tbuckley/cabot-search huggingface dataset:
Detector-C: A blood-based IVD with high sensitivity and specificity for early detection of colorectal cancer.
Authors: A. Rosenthal, D. Nuernberg, M. Pross, J. Pertschy, P. Nartschik, T. Manger, B. Unger, W. Pommerien, H. Adams
Journal: Journal of Clinical Oncology (2010)

3580 Background: Colonoscopy is the gold standard for screening of colorectal cancer (CRC). However, only 20%-30% of the screening population aged 55-75 years use colonoscopy due to its inconvenience and invasive nature. There is a need for an accurate, noninvasive blood test. Methods: We randomized 572 PAX-RNA blood samples from two prospective, multicentre clinical studies. CRC cases originated from the MSKK study, controls from the CRC.SCR.2 study which enrolled healthy individuals from a screening population undergoing colonoscopy. Blood was drawn prior to surgery or prior to colonoscopy. RNA was isolated, QC checked, hybridized onto the Affymetrix U133 2.0 Plus arrays, and QC checked. Clinical data were monitored. Results: After all QCs data of 462 pts remained. Data from 119 pts (55 cases, 64 controls) were utilized for discovery of gene signatures using a double nested bootstrap with random forrest and SVM as feature selection methods. The best signature, Detector-C, discriminating between cases and controls contained 202 probe sets and resulted in a prospective sensitivity (S+) of 85.3% and a prospective specificity (S-) of 93.3%. The hypothesis for the prospective performance evaluation (validation) of Detector-C was to show a S+ of > 70% and a S− of > 80% with a one-sided alpha of 2.5% and a power of 97.5%. In order to test this hypothesis at least 122 cases and at least 109 controls would be needed. We used the remaining 210 cases and 133 controls for the prospective validation. S+ was 90% (95% CI: 0.851-0.937) and S− was 88% (95% CI: 0.812-0.930). S+ by UICC stage was: stage I: 0.89 (95% CI: 0.774-0.958), stage II: 0.90 (95% CI: 0.788-0.961), stage III: 90% (95% CI: 0.805-0.959) and stage IV: 93% (95% CI: 0.765-0.991). Detector-C also identified high-grade intraepithelial neoplasia with S+ of 66%. Multivariate analysis showed no significant effect of stage, age, gender, tumor localization, or RNA quality on correct prediction. Conclusions: Detector-C measures the host response (host defense, immune answer, wound healing, inflammation) of white blood cells to tumor lesions and is highly suited for screening of CRC due its easy of use, noninvasiveness and its high sensitivity for early-stage CRC/neoplastic lesions. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Signature Diagnostics AG Signature Diagnostics AG Signature Diagnostics AG Signature Diagnostics AG
CPG 7909, a TLR9 agonist immunomodulator in metastatic melanoma: A randomized phase II trial comparing two doses and in combination with DTIC
Authors: S. Wagner, J. Weber, B. Redman, T. Schmalbach, D. Bright, M. Al-Adhami, H. Zarour, U. Trefzer
Journal: Journal of Clinical Oncology (2005)

7526 Background: Malignant melanoma is widely accepted as an immunologically responsive tumor. Expectations for major clinical benefit with treatment by interferons or from biochemotherapy trials have not been met, and the prognosis for patients (pts) with metastatic disease remains poor. A new synthetic chemical immunomodulator, CPG 7909 (ProMune), is now being studied in a large randomized phase II trial based on single agent tumor activity in metastatic pts. CPG 7909 is a non-antisense oligodeoxynucleotide which activates plasmacytoid dendritic cells and B cells through targeted agonism of the Toll-like receptor 9 (TLR9) and is a strong activator of both innate and adaptive immunity. Methods: 184 pts with the diagnosis of metastatic melanoma were enrolled in 48 sites. Pts were randomized into 4 arms: CPG 7909 10 mg, CPG 7909 40 mg, CPG 7909 40 mg in combination with DTIC, or DTIC alone. All CPG 7909 was administered by weekly S.C. injection in multiple sites. DTIC (850 mg/m2) was administered I.V. every 21 days. Treatment was continued until disease progression. Randomization was stratified for presence or absence of liver metastases. The primary study endpoint was response by RECIST criteria, with follow up for survival. Results: Enrollment has been completed and treatment is ongoing. These S.C. doses of CPG 7909 are generally well tolerated and do not complicate DTIC treatment. Preliminary response assessments on 92 pts include 4 PRs in the combination arm vs. 2 PRs on DTIC, 1 PR on CPG 7909 10 mg and none on CPG 7909 40 mg. 57 pts had disease progression at or before the 9 week (3rd cycle) evaluation. Adverse events included transient injection site reactions, fever and arthralgias. Three SAE’s included a case of an anaphylactoid reaction (wheezing and angioedema within two minutes), a vasovagal reaction with hypotension, and one sudden death following an acute MI. PK and PD analyses are ongoing. Conclusions: Subcutaneous administration of CPG 7909 at doses up to 40mg once weekly is safe and well tolerated by most pts. A new combination of DTIC with a potent TLR9 agonist may show a better response than does DTIC alone in metastatic melanoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Coley Pharmaceutical Group Coley Pharmaceutical Group Coley Pharmaceutical Group
Biomolecular Markers within the Core Axis of Aging and Particulate Air Pollution Exposure in the Elderly: A Cross-Sectional Study
Authors: Nicky Pieters, Bram G. Janssen, Harrie Dewitte, Bianca Cox, Ann Cuypers, Wouter Lefebvre, Karen Smeets, Charlotte Vanpoucke, Michelle Plusquin, Tim S. Nawrot
Journal: Environmental Health Perspectives (2015)

Telomere length and mitochondrial DNA (mtDNA) content are markers of aging and aging-related diseases. There is inconclusive evidence concerning the mechanistic effects of airborne particulate matter (PM) exposure on biomolecular markers of aging.The present study examines the association between short- and long-term PM exposure with telomere length and mtDNA content in the elderly and investigates to what extent this association is mediated by expression of genes playing a role in the telomere-mitochondrial axis of aging.Among 166 nonsmoking elderly participants, we used qPCR to measure telomere length and mtDNA content in leukocytes and RNA from whole blood to measure expression of SIRT1, TP53, PPARGC1A, PPARGC1B, NRF1, and NFE2L2. Associations between PM exposure and markers of aging were estimated using multivariable linear regression models adjusted for sex, age, BMI, socioeconomic status, statin use, past smoking status, white blood cell count, and percentage of neutrophils. Mediation analysis was performed to explore the role of age-related markers between the association of PM exposure and outcome. Annual PM2.5 exposure was calculated for each participant's home address using a high-resolution spatial-temporal interpolation model.Annual PM2.5 concentrations ranged from 15 to 23 μg/m3. A 5-μg/m3 increment in annual PM2.5 concentration was associated with a relative decrease of 16.8% (95% CI: -26.0%, -7.4%, p = 0.0005) in telomere length and a relative decrease of 25.7% (95% CI: -35.2%, -16.2%, p < 0.0001) in mtDNA content. Assuming causality, results of the mediation analysis indicated that SIRT1 mediated 19.5% and 22.5% of the estimated effect of PM2.5 exposure on telomere length and mtDNA content, respectively.Our findings suggest that the estimated effects of PM2.5 exposure on the telomere-mitochondrial axis of aging may play an important role in chronic health effects of PM2.5.Pieters N, Janssen BG, Dewitte H, Cox B, Cuypers A, Lefebvre W, Smeets K, Vanpoucke C, Plusquin M, Nawrot TS. 2016. Biomolecular markers within the core axis of aging and particulate air pollution exposure in the elderly: a cross-sectional study. Environ Health Perspect 124:943-950; http://dx.doi.org/10.1289/ehp.1509728.
Abstract #950: Chemopreventive and chemotherapeutic properties of Curcumin in various cancers
Authors: Peter Killian, Emanuel Kronski, Ulrich Pfeffer, Andreas Nerlich, Beatrice Bachmeier
Journal: Cancer Research (2009)

Curcumin is a polyphenol, derived from the plant Curcuma longa that has promising anticancer properties. We demonstrate that this natural substance inhibits cell proliferation and expression of tumor-associated proteinases (matrix metalloproteinases - MMPs) as well as invasion in various cancer types and reduces the formation of breast cancer metastasis in vivo. Application of Curcumin in breast cancer (MDA-MB-231) and prostate cancer (PC3, DU145) cells reduces proliferation (BrdU assay) and invasion (Matrigel assay) in a time and dose dependent manner. The underlying regulation mechanism involves the transcription factors AP-1 and NF\#922;B which are clearly down-regulated by Curcumin and which control apoptosis and the expression of tumor progression related gene products like the matrix degrading enzymes MMPs. Thereby the polyphenol induces apoptosis and diminishes mRNA and protein expression as well as activity of MMP-1, -2 and -9. Furthermore expression of the pro-inflammatory cytokines CXCL1 and -2 are impaired upon Curcumin treatment, which leads to down-regulation of a variety of metastasis related genes like SPARC, CXCR4, PTGS2, ALDH, and the angiogenic factor ANGPT. All these molecular effects together are the reason that the formation of haematogenous metastasis was statistically significantly (Mann-Whitney p=0.0035) reduced in immunodeficient mice which obtained 1% Curcumin orally in their standard diet. Taken together, the inhibition of MMP-2, -9 and ANGPT clearly implicates the anti-angiogenic potential of Curcumin in breast and prostate cancer. These features along with its properties to inhibit proliferation, invasion and formation of metastasis in vivo make Curcumin a promising drug for cancer chemoprevention and antitumor therapy.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 950.
An all-oral combination of capecitabine (X) and cyclophosphamide (C): Findings from a phase I study and an additional feasibility study in patients (pts) with metastatic breast cancer (MBC)
Authors: S. Ohno, S. Mitsuyama, K. Tamura, R. Nishimura, M. Tanaka, Y. Hamada, S. Kuroki
Journal: Journal of Clinical Oncology (2005)

849 Background: Both X and C have single-agent activity in MBC. A combination of X and C is reported to show a synergistic effect in xenograft models. We performed a phase I study to determine the maximum tolerated doses (MTD) and recommended phase II doses (RD) for an all-oral combination of XC. Methods: Eligible pts had histologically confirmed MBC, age 20–75, ECOG PS ≥2, ≥1 prior chemotherapy regimen, and adequate bone marrow, renal, hepatic, and cardiac function. X and C were administered bid on days 1 -14 every 3 weeks. In the phase I study, toxicity was evaluated after 2 cycles of therapy. Dose limiting toxicity (DLT) was defined as grade (G) 4 hematological toxicity, G 3/4 non-hematological toxicity, and >1 week treatment delay at day 1 of cycle 2. X and C were administered at 3 dose levels: DL1 (X/C 1225/65mg/m2/day); DL2 (X/C 1657/65mg/m2/day); and DL3 (X/C 1657/100mg/m2/day). Results: 9 pts (6 at DL1 and 3 at DL2) were enrolled in the phase I study. 8 pts had received ≥2 prior-chemotherapies (5 pts, ≥3 prior-chemotherapies). No DLT was observed at DL1. Two DLTs (treatment delays of 2 or 3 weeks) occurred at DL2, indicating that DL2 is the MTD. The DLTs (2 treatment delays) resulted from prolonged moderate neutropenia. One G3/4 hematological event (G3 neutropenia) occurred, but no febrile neutropenia and no G3/4 non-hematological toxicities were observed. PR was seen in 1/4 pts. Conclusions: The RD for XC therapy is determined to be X/C 1225/65 mg/m2/day for heavily-pretreated pts. Considering that DL2 would not be an MTD for non-heavily-pretreated pts, the additional feasibility study was conducted with DL2. In the study, 6 pts were accrued and their safety profiles were evaluated after 2 and 6 cycles. No DLT was observed in the first 3 pts, and 3 further pts will be treated. For pts who are not heavily pretreated, the RD for XC therapy could be X/C 1657/65 mg/m2/day. No significant financial relationships to disclose.
The effects of race on stage of presentation and survival for patients with adenocarcinoma of the colon/rectum at an urban teaching facility
Authors: C. D. Kingsley, J. Y. Wan, K. S. Patterson, K. Wright, L. Donnelly, P. Adler
Journal: Journal of Clinical Oncology (2005)

3637 Background: Studies have shown that Caucasians have improved survival over African Americans with adenocarcinoma of the colon/rectum. The improved survival may be related to socio-economic status, access to healthcare, and possibly genetic factors. This retrospective study was undertaken to evaluate the role of race on overall survival as correlated with stage of presentation. Methods: A retrospective review of tumor registry data from a single, urban teaching facility in Memphis, Tennessee was undertaken. The review consisted of data from the years 1994 through 2004. Data was examined for race and stage of tumor at diagnosis. A total of 2262 patients (1002 African American, 1240 Caucasian) was stratified based upon race and tumor stage at diagnosis and evaluated for survival. Survival was listed as known date of death or censored at time of last known visit. The data was analyzed using chi-square and Cox regression model. Results: African Americans (n=540 or 52.8%) were more likely to present with a more advanced stage tumor (III or IV) than Caucasians (n=560 or 45.2%) (P<.001). African Americans were also found to have a worse survival experience (P = 0.009), even after controlling for stage using Cox regression model. Conclusions: In this study, an attempt was made to limit possible confounders such as access to healthcare and socio-economic status by limiting the data to a single teaching facility. As there was still a discrepancy between the races, further study is indicated. A genetic component may be responsible for the difference, but issues such as access to healthcare, personal and religious beliefs, and socio-economic status also need to be more fully evaluated before a final conclusion can be drawn regarding differences in survival. No significant financial relationships to disclose.
A phase II trial of weekly alternating sequential administration of BIBF1120 and BIBW2992 in patients with advanced colorectal cancer
Authors: O. Bouché, M. Ducreux, G. Lledo, T. André, F. Maindrault-Goebel, P. Stopfer, Z. Oum’Hamed, M. Chadjaa, A. de Gramont
Journal: Journal of Clinical Oncology (2008)

15001 Background: BIBF1120 is a triple angiokinase inhibitor (VEGFR1–3, PDGFR and FGFR). BIBW2992 is an inhibitor of EGFR and HER2. Combined blockade of these targets may have additive or synergistic effects on tumour response. Methods: BIBF1120 was administered orally twice daily at 250 mg on days 1 to 7, followed by BIBW2992 at 50 mg once daily on days 8–14. Sequential administration was repeated in 4 weeks (wks) cycles for at least 24 wks. Patients (pts) were eligible for repeated treatment courses in the absence of progression of disease (PD). Objective response rate (OR) was used as primary endpoint. Plasma samples were taken to determine pharmakokinetics and potential drug-drug interactions between BIBF 1120 and BIBW2992. Results: A total of 46 (28 male/18 female) pts with a median age of 58.5 years (range 42–79) were treated for median of 9 wks (range: 2–32). 45 pts (97.8%) previously received at least two lines of treatment, 38 (82.6%) three lines and 26 (56.5%) more than three lines. Twenty-four pts (52.2%) previously received bevacizumab and 41 (89.1%) cetuximab. The best response observed was stable disease in 20 pts (43.5%) and PD in 26 pts (56.5%). Median Progression free survival (PFS) was 1.8 months and median overall survival (OS) was 5.1 months. 43 pts (93.5%) experienced at least one drug-related adverse event. The most common were diarrhoea as reported in 37 pts (80.4%), with 2.2% grade 4 and 13% grade 3 events. Nausea was prevalent in 20 pts (43.5%), with 2.2% grade 3 and vomiting in 15 pts (32.6%) with 4.3% grade 3. Rash was experienced by 19 pts (41.3%). Asthenia was reported in 22 pts (47.8%) with 8.7% grade 3. Increased alanine aminotransferase grade 3 was observed in 4 pts (8.7%). Conclusions: The sequential weekly administration of BIBF1120 and BIBW 2992 has an acceptable safety profile.The combination treatment shows no OR in heavily pre-treated patients with metastatic colorectal cancer. Other schedules of administration warrant further evaluation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Boehringer Ingelheim Amgen, Pfizer Oncology, Roche Amgen, Boehringer Ingelheim, Merck, Roche, sanofi-aventis
Final safety and efficacy data for Asian patients (pts) in the MO19390 (SAiL) trial: First-line bevacizumab (Bv) plus chemotherapy in advanced or recurrent non-small cell lung cancer (NSCLC).
Authors: C. Tsai, C. Zhou, G. Jiang, Z. Guan, W. M. Zhao, Y. Wu
Journal: Journal of Clinical Oncology (2010)

e18101 Background: Data from Asian pts in China, Hong Kong and Taiwan enrolled in the multinational MO19390 (SAiL) trial were analyzed retrospectively to assess the safety profile of first-line Bv-based therapy in advanced NSCLC in that patient subgroup. Final safety and efficacy results are presented here. Methods: 2,252 pts were enrolled in SAiL. The ITT Asian pt population included 314 chemo-naïve pts with advanced or recurrent non-squamous NSCLC, ECOG PS 0–2, life expectancy ≥ 3 months and adequate bone marrow, hepatic and renal function. Pts were excluded for having evidence of CNS metastases, hemoptysis (≥ 2.5 mL red blood), uncontrolled hypertension or active cardiovascular disease. Eligible pts received Bv (7.5 or 15 mg/kg) plus chemotherapy for up to 6 cycles, followed by Bv monotherapy until progression or unacceptable toxicity. Primary endpoint was safety; secondary endpoints included time to disease progression (TTP) and overall survival (OS). Results: The Asian population consisted of 314 pts (%): male (56); mean age 56 years; stage IV (71). Median follow-up was 16.4 months and median number of Bv cycles was 9. The incidence of clinically significant (grade [G] ≥ 3) adverse events (AEs) was low. The most common AEs of special interest were G1–2 proteinuria (35.7%) and epistaxis (36.6%). 15.6% of pts had any G ≥ 3 AE of special interest; proteinuria (7.6%), hypertension (4.8%), epistaxis (1.0%), hemoptysis (0.6%) and thromboembolism (2.2%). No G ≥ 3 CNS bleeding, wound-healing complications or congestive heart failure events were reported. 5.2% of AEs led to interruption or discontinuation of Bv. Only five G 5 events were reported: hemoptysis, pulmonary embolism, cerebral infarction, lacunar infarction and acute hepatitis. Efficacy outcomes were notable: overall response rate 57.7%; disease control rate 94.1%; median TTP 8.3 months; median OS 18.9 months. Conclusions: These results of first-line Bv in combination with chemotherapy in Asian pts in SAiL supports the overall benefit and safety profile of Bv-based therapy as already demonstrated in E4599 and AVAiL. No unexpected toxicity or new safety signals were identified. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Boehringer Ingelheim, Pfizer AstraZeneca, Lilly, Pfizer, Roche, sanofi-aventis
Health department beefed up Keogh strike letter, says<i>Independent</i>
Authors: Abi Rimmer
Journal: BMJ (2016)

The Department of Health for England strengthened a letter sent by the medical director of NHS England to the BMA that questioned whether striking doctors would respond in the event of a terrorist attack, the Independent newspaper has claimed.

The newspaper said that it had seen leaked emails showing that a letter sent by Bruce Keogh went through various revisions “to ensure concerns about the possible impact of a major incident during the strike were made as ‘hard-edged’ as possible.”1 It also claimed that the letter’s specific reference to terrorist attacks in Paris “may have been added …
Prognostic impact of the time interval between primary surgery and start of first-line chemotherapy in patients with advanced ovarian cancer: Analysis of prospective randomized phase III trials
Authors: S. Mahner, A. Staehle, C. zu Eulenburg, K. Wegscheider, A. Reuss, E. Pujade-Lauraine, P. Harter, I. Ray-Coquard, J. Pfisterer, A. du Bois
Journal: Journal of Clinical Oncology (2009)

5514 Background: Primary surgery followed by platinum-taxane chemotherapy is the standard therapy of advanced ovarian cancer. It is not clear, whether the time interval between surgery and start of first line chemotherapy (time to chemo - TTC) has an impact on the clinical outcome. Methods: Individual patient data meta-analysis of three prospective randomized AGO-OVAR/GINECO trials (AGO OVAR 3, 5, and 7) conducted between 1995 and 2002 to investigate platinum-taxane based chemotherapy regimens in advanced ovarian cancer. Cox proportional hazard models were applied to evaluate the prognostic impact of different variables on survival; TTC was introduced as a continuous variable. Results: A total of 3,326 patients were analyzed. Chemotherapy was started within 8 weeks after surgery. Median progression-free survival (PFS) was 17.91 months (95% CI: 17.15–18.73 months) and median overall survival (OS) 37.83 months (95% CI: 36.57–38.90 months). The median TTC was 19 days (95% CI: 18–19 days, range 1–56 days). By multivariate analysis of the total cohort, there was no significant association between TTC and PFS (p = 0.131) or OS (p = 0.372). In the subgroup of patients with no residual tumor after debulking surgery (n = 1.101), a significant and independent correlation between early start of chemotherapy and improved overall survival was observed (p = 0.022). Conclusions: Our analysis represents the largest study investigating treatment delivery and outcome in ovarian cancer. The time interval between primary surgery and start of first line chemotherapy seems to have no general impact in all patients. However, it could be demonstrated for the first time that a delayed start of chemotherapy was independently associated with decreased overall survival in patients with complete surgical debulking. As previously shown for other biological factors in ovarian cancer, the presence of residual tumor after surgery seems to prevail over the prognostic impact of therapy initiation. No significant financial relationships to disclose.
Correlation between BRAF mutational status and clinical response to pembrolizumab in advanced melanoma patients
Authors: Ester Simeone, Antonio Grimaldi, Lucia Festino, Diana Giannarelli, Marco Palla, Corrado Caracò, Marcello Curvietto, Assunta Esposito, Miriam Paone, Giovanni Rinaldi, Maria Grimaldi, Nicola Mozzillo, Paolo A Ascierto
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts About 50% of melanoma (MM) have BRAF V600 mutation and BRAF inhibitors, such as vemurafenib and dabrafenib, have shown an high response rate (RR) and overall survival (OS) improvement in BRAF-mutated MM patients (pts). Pembrolizumab, a monoclonal antibody anti-PD-1, has shown a