Mutations affecting the KRAS gene are established predictive markers of outcome with anti-epithelial growth factor receptor (EGFR) antibodies in advanced colorectal cancer (CRC). The relevance of ...these markers for anti-vascular endothelial growth factor (VEGF) therapy is controversial. This analysis was performed to assess the predictive and prognostic impact of KRAS and BRAF gene mutation status in patients receiving capecitabine with bevacizumab (CG) or capecitabine without bevacizumab in the phase III AGITG MAX (Australasian Gastrointestinal Trials Group MAX) study.
Mutation status was determined for 315 (66.9%) of the original 471 patients. Mutation status was correlated with efficacy outcomes (response rate, progression-free survival PFS, and overall survival OS), and a predictive analyses was undertaken.
Mutations in KRAS and BRAF genes were observed in 28.8% and 10.6% of patients, respectively. KRAS gene mutation status (wild type WT v mutated MT) had no prognostic impact for PFS (hazard ratio HR, 0.89; CI, 0.69 to 1.14) or OS (HR, 0.97; CI, 0.73 to 1.28). BRAF mutation status (WT v MT) was not prognostic for PFS (HR, 0.80; CI, 0.54 to 1.18) but was prognostic for OS (HR, 0.49; CI, 0.33 to 0.73; P = .001). By using the comparison of capecitabine versus capecitabine and bevacizumab (CB) and CB plus mitomycin (CBM), KRAS gene mutation status was not predictive of the effectiveness of bevacizumab for PFS or OS (test for interaction P = .95 and 0.43, respectively). Similarly, BRAF gene mutation status was not predictive of the effectiveness of bevacizumab for PFS or OS (test for interaction P = .46 and 0.32, respectively).
KRAS gene mutation status was neither prognostic for OS nor predictive of bevacizumab outcome in patients with advanced CRC. BRAF gene mutation status was prognostic for OS but was not predictive of outcome with bevacizumab.
•Ascites has more abundant and tumour enriched cfDNA than plasma.•Tumour-derived cfDNA proportion in plasma was positively correlated with CA125 level.•Tumour-derived cfDNA proportion over 75 % in ...ascites was associated with shorter time to paracentesis (or death).•Tumour-derived cfDNA detection in plasma was associated with shorter survival.•Plasma and ascites provide an ideal template to monitor biomarkers in clinical trials with the study of cell-free DNA.
To investigate cell-free DNA (cfDNA) in plasma and ascites and its association with clinical outcomes (paracentesis-free interval, overall survival) and CA125 level in participants with advanced ovarian cancer, treated with palliative intraperitoneal bevacizumab to delay re-accumulation of ascites.
cfDNA was extracted from 0.3 to 1 mL samples from 20/24 participants of the REZOLVE trial. Standard and methylation-specific PCRs were performed to measure 3 biomarkers: total cfDNA (Alu), tumour-derived cfDNA (ctDNA, methylated IFFO1 promoter) and endothelium-derived cfDNA (ec-cfDNA, unmethylated CDH5 promoter). Values were correlated to clinical outcomes.
cfDNA was detected in all samples, with higher yield in ascites (mean 669 ng/mL) than plasma (mean 75 ng/mL, p < 0.0001). Ascites had a higher ctDNA proportion than plasma (74 % vs. 20 %, p < 0.0001) and plasma had a higher ec-cfDNA proportion than ascites (24 % vs. 16 %, p < 0.002). High ctDNA proportion (>75 %) in ascites was associated with a significantly shorter paracentesis-free interval (median interval 47.5 versus 84 days, hazard ratio (HR) 2.21, 95 % confidence interval (CI) 0.85 to 5.73, p = 0.039) and ctDNA presence in plasma was unfavourable for survival (median survival 56 versus 242 days, HR 3.21, 95 % CI 1.15 to 9.00, p = 0.008). A significant positive correlation was observed between ctDNA proportion in plasma and CA125 level (p = 0.012). No significant difference in total cfDNA, ctDNA nor ec-cfDNA was observed between participants who were responders versus non-responders.
Sufficient cfDNA was detected in both plasma and ascites to study three biomarkers. These samples can provide useful information and should be considered in the design of future ovarian cancer trials.
IntroductionThere is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials ...DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505) combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial.Methods and analysisThis multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m2) 4–6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4–6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18–70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma.Ethics and disseminationThe protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.Drug SupplyAstraZeneca.Protocol versionCTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021.Trial registration numberClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.
To determine whether adding bevacizumab, with or without mitomycin, to capecitabine monotherapy improves progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) in an ...open-label, three-arm randomized trial.
Overall, 471 patients in Australia, New Zealand, and the United Kingdom with previously untreated, unresectable mCRC were randomly assigned to the following: capecitabine; capecitabine plus bevacizumab (CB); or capecitabine, bevacizumab, and mitomycin (CBM). We compared CB with capecitabine and CBM with capecitabine for progression-free survival (PFS). Secondary end points included overall survival (OS), toxicity, response rate (RR), and quality of life (QOL).
Median PFS was 5.7 months for capecitabine, 8.5 months for CB, and 8.4 months for CBM (capecitabine v CB: hazard ratio HR, 0.63; 95% CI, 0.50 to 0.79; P < .001; C v CBM: HR, 0.59; 95% CI, 0.47 to 0.75; P < .001). After a median follow-up of 31 months, median OS was 18.9 months for capecitabine and was 16.4 months for CBM; these data were not significantly different. Toxicity rates were acceptable, and all treatment regimens well tolerated. Bevacizumab toxicities were similar to those in previous studies. Measures of overall QOL were similar in all groups.
Adding bevacizumab to capecitabine, with or without mitomycin, significantly improves PFS without major additional toxicity or impairment of QOL.
Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed ...to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.
Despite the nation's rising epidemic of childhood obesity and diabetes, schools struggle to promote physical activities that help reduce risks for cardiovascular disease. Emerging data suggest that ...adopting novel activities into physical education (PE) curriculum may serve as an effective strategy for increasing physical activity in children. The purpose of this investigation was to characterize activity in the water and heart rates (HRs) of high school students participating in surf PE courses. Twenty-four male (n = 20) and female (n = 4) high school students (mean age = 16.7 ± 1.0 years) who were enrolled in surf PE courses at 2 high schools participated in this investigation. Daily measurements of surfing durations, average HR, and maximum HR were made on the students with HR monitors (PolarFT1) over an 8-week period. In addition, HR and activity in the water was evaluated during a single session in a subset of students (n = 11) using a HR monitor (PolarRCX5) and a video camera (Canon HD). Activity and HR were synchronized and evaluated in 5-second intervals during data analyses. The average duration that PE students participated in surfing during class was 61.7 ± 1.0 minutes. Stationary, paddling, wave riding, and miscellaneous activities comprised 42.7 ± 9.5, 36.7 ± 7.9, 2.9 ± 1.4, and 17.8 ± 11.4 percent of the surf session, respectively. The average and maximum HRs during these activities were 131.1 ± 0.9 and 177.2 ± 1.0 b·min, respectively. These data suggest that high school students participating in surf PE attained HRs and durations that are consistent with recommendations with cardiovascular fitness and health. In the future, PE programs should consider incorporating other action sports into their curriculum to enhance cardiovascular health.
ASPiRATION is a national prospective observational cohort study assessing the feasibility, clinical and economic value of up-front tissue-based comprehensive genomic profiling (CGP) to identify ...actionable genomic alterations in participants with newly diagnosed metastatic non-squamous non-small-cell lung cancer in Australia. This study will enrol 1000 participants with tumor available for CGP and standard of care molecular testing (
/
). Participants with actionable variants may receive novel targeted treatments through ASPiRATION-specific substudies, other trials/programs. Clinical outcome data will be collected for a minimum of 2 years. Study outcomes are descriptive, including the ability of CGP to identify additional actionable variants, leading to personalized treatment recommendations, and will describe the feasibility, efficiency, cost and utility of implementation of CGP nationally.
Abstract We have previously reported that P2Y2 purinoceptors and muscarinic M3 receptors trigger Ca2+ responses in HT-29 cells that differ in their timecourse, the Ca2+ response to P2Y2 receptor ...activation being marked by a more rapid decline of intracellular Ca2+ concentration (Ca2+ i ) after the peak response and that this rapid decline of Ca2+ i was slowed in cells expressing heterologous β-adrenergic receptor kinase (βARK). In the present study, we demonstrate that, during P2Y2 receptor activation, βARK expression increases the rate of Gd3+ -sensitive Mn2+ influx, a measure of the rate of store-operated Ca2+ entry from the extracellular space, during P2Y2 activation and that this effect of βARK is mimicked by exogenous α-subunits of Gq , G11 and Gi2 . The effect of βARK on the rate of Mn2+ influx is thus attributable to its ability to scavenge G protein βγ-subunits released during activation of P2Y2 receptor. We further find that the effect of βARK on the rate of Mn2+ influx during P2Y2 receptor activation can be overcome by arachidonic acid. In addition, the UTP-induced Mn2+ influx rate was significantly increased by inhibitors of phospholipase A2 (PLA2 ) and an siRNA directed against PLA2 β, but not by an siRNA directed against PLA2 α or by inhibitors of arachidonic acid metabolism. These findings provide evidence for the existence of a P2Y2 receptor-activated signalling system that acts in parallel with depletion of intracellular Ca2+ stores to inhibit Ca2+ influx across the cell membrane. This signalling process is mediated via Gβγ and involves PLA2 β and arachidonic acid.
Spontaneous neoplasia in the baboon (Papio spp.) Cianciolo, Rachel E; Butler, Stephanie D; Eggers, Jeffery S ...
Journal of medical primatology,
April 2007, Volume:
36, Issue:
2
Journal Article
Peer reviewed
There are several comprehensive reviews of spontaneous neoplasia in non-human primates that compile individual cases or small numbers of cases, but do not provide statistical analysis of tumor ...incidence, demographics, or epidemiology. This paper reports all spontaneous neoplasms (n = 363) diagnosed over a 15-year period in a baboon colony with an average annual colony population of 4000. A total of 363 spontaneous neoplasms were diagnosed in 313 baboons: 77 cases were males (25%) and 236 were females (75%); ages ranged from 1 month to 33 years (mean 16.5, median 17). The organ systems affected in descending order of number of neoplasms were hematopoietic organs (n = 101, 28%), urogenital tract (n = 78, 21%), integument (n = 43, 12%), alimentary tract (n = 43, 12%), endocrine organs (n = 40, 11%), nervous system (n = 33, 9%), musculoskeletal system (n = 5, 1%), and respiratory system (n = 4, 1%). Malignant cases numbered 171 (47%); 192 (53%) cases were benign.
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