tbuckley/cabot-search huggingface dataset:
Phase II study of weekly paclitaxel (PAC) and bryostatin-1 (BRYO) in hormone refractory prostate cancer (HRPC)
Authors: G. R. Hudes, P. Celano, F. Torti, A. Tabatabai, A. Murgo, A. Hussain
Journal: Journal of Clinical Oncology (2005)

4714 Background: Augmenting the antitumor activity of taxanes is a logical approach to improve treatment for patients with HRPC. BRYO, an inhibitor of protein kinase C and CDK2 activity, enhances the antitumor activity of PAC in vivo when administered approximately 12 hours after the taxane (Koutcher JA et al, Clin Cancer Res 2000). Methods: We conducted a Phase II trial of PAC and BRYO in patients with metastatic HRPC. PAC was given on day 1 and BRYO on day 2, each as a 1-hour IV infusion weekly x 3, for 4 weeks. The primary efficacy endpoint was proportion of patients with ≥ 50% decrease in pre-treatment PSA maintained for a minimum of 4 weeks. The study was designed to differentiate response proportions of 35% and 55% with type 1 and 2 errors of 10%. Results: A total of 21 patients (ECOG PS 0–1, median age 70, median PSA 180.3) were enrolled. The initial doses of BRYO (50 μg/m2) and PAC (90mg/m2) caused severe myalgias, fatigue, and early discontinuation (≤1 mo.) in the first four patients, prompting reduction of the starting doses. The remaining 17 patients received BRYO, 25 μg/m2 and PAC 80 mg/m2 for a median of four cycles (range, 1–9). Myalgias (52%), fatigue (52%), anemia (43%), and leukopenia (29%) were the most common toxicities. PSA decreased by ≥ 50% for at least 4 weeks in 3/17 patients (18%, 95% confidence bounds 3.5–43%) receiving PAC 80 mg/m2 and BRYO 25 μg/m2. None of the 6 patients with measurable soft tissue disease had objective responses. Median time to progression was 4.5 months. Based on the primary endpoint of PSA change, the null hypothesis was accepted and the study was terminated after first stage accrual. Conclusion: The weekly x 3, sequential schedule of PAC and BRYO is safe at doses of 80 mg/m2 and 25 μg/m2, but the limited antitumor activity discourages further study of this combination in HRPC. No significant financial relationships to disclose.
Effect of aromatase inhibitor or tamoxifen therapy on steroid sulfatase activity and DHEA-DHEAS concentrations in postmenopausal women with breast cancer
Authors: S. J. Stanway, A. Purohit, R. Ward, C. Palmieri, C. R. Coombes, M. J. Reed
Journal: Journal of Clinical Oncology (2008)

1134 Background: Steroid sulfatase (STS) is an important enzyme for the hydrolysis of DHEAS to DHEA and E1S to E1, which can be converted to Adiol and E2 respectively. It has been previously shown that inhibition of STS in postmenopausal (PM) women with breast cancer can lead to significant reductions in the serum concentrations of E1, E2 and Adiol, all capable of acting as ligands at the ER, and an increase in the DHEAS:DHEA ratio. As little is known about the effects of AI or tamoxifen therapy on STS activity or the DHEAS:DHEA ratio we have examined the effects of such therapies on these parameters in PM women with breast cancer. Methods: A cohort of PM patients receiving endocrine therapy with anastrozole (n=15) or tamoxifen (n=7) had blood taken pre and 4 weeks post initation of therapy for preparation of serum (for DHEAS and DHEA measurement) and PBLs (for the assessment of STS activity). Results: Mean DHEAS and DHEA in the patients taking AI therapy were 153μg/ml and 11μg/ml pre treatment and 135μg/ml and 8μg/ml respectively post therapy. Mean DHEAS and DHEA in the patients taking tamoxifen therapy were 57μg/ml and 4μg/ml pre treatment and 66μg/ml and 4μg/ml respectively post therapy. There were no statistical differences in the concentrations of DHEAS pre or post AI or tamoxifen therapy. Also no changes in the ratios of DHEAS:DHEA were detected after AI or tamoxifen therapy. Neither AI nor tamoxifen therapy had any effect on STS activity. Conclusions: AI treatment is known to suppress serum estrogen concentrations to the limit of detection. It has been shown in the phase I trial of STX64, a STS inhibitor, that estrogen levels are significantly reduced. However, as this study has shown AI therapy and tamoxifen therapy do not affect DHEAS or DHEA concentrations or the DHEAS:DHEA ratio. In contrast, STS inhibitor therapy is known to lead to decreases in Adiol, by virtue of inhibiting DHEAS hydrolysis. This is important as, even if estrogen levels are suppressed to very low levels, Adiol could cause proliferation of ER-positive breast cancer cells leading to disease relapse/progression. We propose that treatment with STS inhibitor therapy alone or in combination with AI therapy may be superior to treatment with AI therapy alone. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ipsen CRUK, Ipsen
Low omega-3 fatty acid levels associate with frequent gout attacks: a case control study
Authors: A Abhishek, Ana M Valdes, Michael Doherty
Journal: Annals of the Rheumatic Diseases (2015)

Eicosapentaenoic acid and docosahexaenoic acid are omega-3 polyunsaturated fatty acids with anti-inflammatory effects. They inhibit several pathways like toll-like receptor activation, NALP-3 inflammasome assembly, neutrophil chemotaxis, prostaglandin synthesis and nucleating factor-kB activity through which monosodium urate (MSU) crystals induce inflammation.1–6 In keeping with these findings, mice fed on diet rich in omega-3 fatty acids developed less inflammation after subcutaneous injection of MSU crystals than those on standard diets.1 ,7 Thus, omega-3 fatty acids have the potential of preventing acute attacks of gout. However, the association between omega-3 fatty acid levels and frequency of gout attacks has not been examined in humans. The objective of this study was to examine if omega-3 fatty acid levels associate with frequent gout attacks.

Data …
Impact of fish-oil supplement on nutritional parameters, inflammation and chemotherapy induced toxicity in colorectal cancer (CRC) patients receiving FOLFIRI- a pilot study
Authors: J. A. Read, P. J. Beale, L. G. Horvath, D. Volker, A. Childs, N. Smith, S. J. Clarke
Journal: Journal of Clinical Oncology (2005)

8243 Background: Fish-oil supplements containing EPA have been shown to increase lean body mass and quality of life compared to other supplements in pancreas cancer patients. Reduced toxicity to irinotecan has been seen in mice consuming EPA. The aim of this study was to determine if EPA could maintain CRC pts nutritional and inflammatory markers, “quality of life” parameters, and improve tolerance of FOLFIRI chemotherapy. Methods: Pts with stage IV CRC, PS 0–2, who had <2 prior chemo regimens were eligible. They were given 2 tetrapaks of Prosure for 3 wks prior to FOLFIRI, and continued for 9 wks. Nutritional/inflammatory markers were collected at baseline and wks 3 and 9. Nutritional parameters included the PGSGA, triceps skin fold thickness (TSF), fat free mass (FFM), dietary intake, and quality of life (QOL). Inflammatory markers included CRP, IL1 and IL6. Toxicity and response were recorded. Results: 25 patients (17 males, 8 females, median age 61 years) have been enrolled. 19 patients completed to the end of 3 wks and 13 to wk 9. Patients withdrew due to; PD (6), supplement intolerance (3), toxicity (1) and 2 remain on study. Average intake was 1.7 tetrapaks/day. At 3 wks, there was a significant increase in weight (p=0.046) and a decrease in PGSGA score (p<0.001). PGSGA scores decreased significantly over the total study period (p=0.002). There were no significant changes in FFM, TSF and QOL scores at 3 or 9 weeks. There was no significant change in weight between 3 and 9 weeks. 14 patients had elevated CRP (>10mmol/L). CRP increased significantly (p< 0.001) from 0–3 weeks, however there was no significant change in CRP from 0–9 weeks (p=0.26). Cytokine analyses are pending. 18 pts received chemotherapy; 4 pts experienced grade 3 diarrhoea and 3 grade 3 fatigue. No grade 4 tox. was seen. 6 pts experienced grade 2 neutropenia and 1 each of grade 3 and 4 leukopenia. Partial response was seen in 6 pts (33%). Conclusions: Prosure helps maintain weight and nutritional and QOL markers in pts with CRC. CRP was stabilised, however toxicity did not appear different to historical data. A randomised trial is needed to further evaluate these data. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott
Who are the later adopters of cancer screening? Inequalities in early adoption of cancer screening and regular participation from a diffusion of innovation perspective.
Authors: M. Hahm, E. Park, K. Choi, H. Lee, J. Park, S. Park
Journal: Journal of Clinical Oncology (2010)

e12039 Background: Although national level organized cancer screening programs have reduced barriers to screening for people of low socioeconomic status, barriers to early screening remain. Our aim was to identify the diffusion pattern and factors associated with early adoption of stomach and breast cancer screening. Methods: The study population was deprived from the Korean National Cancer Screening Survey, conducted in 2007. A stratified random sample of people aged 40 years and older from a nationwide population-based database was gathered in Korea (n = 1,517) in 2007. Time of adoption of early screening was defined as the number of elapsed years between thirty years of age and each person's age at first screening. Results: Significant differences were observed in the probability of adopting stomach and breast cancer screening in relation to education, household income, and job level. Results from Cox's proportional hazard model indicated that higher household income was significantly associated with an increased probability of adopting stomach cancer screening earlier (p < 0.05), and people with high household incomes were more likely to adopt breast cancer screening earlier than those with incomes under 1,500 US dollars per month (p < 0.01). When considered at a significance level of 0.1, we found that the most highly educated women were more likely than the least educated to adopt early. Conclusions: Despite organized governmental screening programs, there are still inequalities in the early adoption of cancer screening. The results of this study also suggest that inequalities in early adoption may affect regular screening. No significant financial relationships to disclose.
Induction of spermine oxidase by enterotoxigenic Bacteroides fragilis in colon models results in DNA damage
Authors: Andrew Goodwin, Shaoguang Wu, Yonggang Zhang, Theodore DeWeese, Cynthia Sears, Robert Casero
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

3131 

It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, though the molecular events linking inflammation and the necessary carcinogenic mutations remain to be clarified. In the context of gastrointestinal disease, bacterial infection by Helicobacter pylori and enterotoxigenic Bacteroides fragilis (ETBF) are significant sources of chronic inflammation and have been identified as risk factors for the development of gastric and colon cancer, respectively. We have previously demonstrated that H. pylori and the cytokine tumor necrosis factor-α (TNF-α) rapidly induce spermine oxidase (SMO), resulting in increased cellular reactive oxygen species (ROS) and DNA damage, in gastric and lung epithelial cells. To test the hypothesis that ETBF-induced SMO expression may be a source of oxidative damage in the colon, HT29/c1 and T84 human colon epithelial cell lines were treated with purified recombinant B. fragilis toxin (BFT). BFT treatment resulted in a rapid induction of SMO expression as measured by quantitative real-time PCR and western blotting, increased ROS detected by flow cytometry utilizing a H2DCFDA probe, and increased formation of 8-oxodeoxyguanosine measured by mass spectrometry. BFT treatment resulted in increased phosphorylated c-Jun N-terminal kinase (JNK) by western blotting and pre-treatment of HT29/c1 cells with the selective JNK inhibitor SP600125 abrogated SMO induction, suggesting a role for the activator protein-1 (AP-1) signaling pathway in the ETBF-mediated induction of SMO. These results are consistent with a recent report demonstrating the importance of AP-1 in ETBF-induced enteritis and our previous studies in gastric and lung epithelial cells. Our studies suggest that induction of SMO by inflammatory stimuli occurs in multiple epithelial systems and results in oxidative DNA damage, suggesting that SMO may represent one molecular link between chronic inflammation and epithelial carcinogenesis.
Individual benefits from adjuvant anthracycline-based chemotherapy can be predicted from a predictive nomogram created from primary chemotherapy (PC) data: Results of a randomized trial
Authors: R. Rouzier, F. Andre, R. Arriagada, L. Pusztai, M. Spielmann, M.-C. Mathieu, H. Marsiglia, A. Dunant, G. N. Hortobagyi, S. Delaloge
Journal: Journal of Clinical Oncology (2005)

623 Background: The benefit provided by chemotherapy (CT) for breast cancer patients is based on the risk of recurrence at a population level and not on an individual benefit. Pathologic complete response (pCR) to primary chemotherapy (PC) has been demonstrtated to be a surrogate marker of survival, demonstrtaing that patients that achieve a pCR are the most likely to benefit from CT. We hypothesized that individuals who benefit from adjuvant CT share the same clinico-pathologic characteristics as patients with pCR after PC and therefore that the same nomogram can be used to evaluate the probability of pCR and the benefit from receiving adjuvant CT after initial surgery. Methods: Two cohorts of patients treated at the IGR were studied. The first cohort (n=502) has received anthracycline-based PC. The second cohort (n=788) has been treated with initial surgery and has been randomized to receive either an adjuvant anthracycline-based CT or no CT. This trial demonstrated a disease-free survival benefit in the CT arm. We developed a nomogram to determine the probability of pCR in first cohort. For each patient of the second cohort, we calculated the theoretical probability of pCR. These patients were then categorized according to the probability of achieving pCR. Survivals were compared within each category according to the treatment arm. Results: A nomogram, based on age, tumor size, histologic grade and estrogen receptor status provided a good estimation of the probability of pCR (area under the curve=0.72). Achieving a pCR was associated with a 15 to 25% survival benefit. When applied to the cohort of patients treated with initial surgery, 49, 372 and 366 patients theoretically had less than 5%, between 5 and 10% and more than 10% chance to achieve pCR, respectively. The absolut survival benefits of adjuvant CT at 10 years were 0, 4 and 7%, respectively for the three categories (p: 0.05, linear trend). Conclusions: Probability of pCR after PC and individual benefit from adjuvant anthracycline-based CT are correlated. Our study suggests that indication of adjuvant CT could be based on individual benefit and not on a population risk. No significant financial relationships to disclose.
Predictive biomarkers to improve treatment of metastatic colorectal cancer (mCRC): Outcomes with cetuximab plus FOLFIRI in the CRYSTAL trial
Authors: C. Kohne, D. Stroiakovski, C. Chang-chien, R. Lim, T. Pintér, G. Bodoky, C. Stroh, I. Celik, P. Rougier, E. Van Cutsem
Journal: Journal of Clinical Oncology (2009)

4068 Background: KRAS oncogene mutation status is predictive of efficacy of cetuximab alone or combined with chemotherapy (CT) in mCRC. Previous data from the phase III CRYSTAL trial showed that adding cetuximab to FOLFIRI in first-line mCRC significantly improved the overall response rate (ORR) and progression-free survival (PFS) in pts with KRAS wild-type (wt) tumors. The serine-threonine kinase BRAF is a direct downstream effector of KRAS. Here, we report the influence of KRAS and BRAF status on mature overall survival (OS) data. Methods: DNA was extracted from archived tumor material where available from randomized pts. KRAS and BRAF mutation status (wt or mutant [mt]) was determined by quantitative PCR. Treatment arms were compared using two-sided log-rank tests (5% significance level) for PFS and OS, and the CMH test for best ORR. Results: The KRAS-evaluable cohort (n=540; 64.4% KRAS wt) was similar to the overall ITT group. In KRAS wt pts, adding cetuximab to FOLFIRI significantly increased the odds for tumor response nearly 2-fold, reduced the risk of progression by 32% and extended median OS from 21.0 months (mo) to 24.9 mo (details in Table ). KRAS mt pts did not benefit from cetuximab. Data on the impact of BRAF mutations on cetuximab activity will be presented at the meeting. In the FOLFIRI and cetuximab + FOLFIRI arms, 31.2% and 36.1% of pts, respectively, received no further line of therapy, while 25.4% and 6.2%, respectively, received EGFR antibody therapy. Conclusions: The benefits of adding cetuximab to CT were greater in KRAS wt pts than ITT pts for all clinically relevant endpoints. KRAS is a key biomarker for selecting a targeted therapy combined with standard CT in first-line mCRC. [Table: see text] [Table: see text]
Abstract P3-10-07: Phase I trial of eribulin in combination with S-1 for advanced and recurrent breast cancer patients
Authors: Tsutomu Iwasa, Junji Tsurutani, Satomi Nishida, Yoshifumi Komoike, Kazuhiko Nakagawa
Journal: Cancer Research (2015)

Abstract Introduction: Eribulin is a non-taxane microtubule dynamics inhibitor that has been proved to prolong overall survival in patients with advanced and recurrent breast cancer compared to treatment of physician’s choice. S-1 is an oral fluoropyrimidine anticancer agent that combines tegafur as the effector drug with two modulators, gimeracil, and oteracil potassium, and has shown promising antitumor activity as a single agent for the treatment of advanced breast cancer. In the basis of these results, we aimed to assess the efficacy of the combination of these two drugs in patients with advanced and recurrent breast cancer. In this trial, we determined maximum tolerated dose (MTD) and phase II recommended dose of Eribulin and S-1 combination therapy. Methods: A traditional 3+3 dose escalation design was implemented. 12 patients pre-treated with anthracycline and taxane were enrolled. As an initiation level, patients received s-1 50 mg/m2 from day1 to day14, and Eribulin 1.1mg/m2 on day1, and day8. In level 2, Eribulin dose was increased to 1.4mg/m2. In level 3, S-1 dose was increased to 80 mg/m2. Results: In level 1 or 2, no dose limiting toxicity (DLT) was observed. In level 3, grade 3 hypokalemia occurred in 1 case. The level 3 dose level was determined as phase II recommended dose. Neutropenia was observed in all cases, 3 of which was grade 3 febrile neutropenia. However, other non-hematological toxicity was mild, and the toxicity of the both drugs Safety (N=12)Adverse EventGrade 3/4Leukopenia3 (25%)Neutropenia10 (83%)Febrile Neutropenia3 (25%)Hypokalemia1 (8%) was not enhanced by the combination. Partial response Efficacy (N=12)CR0 (0%)PR5 (41%)SD≥24 weeks2 (17%)SD&amp;lt;24 weeks3 (25%)PD2 (17%)Clinical Benefit7 (58%)Disease Control Rate10 (83%) is confirmed in 5/11 patients with measurable lesions. Conclusion: We have shown that treatment with Eribulin and S-1 is active and well tolerated in patients with advanced and recurrent breast cancer, suggesting that this combination therapy may have potential as a new treatment option. A phase II study is being conducted to evaluate the efficacy and safety. Citation Format: Tsutomu Iwasa, Junji Tsurutani, Satomi Nishida, Yoshifumi Komoike, Kazuhiko Nakagawa. Phase I trial of eribulin in combination with S-1 for advanced and recurrent breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-10-07.
Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies
Authors: Jennifer W. Wu, Kristian B. Filion, Laurent Azoulay, Margaret K. Doll, Samy Suissa
Journal: Diabetes Care (2016)

OBJECTIVE Observational studies examining the association between long-acting insulin analogs and cancer incidence have produced inconsistent results. We conducted a systematic review of these studies, focusing on their methodological strengths and weaknesses. RESEARCH DESIGN AND METHODS We systematically searched MEDLINE and EMBASE from 2000 to 2014 to identify all observational studies evaluating the relationship between the long-acting insulin analogs and the risk of any and site-specific cancers (breast, colorectal, prostate). We included cohort and case-control studies published in English on insulin glargine and detemir and any cancer incidence among patients with type 1 or 2 diabetes. The methodological assessment involved the inclusion of prevalent users, inclusion of lag periods, time-related biases, and duration of follow-up between insulin initiation and cancer incidence. RESULTS A total of 16 cohort and 3 case-control studies met our inclusion criteria. All studies evaluated insulin glargine, and four studies also examined insulin detemir. Follow-up ranged from 0.9 to 7.0 years. Thirteen of 15 studies reported no association between insulin glargine and detemir and any cancer. Four of 13 studies reported an increased risk of breast cancer with insulin glargine. In the quality assessment, 7 studies included prevalent users, 11 did not consider a lag period, 6 had time-related biases, and 16 had short (&amp;lt;5 years) follow-up. CONCLUSIONS The observational studies examining the risk of cancer associated with long-acting insulin analogs have important methodological shortcomings that limit the conclusions that can be drawn. Thus, uncertainty remains, particularly for breast cancer risk.
410 P1-INTEGRINS AND BASAL CELL ADHESION MOLECULE PLAY A ROLE IN THE ADHESION OF ES CELL-DERIVED HEPATOCYE-LIKE CELLS TO ECM AND HEPATIC SINUSOIDAL CELLS
Authors: N.J. Davies, P. Lalor, D. Adams, D. Hay, P. Newsome
Journal: Journal of Hepatology (2012)