIT mutant isoform (308 days) or had no detectable kinase mutation (251 days, p=0.0012). There was a trend toward increased overall survival for pts with KIT exon 11 mutant GISTs when compared to pts with any other KIT mutation or wild-type GISTs, but this difference was not statistically significant (p=0.04, NS adjusted for multiple comparisons). Conclusions: Activating mutations of KIT or PDGFRA are found in the vast majority of KIT+ GISTs and KIT exon 11 tumor genotype correlates with the most favorable clinical responses and TTF. New therapeutic strategies may further improve these results, especially for those patients whose GISTs do not express the exon 11 mutant KIT isoform. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium, Novartis Novartis Novartis
Relative efficacy of various 5- hydroxytryptamine receptor antagonists in the prevention and control of acute nausea and vomiting associated with platinum-based chemotherapy
Authors: M. Hamadani, R. Padmanabhan, L. Chaudhary, A. Tfayli
Journal: Journal of Clinical Oncology (2006)

8623 Background: The introduction of 5-Hydroxytryptamine-3 receptor (5-HT 3 ) antagonists has represented a significant clinical advance in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV), particularly for patients receiving highly emetogenic platinum-based regimens. However no study to date has compared the relative efficacy of Dolasetron, Granisetron, Ondansetron and Palonosetron with Dexamethasone in the prevention and control of acute CINV in patients undergoing platinum-based therapy. Methods: Retrospective data were reviewed for 207 consecutive patients receiving Platinum-based chemotherapy in our infusion center between November 1999 and August 2005. Patients receiving 5-HT 3 antagonists without Dexamethasone (n=11) were not eligible for the study. Further 15 patients were excluded because of no documentation of CINV. The remaining 181 patients constitute the subject of this study. Patient characteristics including age, sex, race, diagnosis, history of heavy alcohol intake, chemotherapy regimen administered, number of cycles, and performance status at the start of therapy were noted. Primary outcome measure was complete control of acute CINV. National Cancer Institute Common Toxicity Criteria version 2.0 was used to assess toxicity. Results: The 181 patients received 572 cycles of platinum-based therapy. Dolasetron (n=157), Granisetron (n=81), Ondansetron (n=131) and Palonosetron (n=203) (each given with Dexamethasone) achieved complete control of vomiting in 89.8%, 95.5%, 92.3% and 88.1% (ρ=0.86) of cycles respectively. Respectively, complete nausea control was observed in 68.1%, 75.3%, 69.4% and 73.3% (ρ=0.35). DEX 20 mg was not superior to 10mg in complete control of nausea and vomiting (ρ=0.06 and ρ=0.67 respectively). Similarly complete control of nausea and vomiting (ρ=0.12 and ρ=0.10 respectively) was not significantly different in patients getting cisplatin compared to carboplatin based regimens. Conclusion: This study does not demonstrate a significant difference in the efficacy of the four 5-HT3 antagonists in controlling acute CINV. The higher dose of Dexamethasone confers no added benefit over the lower 10mg dose. No significant financial relationships to disclose.
Early prediction of clinical response to first-line treatment with gefitinib using integrated FDG-PET for patients with advanced non-small cell lung cancer.
Authors: M. Kanadzu, K. Asami, S. Hamaguchi, Y. Kurahara, T. Tsuji, K. Nakao, K. Nishie, T. Goto, A. Hirooka, N. Takeuchi, T. Kagawa, A. Tamiya, Y. Matsuda, H. Yamanaka, K. Okishio, T. Kawaguchi, S. Atagi, K. Maruyama, M. Takada
Journal: Journal of Clinical Oncology (2011)

e18049 Background: Early prediction of clinical response is of great value in patients with advanced non-small cell lung cancer (NSCLC) in avoiding unnecessary toxicity and giving them another chance for different treatment. This study aimed to assess the integrated 18-fluorodeoxyglucose positron emission tomography (FDG-PET) at 3 days after treatment as a tool for early response predictor in the patients treated with gefitinib or carboplatin plus paclitaxel (CP). Methods: Patients with stage IIIB or IV NSCLC were scheduled to receive first-line treatment were eligible for this study. Patients were treated with gefitinib (250mg) once daily or with CP every 3-week cycle as first-line treatment. FDG-PET was performed before and 3 day after initiation of each treatment. Based on previous studies, a reduction of tumor FDG uptake was assessed by using standardized uptake value (SUV). ROC analyses were performed to compare the results of the visually interpreted FDG-PET findings and the findings obtained with the use of an SUV threshold. Results: A total 38 patients were included in this study. Nineteen patients (50%) received gefitinib, and 19 (50%) received CP. The overall response rate (RR) was 36% with 7 partial response (PR) in gefitinig group and 16% with 3 PR in CP group. The optimal differentiation achieved by a cut-off value in reduction of SUV level was 20% in gefitinib group and 15% in CPgroup. Applying this cut-off value as a criterion for a metabolic response, sensitivity and specificity for predicted clinical response was of 91% and 100% in patients with gefitinib, 81% and 67% in patients with CP, respectively. , Metabolic responder had significant longer survival than non-responder in gefitinib group (median overall survival (OS): 22.6m, 95%CI: 7.4-37.8 vs median OS: 7.7m, 95%CI: 1.7-13.7, p=0.04), while there was no correlation between a reduction of SUV level and OS in CP group (median OS: 13.9m, 95%CI: 10.0-17.8 vs median OS: 10.5m, 95%CI: 7.3-13.7, p=0.56). Conclusions: The reduction of SUV level by using FDG-PET at 3 day after treatment can predict response and survival in gefitinib-treated patients.
Atopic dermatitis in children costs ?47m each year.
Authors: Roger Dobson
Journal: BMJ (2001)

Treating atopic dermatitis in preschool children may be costing as much as £47m ($70.5m) a year in the United Kingdom, according to new research (British Journal of Dermatology 2001;144:514-22). Almost one in seven children now has an episode of atopic dermatitis at some time.

The authors, from the Queen's Medical Centre, Nottingham, …
Rodent L1 evolution has been driven by a single dominant lineage that has repeatedly acquired new transcriptional regulatory sequences.
Authors: N B Adey, S A Schichman, D K Graham, S N Peterson, M H Edgell, C A Hutchison
Journal: Molecular Biology and Evolution (1994)

All mammalian genomes contain approximately 100,000 copies of the transposable element LINES-1 (L1). Phylogenetic analysis indicates that the L1 progenitor predates the mammalian radiation; since that time, the open reading frames encoded in L1 have evolved under selection. The least conserved regions within L1 are the 5'-terminal transcriptional regulatory sequences. In rodents, four types of L1 elements (A, F, and V from mouse and R from rat) have been defined according to the type of apparently nonhomologous promoter sequence present at the 5' end. In this study, we investigate the relationships between these four types of promoters. DNA sequence was determined from approximately 1.5-kb regions from the 5' ends of seven F- and three V-type L1 elements. These sequences were aligned with 29 previously reported L1 elements. Phylogenetic analysis was then performed on the homologous regions of the alignment. The results indicate that in mouse all of the A-, F-, and V-type elements belong to a single dominant lineage but were inserted into the genome during different time periods; V-type elements are the oldest, while A-type elements are the most recently inserted. V-type elements also appear ancestral to the R-type elements found in rat and therefore were replicatively competent prior to the divergence of rat and mouse. Analysis of sequence identity indicates that the different 5' promoters did not derive from a common ancestor. Therefore, the dominant L1 lineage appears to have acquired novel promoter sequences from non-L1 sources. Transposable elements from a wide range of species show similar structural rearrangements, suggesting that acquisition of new sequences may be a common theme in their evolution.