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PURPOSE Despite extensive randomized evidence supporting the use of treatment breaks in metastatic colorectal cancer (mCRC), they are not universally offered to patients despite improvements in quality of life without detriment to overall survival (OS). FOCUS4-N was set up to explore the impact of oral maintenance therapy in patients who are responding to first-line therapy. METHODS FOCUS4 was a molecularly stratified trial program that registered patients with newly diagnosed mCRC. The FOCUS4-N trial was offered to patients in whom a targeted subtrial was unavailable or biomarker tests failed. Patients were randomly assigned using a 1:1 ratio between maintenance capecitabine and active monitoring (AM). The primary outcome was progression-free survival (PFS) with secondary outcomes including OS toxicity and tolerability. RESULTS Between March 2014 and March 2020, 254 patients were randomly assigned (127 to capecitabine and 127 to AM) across 88 UK sites. Baseline characteristics were balanced. There was strong evidence of efficacy for PFS (hazard ratio = 0.40; 95% CI, 0.21 to 0.75; P < .0001), but no significant improvement in OS (hazard ratio, 0.93; 95% CI, 0.69 to 1.27; P = .66) was observed. Compliance with treatment was good, and toxicity from capecitabine versus AM was as expected with grade ≥ 2 fatigue (25% v 12%), diarrhea (23% v 13%), and hand-foot syndrome (26% v 3%). Quality of life showed little difference between the groups. CONCLUSION Despite strong evidence of disease control with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as safe management alternatives for patients who are stable or responding to first-line treatment for mCRC. Capecitabine without bevacizumab may be used to extend PFS in the interval after 16 weeks of first-line therapy.

Clinical trials for MET inhibitors have demonstrated limited success for their use in colon cancer (CC). However, clinical efficacy may be obscured by a lack of standardisation in MET assessment for patient stratification. In this study, we aimed to determine the molecular context in which MET is deregulated in CC using a series of genomic and proteomic tests to define MET expression and identify patient subgroups that should be considered in future studies with MET‐targeted agents. To this aim, orthogonal expression analysis of MET was conducted in a population‐representative cohort of stage II/III CC patients (n = 240) diagnosed in Northern Ireland from 2004 to 2008. Targeted sequencing was used to determine the relative incidence of MET R970C and MET T992I mutations within the cohort. MET amplification was assessed using dual‐colour dual‐hapten brightfield in situ hybridisation (DDISH). Expression of transcribed MET and c‐MET protein within the cohort was assessed using digital image analysis on MET RNA in situ hybridisation (ISH) and c‐MET immunohistochemistry (IHC) stained slides. We found that less than 2% of the stage II/III CC patient population assessed demonstrated a genetic MET aberration. Determination of a high MET RNA‐ISH/low c‐MET IHC protein subgroup was found to be associated with poor 5‐year cancer‐specific outcomes compared to patients with concordant MET RNA‐ISH and c‐MET IHC protein expression (HR 2.12 [95%CI: 1.27–3.68]). The MET RNA‐ISH/c‐MET IHC protein biomarker paradigm identified in this study demonstrates that subtyping of MET expression may be required to identify MET‐addicted malignancies in CC patients who will truly benefit from MET inhibition., A population representative study looking at the molecular context in which MET is deregulated in colon cancer using a series of genomic and proteomic tests. This study demonstrates the limited number of genetic MET aberrations present in a Northern Irish colon cancer cohort and identifies a cancer‐specific poor prognosis MET RNA/c‐MET protein subgroup that may be amenable to targeted therapy.

The Auditec of St. Louis and the Department of Veterans Affairs (VA) recorded versions of the Northwestern University Auditory Test No. 6 (NU-6) are in common usage. Data on young adults with normal hearing for pure tones (YNH) demonstrate equal recognition performances on the two versions when the VA version is presented 5 dB higher but similar data on older listeners with sensorineural hearing loss (OHL) are lacking.To compare word-recognition performances on the Auditec and VA versions of NU-6 presented at six presentation levels with YNH and OHL listeners.A quasi-experimental, repeated-measures design was used.Twelve YNH (M = 24.0 years; PTA = 9.9-dB HL) and 36 OHL listeners (M = 71.6 years; PTA = 26.7-dB HL) participated in three, one-hour sessions.Each listener received 100 stimulus words that were randomized by 6 presentation levels for each of two speakers (YNH, −2 to 28-dB SL; OHL, −2 to 38-dB SL). The sessions were limited to 25 practice and 400 experimental words. Digital versions of the 16, 25-word tracks for each session were alternated between speakers.Each of the 48 listeners had higher recognition performances on the Auditec version of NU-6 than on the VA version. The respective overall recognition performances on the Auditec and VA versions were 71.4% and 64.1% (YNH) and 68.7% and 58.2% (OHL). At the highest presentation levels, recognition performances on the two versions differed by only 0.5% (YNH) and 3.3% (OHL). At the 50% correct point, performances on the Auditec version were 3.2 dB (YNH) and 6.1 dB (OHL) better than those on the VA version. The slopes at the 50% points on the mean functions for both speakers were about 4.9%/dB (YNH) and 3.0%/dB (OHL); however, the slopes evaluated from the individual listener data were steeper, 5.2 to 5.3%/dB (YNH) and 3.3 to 3.5%/dB (OHL). When the individual data were transformed from dB SL to dB HL, the differences between the two listener groups were emphasized. The four functions (2 speakers by 2 listener groups) were plotted for each of the 48 participants and each of the 200 words, which revealed the gamut of relations among the datasets. Examination of the data for each speaker across test sessions, in the traditional 50-word lists, and in the typically used 25-word lists of Randomization A revealed no differences of clinical concern. Finally, introspective reports from the listeners revealed that 91.7% and 83.3% of the YNH and OHL listeners, respectively, thought the Auditec speaker was easier to understand than the VA speaker. Recognition performances on each participant and on each word are presented.

Purpose: Small-bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic disease beyond first-line FOLFOX/CAPOX. SBA has higher rates of microsatellite instability (MSI-H) and T-lymphocyte infiltration than other gastrointestinal cancers. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. Patients and Methods: Patients with previously treated advanced SBA received pembrolizumab 200 mg i.v. every 3 weeks until disease progression (PD), toxicity, or 35 doses maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary progression-free survival (PFS), overall survival (OS), and toxicity assessment endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. Results: Forty patients were treated for a median duration of four cycles (range, 1–35). All patients are off study treatment due to PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AEs, 5%). Three confirmed partial responses [PRs; 8%; 95% confidence interval (CI), 2–20] did not meet predefined success criteria of ORR 30%. Median OS (7.1 months; 95% CI, 5.1–17.1) and median PFS (2.8 months; 95% CI, 2.7–4.2) were similar across primary tumor sites. One confirmed PR (3%) was seen in patients with low MSS/MSI tumors and correlated with high tumor mutation burden (TMB). Fifty percent of patients with MSI-H tumors achieved PR and remain alive without progression. Twenty-five patients (63%) had grade ≥3 AEs and 11 patients (28%) had grade 4/5 AEs. Conclusions: In the largest study of SBA to date, pembrolizumab did not induce the hypothesized response rate; however, we did identify responses in key biomarker-selected cohorts.

Background Neutropenic sepsis remains a common treatment complication for patients receiving systemic anti-cancer treatment. The UK National Institute for Health and Care Excellence have not recommended switching from empirical intravenous antibiotics to oral antibiotics within 48 h for patients assessed as low risk for septic complications because of uncertainty about whether this would achieve comparable outcomes to using intravenous antibiotics for longer. The UK National Institute for Health Research funded the EASI-SWITCH trial to tackle this uncertainty. Methods The trial is a pragmatic, randomised, non-inferiority trial that aims to establish the clinical and cost-effectiveness of early switching from intravenous to oral antibiotics in cancer patients with low-risk neutropenic sepsis. Patients ≥ 16 years, receiving systemic anti-cancer treatment (acute leukaemics/stem cell transplants excluded), with a temperature of > 38 °C, neutrophil count ≤ 1.0 × 109/L, MASCC (Multinational Association of Supportive Care in Cancer) score ≥ 21 and receiving IV piperacillin/tazobactam or meropenem for less than 24 h are eligible to participate. Patients are randomised 1:1 either (i) to switch to oral ciprofloxacin and co-amoxiclav within 12–24 h of commencing intravenous antibiotics, completing at least 5 days total antibiotics (intervention), or (ii) to continue intravenous antibiotics for at least 48 h, with ongoing antibiotics being continued at the physician’s discretion (control). Patients are discharged home when their physician deems it appropriate. The primary outcome measure is a composite of treatment failures as assessed at day 14. The criteria for treatment failure include fever persistence or recurrence 72 h after starting intravenous antibiotics, escalation from protocolised antibiotics, hospital readmission related to infection/antibiotics, critical care support or death. Based on a 15% treatment failure rate in the control group and a 15% non-inferiority margin, the recruitment target is 230 patients. Discussion If the trial demonstrates non-inferiority of early switching to oral antibiotics, with potential benefits for patient quality of life and resource savings, this finding will have significant implications for the routine clinical management of those with low-risk neutropenic sepsis. Trial registration ISRCTN: 84288963. Registered on the 1 July 2015. 10.1186/ISRCTN84288963. EudraCT: 2015-002830-35.

Background: Small bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic SBA beyond first-line FOLFOX/CAPOX. Later-line therapy has been extrapolated from colorectal cancer (CRC) studies, though SBA is biologically distinct with higher rates microsatellite instability (MSI-H) and intratumoral T-lymphocyte infiltration. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. Methods: Previously treated advanced SBA patients received pembrolizumab 200 mg IV q3 weeks until disease progression (PD), toxicity, or to 35 dose maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary survival and safety endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. Findings: 40 patients were treated for median duration of 4 cycles (range 1-35). MSI status was available for 36 patients (90%). All 40 patients are off study treatment due to: PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AE, 5%). Three confirmed partial responses (PR) (8%; 95% CI: 2-20) did not meet pre-defined success criteria. Median overall survival (OS) 7 . 1 mo (95% CI: 5 . 1-17 . 1) and median progression free survival (PFS) 2 . 8 mo (95% CI: 2 . 7-4 . 2) were similar across primary tumor sites. One confirmed PR was seen in 32 MSS/MSI-low patients (3%). MSS response correlated with high tumor mutation burden (TMB). Two of four MSI-H patients had a confirmed PR (50%) and remain alive without progression. 25 patients (63%) had grade ≥ 3 AEs, 11 pts (28%) had grade 4/5 AEs. Interpretation: In the largest study of SBA to date, and the first using immunotherapy, pembrolizumab did not achieve the hypothesized response rate; however, we did identify responses in certain biomarker-selected cohorts. Trial Registration: RU021502I (ACCRU), MISP #52192 (Merck), NCT02949219 (clinicaltrials.gov). Funding Statement: Primary study funding and investigational product was provided by the Merck Investigator Studies Program (MISP), and additional site-specific funding provided by the Kavanagh Family Foundation (MDACC) and Kevin T. Doner Memorial Fund (MDACC). Declaration of Interests: None to declare Ethics Approval Statement: Ethics board review and human research protections monitoring were performed at each institution. The trial was conducted according to ICH GCP.

3504 Background: There is extensive randomised evidence supporting the use of treatment breaks in mCRC, but breaks from treatment are not universally offered to patients despite reductions in toxicity, without detriment to OS. Prior trials have shown that the combination of Cp and bevacizumab extend PFS but not OS. FOCUS4-N explores oral maintenance Cp monotherapy in patients with disease control on first line therapy. Methods: FOCUS4 was a molecularly stratified trial programme registering patients with newly diagnosed mCRC from 88 hospitals in the UK. Whilst undergoing 16 wks of first line treatment, a sample of tumour was sent for laboratory testing to stratify their disease into molecular subtypes: MSI, BRAF, PIK3CA, TP53 and RAS mutations. For some molecular groups, a targeted therapy subtrial was available but entry into the FOCUS4-N trial was offered to those in whom a targeted subtrial was unavailable. Patients were randomised 1:1 between maintenance Cp therapy or AM. The primary outcome was PFS assessed using 8-wkly RECIST reported CT scans with quality of life (using EQ5D 8 weekly) and OS as secondary outcomes. Toxicity and tolerability were assessed 4-wkly. On progression, from the nadir, patients recommenced first line treatment. Cox regression was used to assess efficacy by intention-to-treat (ITT) with adjustment for tumour location, WHO status, metastatic burden, first line treatment and biomarker subtype. Results: Between March 2014 and March 2020, 254 patients were randomised (127 to Cp and 127 to AM). Baseline characteristics were balanced between groups but event rates were higher than anticipated in the AM group and the final analysis was triggered early as a result of the COVID-19 pandemic halting recruitment. The table presents results for PFS and OS. Compliance with treatment was good with per-protocol analysis results very similar to ITT (PFS HR=0.38 (95% CI 0.28-0.51)). Toxicity from Cp v AM was as expected with G≥2 fatigue (25% v 12%), diarrhoea (23% v 13%) and hand-foot syndrome (26% v 3%). Quality of life showed no statistically significant differences between the two arms. Conclusions: Despite strong evidence of prolongation of PFS with maintenance therapy, OS remains unaffected and FOCUS4-N provides additional evidence to support the use of treatment breaks as a safe management alternative for patients who are stable or responding well to first line treatment for mCRC. Cp without bevacizumab may be used to extend PFS, in the interval after 16 weeks of combination therapy. Clinical trial information: ISRCTN#90061546. [Table: see text]

The aim of this study was to document cancer trial participation since establishment of the Northern Ireland Cancer Trials Network and investigate population and disease factors associated with trial participation. An independent cohort of over 51 000 cancer patients from the Northern Ireland Cancer Registry covering the same population (2007-2012) was linked to a database of 1316 interventional cancer trial participants in a UK region. The primary outcome measure was participation in an intervention clinical trial. Patients were followed up until 31 March 2013. Kaplan-Meier tests and Cox proportional hazard models using person days at risk to allow for death were used to investigate factors associated with trial participation. Multivariate analysis assessed the impact of age, cancer type and stage, distance from the cancer centre (radiotherapy), marital status, deprivation quintile and rurality. Participation was analysed separately for children (

BACKGROUNDSignet ring cell colorectal cancer (SRCCa) has a bleak prognosis. Employing molecular pathology techniques we investigated the potential of precision medicine in this disease.METHODSUsing test (n=26) and validation (n=18) cohorts, analysis of mutations, DNA methylation and transcriptome was carried out. Microsatellite instability (MSI) status was established and immunohistochemistry (IHC) was used to test for adaptive immunity (CD3) and the immune checkpoint PDL1.RESULTS DNA methylation data split the cohorts into hypermethylated (n=18, 41%) and hypomethylated groups (n=26, 59%). The hypermethylated group predominant in the proximal colon was enriched for CpG island methylator phenotype (CIMP), BRAF V600E mutation and MSI (PC) across both groups. No statistically significant difference in outcome was observed between the two groups.CONCLUSIONS Our data show that SRCCa phenotype comprises two distinct genotypes. The MSI(+)/CIMP(+)/BRAF V600E(+)/CD3(+)/PDL1(+) hypermethylated genotype is an ideal candidate for immune checkpoint inhibitor therapy. In addition, one fourth of SRCCa cases can potentially be targeted by KIT inhibitors.

Purpose: Apoptosis is essential for chemotherapy responses. In this discovery and validation study, we evaluated the suitability of a mathematical model of apoptosis execution (APOPTO-CELL) as a stand-alone signature and as a constituent of further refined prognostic stratification tools. Experimental Design: Apoptosis competency of primary tumor samples from patients with stage III colorectal cancer (n = 120) was calculated by APOPTO-CELL from measured protein concentrations of Procaspase-3, Procaspase-9, SMAC, and XIAP. An enriched APOPTO-CELL signature (APOPTO-CELL-PC3) was synthesized to capture apoptosome-independent effects of Caspase-3. Furthermore, a machine learning Random Forest approach was applied to APOPTO-CELL-PC3 and available molecular and clinicopathologic data to identify a further enhanced signature. Association of the signature with prognosis was evaluated in an independent colon adenocarcinoma cohort (TCGA COAD, n = 136). Results: We identified 3 prognostic biomarkers (P = 0.04, P = 0.006, and P = 0.0004 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively) with increasing stratification accuracy for patients with stage III colorectal cancer. The APOPTO-CELL-PC3 signature ranked highest among all features. The prognostic value of the signatures was independently validated in stage III TCGA COAD patients (P = 0.01, P = 0.04, and P = 0.02 for APOPTO-CELL, APOPTO-CELL-PC3, and Random Forest signatures, respectively). The signatures provided further stratification for patients with CMS1-3 molecular subtype. Conclusions: The integration of a systems-biology–based biomarker for apoptosis competency with machine learning approaches is an appealing and innovative strategy toward refined patient stratification. The prognostic value of apoptosis competency is independent of other available clinicopathologic and molecular factors, with tangible potential of being introduced in the clinical management of patients with stage III colorectal cancer. Clin Cancer Res; 23(5); 1200–12. ©2016 AACR.

BACKGROUND: This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP-ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours.METHODS: Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1-14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles.RESULTS: Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1-7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade ⩾3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml(-1) min(-1). Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (≈17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers.CONCLUSIONS: Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190).British Journal of Cancer advance online publication 21 February 2017; doi:10.1038/bjc.2017.36 www.bjcancer.com.

Background:\ud Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity.\ud \ud Patients and Methods:\ud Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8.\ud \ud Results:\ud We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months.\ud \ud Conclusion:\ud Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases.\ud \ud EudraCT number:\ud 2009-017817-31.

Introduction: \ud Over half of the 1.5 million individuals globally who are diagnosed with colorectal cancer (CRC) present with stage II-III disease. Understanding clinician attitudes towards treatment for this group is paramount to contextualise real-world outcomes and plan future trials. The aim of this study was to assess clinician awareness of trials assessing the optimal duration of CRC adjuvant therapy, their attitudes towards shorter treatment and their self-reported practice.\ud \ud Methods: \ud A survey was developed using OnlineSurveys® and distributed to clinicians in April 2019, with a follow-up survey disseminated to a subset of respondents in August 2020. Microsoft Excel® and Stata® were used for analysis.\ud \ud Results: \ud 265 clinicians replied to the first survey, with the majority aware of findings from the International Duration Evaluation of Adjuvant Therapy collaboration and contributory trials. Practice change was greatest for patients under 70 with low-risk stage III CRC, with most uncertainty around using 3-months of doublet chemotherapy for high-risk stage II disease. In August 2020, clinicians (n = 106) were more likely to use 3-months of FOLFOX for low-risk stage III disease and 3-months of CAPOX for stage II disease compared to April 2019. There was no indication that the COVID-19 pandemic had enduring changes on treatment decisions beyond those made in response to trial evidence.\ud \ud Discussion: \ud Clinicians use a risk-stratified approach to treat CRC the adjuvant setting. Lower utilisation of doublet chemotherapy for older and stage II patients has affected the extent of trial implementation. Active dialogue regarding how trial results apply to these groups may improve consensus.

ObjectiveThe mitochondrial apoptosis pathway is controlled by an interaction of multiple BCL-2 family proteins, and plays a key role in tumour progression and therapy responses. We assessed the prognostic potential of an experimentally validated, mathematical model of BCL-2 protein interactions (DR_MOMP) in patients with stage III colorectal cancer (CRC).DesignAbsolute protein levels of BCL-2 family proteins were determined in primary CRC tumours collected from n=128 resected and chemotherapy-treated patients with stage III CRC. We applied DR_MOMP to categorise patients as high or low risk based on model outputs, and compared model outputs with known prognostic factors (T-stage, N-stage, lymphovascular invasion). DR_MOMP signatures were validated on protein of n=156 patients with CRC from the Cancer Genome Atlas (TCGA) project.ResultsHigh-risk stage III patients identified by DR_MOMP had an approximately fivefold increased risk of death compared with patients identified as low risk (HR 5.2, 95% CI 1.4 to 17.9, p=0.02). The DR_MOMP signature ranked highest among all molecular and pathological features analysed. The prognostic signature was validated in the TCGA colon adenocarcinoma (COAD) cohort (HR 4.2, 95% CI 1.1 to 15.6, p=0.04). DR_MOMP also further stratified patients identified by supervised gene expression risk scores into low-risk and high-risk categories. BCL-2-dependent signalling critically contributed to treatment responses in consensus molecular subtypes 1 and 3, linking for the first time specific molecular subtypes to apoptosis signalling.ConclusionsDR_MOMP delivers a system-based biomarker with significant potential as a prognostic tool for stage III CRC that significantly improves established histopathological risk factors.

Purpose: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear. Experimental Design: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models. Results: Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells. Conclusions: These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. Clin Cancer Res; 22(1); 230–42. ©2015 AACR.

Background: LY3143921 hydrate is an orally administered ATP-competitive inhibitor of CDC7, a serine/threonine kinase regulatory protein overexpressed in many cancer types. Following successful preclinical studies, a first-in-human phase I trial of LY3143921 hydrate was initiated in patients with advanced solid tumors. We report the pharmacokinetics of LY3143921 hydrate in this ongoing Cancer Research UK study. Methods: Eligible patients were those with histologically proven advanced/metastatic solid tumors for which no further standard therapy options were available. Patients were administered LY3143921 hydrate as a single oral dose on Day -7, followed by daily administration (dose levels 30-270mg) or twice daily administration (dose levels 150 and 180mg) on study days 1-21. Drug administration was carried out with patients in either a fasted or fed state as shown in Table 1. Samples for pharmacokinetic analysis were obtained following a single drug dose on Day -7 at 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48 and 72 hours. Additional samples were taken on Day 1 of treatment at doses of 150 and 180mg to investigate potential differences in pharmacokinetics in fed versus fasted states (Day -7 fed versus Day 1 fasted). Samples were analysed using a validated LC-MS/MS assay with a LLOQ of 0.1 ng/mL. Pharmacokinetic analysis was carried out using Certara WinNonlin software (version 6.3) to determine Cmax, Tmax, area under the curve (AUC), plasma half-life, apparent volume of distribution (Vz/F) and apparent clearance (CL/F) of LY3143921 hydrate. Assessment of dose proportionality was made by assessment of graphical plots of AUC versus dose level. Table 1:Summary of LY3143921 hydrate pharmacokinetic data on Day -7 (single dose data)Dose level (mg)Number of patientsFed / fastedCmax (ng/mL)AUC0-24h (ng/mL.h)Half-life (h)CL/F (L/h)Vz/F (L)301Fasted184.44253.3570.1339601Fasted175.05022.42119.44181201Fasted113031382.1738.212018010Fasted144 - 8142505 ± 9904.2 ± 4.079.5 ± 23.9475 ± 4732704Fasted474 - 15126374 ± 14753.4 ± 1.843.8 ± 8.9226 ± 1581503Fed334 - 6321997 ± 4964.4 ± 1.977.2 ± 16.4514 ± 2881803Fed492 - 16002994 ± 9793.2 ± 0.864.2 ± 19.4290 ± 112 Results: Table 1 provides a summary of the pharmacokinetic parameters obtained on Day -7 following a single dose of LY3143921 hydrate (data expressed as range or mean ± SD as appropriate). Overall dose-dependent increases in exposure (based on Cmax and AUC) were observed. There was a general trend towards higher Cmax and AUC values following administration in a fasted versus fed state following a dose of 180 mg, but this was inconsistent across the limited number of patients for who these data were available on both Day -7 (fed) and Day 1 (fasted). Conclusion: The pharmacokinetic data generated to date are consistent with dose dependent increases in drug exposure observed with a flat dosing regimen for LY3143921 hydrate. Citation Format: Shelby Barnett, Melanie Griffin, Richard H. Wilson, Elizabeth R. Plummer, Jeffry T. Evans, Victoria Coyle, Sally Clive, Lisa Godfrey, Nicola Dobbs, Lesley McGuigan, Sue Brook, Gavin Halbert, Gareth J. Veal. Pharmacokinetics of the CDC7 inhibitor LY3143921 hydrate, a CRUK first-in-human phase I trial in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3014.

93 Background: The fluoropyrimidines (FP), 5-Fluorouracil (5-FU) and capecitabine are a mainstay of colorectal cancer (CRC) treatment. Dihydropyrimidine dehydrogenase (DPYD), an enzyme encoded by the DPYD gene, is the initial and rate-limiting step in pyrimidine catabolism, deactivating over 80% of 5-FU. Approximately 5% of the population are deficient in DPYD and can develop severe or fatal FP toxicities. Currently, few national guidelines recommend routine prospective DPYD testing. In July 2019, we commenced a 6 month prospective pilot, testing DPYD status of all CRC patients undergoing first FP treatment in a large regional cancer centre. Methods: All CRC patients eligible for first exposure to FP are tested using a rapid molecular assay screening for five SNPs (detects 70% of DPYD mutations) and we will present data on prevalence of each. We will use electronic chemotherapy prescribing records (July 19-Jan 20) to collect information on dose modifications and toxicities. Once the pilot is completed we will perform a cost-effectiveness analysis. Results: Data from the first 3 months of this pilot have been reviewed and 201 patients have been tested with 15 heterozygotes identified, of which 2 had more than one mutation. No homozygotes were found. All heterozygote patients are started with a dose reduction (or have alternative therapy). One patient treated at 50% dose was hospitalised with several grade 3 toxicities despite dose reduction. Two patients have had subsequent dose escalation (by 25%). Nine patients have received one dose reduced cycle without complication. Three patients are due to start dose-reduced treatment. Conclusions: Routine prospective testing of DPYD status in a large regional cancer centre is feasible and with a sufficiently swift result turnaround to permit up-front dose modification. Detailed toxicity analysis and cost-effectiveness data will be presented.

Background: \ud We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients.\ud \ud Patients and methods: \ud In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively.\ud \ud Results: \ud The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28–18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76–21.25).\ud \ud Discussion: \ud In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC.\ud \ud Clinical trial registration: \ud ClinicialTrials.gov identifier: CNCT02193633.

Tumor-related symptoms can affect treatment choices in metastatic colorectal cancer (mCRC). In the current study, 659 patients with RAS wild-type mCRC were retrospectively analyzed to evaluate the relationship between tumor shrinkage and the time to onset of tumor-related symptoms. Symptom onset was delayed in patients with earlier and greater tumor shrinkage. Therefore, treatments that facilitate cytoreduction may delay symptom development. Background: There is no standardized assessment of symptomatic events in metastatic colorectal cancer (mCRC) despite disease symptoms that affect treatment decisions. Data from 3 first-line panitumumab in mCRC trials were retrospectively analyzed to assess whether early tumor shrinkage (ETS) and depth of response (DpR) were associated with time to occurrence of tumor-related symptoms. Patients and Methods: Patients with RAS wild-type mCRC from PRIME, PEAK, and Study 314 were included. ETS was defined as a reduction of >= 30% in the sum of the longest diameters of lesions at 8 weeks. DpR was calculated as maximum percentage change in tumor size from baseline to nadir. The proportion of patients who developed symptoms (including a composite symptomatic endpoint) during study treatment was calculated. This study was registered at ClinicalTrials.gov as PRIME (NCT00364013), PEAK (NCT00819780), and Study 314 (NCT00508404). Results: Overall, data of 659 patients were analyzed. Onset of symptoms was delayed in patients with ETS >= 30% versus ETS < 30% and in patients with greater DpR. In patients with symptoms at baseline who experienced ETS >= 30%, overall survival was similar to that seen for patients without symptoms at baseline. Conclusion: Both ETS and DpR were associated with delayed onset of symptoms in RAS wildtype mCRC patients. Treatments with high cytoreductive potential may delay symptom development. (C) 2019 The Authors. Published by Elsevier Inc.

Small bowel accounts for only 0.5% of cancer cases in the US but incidence rates have been rising at 2.4% per year over the past decade. One-third of these are adenocarcinomas but little is known about their molecular pathology and no molecular markers are available for clinical use. Using a retrospective 28 patient matched normal-tumor cohort, next-generation sequencing, gene expression arrays and CpG methylation arrays were used for molecular profiling. Next-generation sequencing identified novel mutations in IDH1, CDH1, KIT, FGFR2, FLT3, NPM1, PTEN, MET, AKT1, RET, NOTCH1 and ERBB4. Array data revealed 17% of CpGs and 5% of RNA transcripts assayed to be differentially methylated and expressed respectively (p < 0.01). Merging gene expression and DNA methylation data revealed CHN2 as consistently hypermethylated and downregulated in this disease (Spearman -0.71, p < 0.001). Mutations in TP53 which were found in more than half of the cohort (15/28) and Kazald1 hypomethylation were both were indicative of poor survival (p = 0.03, HR = 3.2 and p = 0.01, HR = 4.9 respectively). By integrating high-throughput mutational, gene expression and DNA methylation data, this study reveals for the first time the distinct molecular profile of small bowel adenocarcinoma and highlights potential clinically exploitable markers.

Importance Small-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. To date, comprehensive genomic analysis of SBA is lacking. Objective To perform in-depth genomic characterization of a large series of SBAs and other gastrointestinal tumors to draw comparisons and identify potentially clinically actionable alterations. Design, Setting, and Participants Prospective analysis was performed of clinical samples from patients with SBA (n = 317), colorectal cancer (n = 6353), and gastric carcinoma (n = 889) collected between August 24, 2012, and February 3, 2016, using hybrid-capture–based genomic profiling, at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. Results Of the 7559 patients included in analysis, 4138 (54.7%) were male; the median age was 56 (range, 12-101) years. The frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer ( APC : 26.8% [85 of 317] vs 75.9% [4823 of 6353], P CDKN2A : 14.5% [46 of 317] vs 2.6% [165 of 6353], P KRAS : 53.6% [170 of 317] vs 14.2% [126 of 889], P APC : 26.8% [85 of 317] vs 7.8% [69 of 889], P SMAD4 : 17.4% [55 of 317] vs 5.2% [46 of 889], P BRAF was mutated in 7.6% (484 of 6353) of colorectal cancer and 9.1% (29 of 317) of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% (3 of 29) of BRAF -mutated cases. The ERBB2/HER2 point mutations (8.2% [26 of 317]), microsatellite instability (7.6% [13 of 170]), and high tumor mutational burden (9.5% [30 of 317]) were all enriched in SBA. Significant differences were noted in the molecular profile of unspecified SBA compared with duodenal adenocarcinoma, as well as in inflammatory bowel disease–associated SBAs. Targetable alterations in several additional genes, including PIK3CA and MEK1 , and receptor tyrosine kinase fusions, were also identified in all 3 series. Conclusions and Relevance This study presents to our knowledge the first large-scale genomic comparison of SBA with colorectal cancer and gastric carcinoma. The distinct genomic differences establish SBA as a molecularly unique intestinal cancer. In addition, genomic profiling can identify potentially targetable genomic alterations in the majority of SBA cases (91%), and the higher incidence of microsatellite instability and tumor mutational burden in SBA suggests a potential role for immunotherapy.

Around 12–15% of patients with locally advanced rectal cancer undergo a pathologically complete response (tumor regression grade 4) to long-course preoperative chemoradiotherapy; the remainder exhibit a spectrum of tumor regression (tumor regression grade 1–3). Understanding therapy-related transcriptional alterations may enable better prediction of response as measured by progression-free and overall survival, in addition to aiding the development of improved strategies based on the underlying biology of the disease. To this end, we performed high-throughput gene expression profiling in 40 pairs of formalin-fixed paraffin-embedded rectal cancer biopsies and matched resections following long-course preoperative chemoradiotherapy (discovery cohort). Differential gene expression analysis was performed contrasting tumor regression grades in resections. Enumeration of the tumor microenvironment cell population was undertaken using in silico analysis of the transcriptional data, and real-time PCR validation of NCR1 undertaken. Immunohistochemistry and survival analysis was used to measure CD56+ cell populations in an independent cohort (n=150). Gene expression traits observed following long-course preoperative chemoradiotherapy in the discovery cohort suggested an increased abundance of natural killer cells in tumors that displayed a clinical response to CRT in a tumor regression grade-dependent manner. CD56+ natural killer-cell populations were measured by immunohistochemistry and found to be significantly higher in tumor regression grade 3 patients compared with tumor regression grade 1–2 in the validation cohort. Furthermore, it was observed that patients positive for CD56 cells after therapy had a better overall survival (HR=0.282, 95% CI=0.109–0.729, χ2=7.854, P=0.005). In conclusion, we have identified a novel post-therapeutic natural killer-like transcription signature in patients responding to long-course preoperative chemoradiotherapy. Furthermore, patients with a higher abundance of CD56-positive natural killer cells post long-course preoperative chemoradiotherapy had better overall survival. Therefore, harnessing a natural killer-like response after therapy may improve outcomes for locally advanced rectal cancer patients. Finally, we hypothesize that future assessment of this natural killer-like response in on-treatment biopsy material may inform clinical decision-making for treatment duration.

Two previous experiments from our laboratory with 70 interrupted monosyllabic words demonstrated that recognition performance was influenced by the temporal location of the interruption pattern. The interruption pattern (10 interruptions/sec, 50% duty cycle) was always the same and referenced word onset; the only difference between the patterns was the temporal location of the on- and off-segments of the interruption cycle. In the first study, both young and older listeners obtained better recognition performances when the initial on-segment coincided with word onset than when the initial on-segment was delayed by 50 msec. The second experiment with 24 young listeners detailed recognition performance as the interruption pattern was incremented in 10-msec steps through the 0- to 90-msec onset range. Across the onset conditions, 95% of the functions were either flat or U-shaped.To define the effects that interruption pattern locations had on word recognition by older listeners with sensorineural hearing loss as the interruption pattern incremented, re: word onset, from 0 to 90 msec in 10-msec steps.A repeated-measures design with ten interruption patterns (onset conditions) and one uninterruption condition.Twenty-four older males (mean = 69.6 yr) with sensorineural hearing loss participated in two 1-hour sessions. The three-frequency pure-tone average was 24.0 dB HL and word recognition was ≥80% correct.Seventy consonant-vowel nucleus-consonant words formed the corpus of materials with 25 additional words used for practice. For each participant, the 700 interrupted stimuli (70 words by 10 onset conditions), the 70 words uninterrupted, and two practice lists each were randomized and recorded on compact disc in 33 tracks of 25 words each.The data were analyzed at the participant and word levels and compared to the results obtained earlier on 24 young listeners with normal hearing. The mean recognition performance on the 70 words uninterrupted was 91.0% with an overall mean performance on the ten interruption conditions of 63.2% (range: 57.9–69.3%), compared to 80.4% (range: 73.0–87.7%) obtained earlier on the young adults. The best performances were at the extremes of the onset conditions. Standard deviations ranged from 22.1% to 28.1% (24 participants) and from 9.2% to 12.8% (70 words). An arithmetic algorithm categorized the shapes of the psychometric functions across the ten onset conditions. With the older participants in the current study, 40% of the functions were flat, 41.4% were U-shaped, and 18.6% were inverted U-shaped, which compared favorably to the function shapes by the young listeners in the earlier study of 50.0%, 41.4%, and 8.6%, respectively. There were two words on which the older listeners had 40% better performances.Collectively, the data are orderly, but at the individual word or participant level, the data are somewhat volatile, which may reflect auditory processing differences between the participant groups. The diversity of recognition performances by the older listeners on the ten interruption conditions with each of the 70 words supports the notion that the term hearing loss is inclusive of processes well beyond the filtering produced by end-organ sensitivity deficits.

Introduction: Because a dose–response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors. Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005–2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available. Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%–80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003). Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%–80% of MTD). Clin Cancer Res; 20(22); 5663–71. ©2014 AACR.

TPS3624 Background: There is now a body of evidence indicating a potential role for aspirin in colorectal cancer (CRC) prevention. In cardiovascular trials, effects on incidence of cancer metastases and short-term mortality suggest further possible roles in the treatment setting, supported by observational studies of aspirin use after cancer diagnosis. In the prevention setting, aspirin use has been limited by toxicity concerns, particularly of serious bleeding. In the adjuvant setting, benefits associated with reducing recurrence and subsequent treatment may outweigh these risks. The Add-Aspirin trial will investigate this, and will also consider possible mechanisms of action for aspirin effects, including the impact of PIK3CA mutations, where there are currently several theories and conflicting data. Methods: Add-Aspirin (ISRCTN74358648) is an international, phase III, double-blind, randomised, placebo-controlled trial recruiting patients who have undergone surgery and relevant adjuvant treatment for stage II or III CRC, as well as those with completely resected CRC liver metastases. Parallel randomised cohorts will address the question in breast, gastro-oesophageal and prostate cancer. Participants take aspirin 100mg daily for an 8-week run-in, to assess adherence and toxicity, and those suitable to proceed are randomised (1:1:1) to aspirin 100mg, aspirin 300mg or placebo daily for at least 5 years. A number of measures – including blood pressure control and PPI use where relevant - are in place to reduce bleeding risk. The primary outcome is disease-free survival (target hazard ratio = 0.8, n = 2600 in 5 years) with a long term analysis of survival planned across the tumour groups. Translational work includes a sub-study monitoring urinary thromboxane B2 as a marker of platelet activation in a subgroup (n = 500) to investigate mechanisms of action. Add-Aspirin opened in 2015 and recruited 1505 CRC patients during the first 3 years from 137 UK centres. 1282 (85%) proceeded to randomisation. A pre-planned feasibility analysis of run-in data (n = 2253 across all 4 tumour groups) provided reassuring data on safety, tolerability and adherence, and recruitment continues with centres in India and Republic of Ireland recently joining. Clinical trial information: 74358648.

PURPOSE: poly(ADP ribose) polymerase inhibition has been shown to potentiate the cytotoxicity of DNA damaging agents. A phase I study of rucaparib and temozolomide showed that full-dose temozolomide could be given during PARP inhibition. We report the results of a phase II study of intravenous rucaparib 12 mg/m(2) and oral temozolomide 200 mg/m(2) on days 1-5 every 28 days in patients with advanced metastatic melanoma. METHODS: Patients with chemotherapy naïve measurable metastatic melanoma, performance status ≤2 and good end-organ function were recruited. Treatment was given until progression. A two stage phase II design was used, with response rate the primary endpoint. Population pharmacokinetics and pharmacodynamics were also explored. RESULTS: Forty-six patients were recruited with 37 patients receiving at least 2 cycles and 17 patients at least 6 cycles. Myelosuppression occurred with 25 patients (54 %) requiring a 25 % dose reduction in temozolomide. The response rate was 17.4 %, median time to progression 3.5 months, median overall survival 9.9 months, and 36 % of patients were progression-free at 6 months. CONCLUSIONS: This study showed that temozolomide (150-200 mg/m(2)/day) can safely be given with a PARP inhibitory dose of rucaparib, increasing progression-free survival over historical controls in metastatic melanoma patients.

There is a pressing need for more-efficient trial designs for biomarker-stratified clinical trials. We suggest a new approach to trial design that links novel treatment evaluation with the concurrent evaluation of a biomarker within a confirmatory phase II/III trial setting. We describe a new protocol using this approach in advanced colorectal cancer called FOCUS4. The protocol will ultimately answer three research questions for a number of treatments and biomarkers: (1) After a period of first-line chemotherapy, do targeted novel therapies provide signals of activity in different biomarker-defined populations? (2) If so, do these definitively improve outcomes? (3) Is evidence of activity restricted to the biomarker-defined groups? The protocol randomizes novel agents against placebo concurrently across a number of different biomarker-defined population-enriched cohorts: BRAF mutation; activated AKT pathway: PI3K mutation/absolute PTEN loss tumors; KRAS and NRAS mutations; and wild type at all the mentioned genes. Within each biomarker-defined population, the trial uses a multistaged approach with flexibility to adapt in response to planned interim analyses for lack of activity. FOCUS4 is the first test of a protocol that assigns all patients with metastatic colorectal cancer to one of a number of parallel population-enriched, biomarker-stratified randomized trials. Using this approach allows questions regarding efficacy and safety of multiple novel therapies to be answered in a relatively quick and efficient manner, while also allowing for the assessment of biomarkers to help target treatment.

Development of colorectal cancer occurs via a number of key pathways, with the clinicopathological features of specific subgroups being driven by underlying molecular changes. Mutations in key genes within the network of signalling pathways have been identified; however, therapeutic strategies to target these aberrations remain limited. As understanding of the biology of colorectal cancer has improved, this has led to a move toward broader genomic testing, collaborative research and innovative, adaptive clinical trial design. Recent developments in therapy include the routine adoption of wider mutational spectrum testing prior to use of targeted therapies and the first promise of effective immunotherapy for colorectal cancer patients. This review details current biomarkers in colorectal cancer for molecular stratification and for treatment allocation purposes, including open and planned precision medicine trials. Advances in our understanding, therapeutic strategy and technology will also be outlined.

Objective: To determine in an interrupted word paradigm (Maryland CNCs; 10 ips, 50% duty cycle) if different locations of the interruption pattern produce different recognition performances. Design: Repeated measures using two interruption patterns that were complementary halves referenced to word onset; one started with word onset (0-ms), the other started 50 ms later. The hypothesis was that recognition performance would be better on the 0-ms condition than on the 50-ms condition, but there would be some words with the reverse relation. Study sample: Twenty-four young adults with normal hearing for pure tones and 32 older adults (mean = 67 years) with sensorineural hearing loss participated. Results: With the young listeners mean recognition performance on the 0-ms condition (63.1%) was significantly better than the mean performance on the 50-ms condition (47.8%). About twice as many words had better performance on the 0-ms condition. With the older listeners, who were given only stimuli on which performances were > 58% by the young normals, performances on the two conditions were the same. Conclusions: The hypothesis was supported with the young listeners. The equal performance by the older listeners on the two conditions was attributed to the manner in which the words were selected.

Background: The authors reviewed the evidence regarding the existence of age-related declines in central auditory processes and the consequences of any such declines for everyday communication. Purpose: This report summarizes the review process and presents its findings. Data Collection and Analysis: The authors reviewed 165 articles germane to central presbycusis. Of the 165 articles, 132 articles with a focus on human behavioral measures for either speech or nonspeech stimuli were selected for further analysis. Results: For 76 smaller-scale studies of speech understanding in older adults reviewed, the following findings emerged: (1) the three most commonly studied behavioral measures were speech in competition, temporally distorted speech, and binaural speech perception (especially dichotic listening); (2) for speech in competition and temporally degraded speech, hearing loss proved to have a significant negative effect on performance in most of the laboratory studies; (3) significant negative effects of age, unconfounded by hearing loss, were observed in most of the studies of speech in competing speech, time-compressed speech, and binaural speech perception; and (4) the influence of cognitive processing on speech understanding has been examined much less frequently, but when included, significant positive associations with speech understanding were observed.For 36 smaller-scale studies of the perception of nonspeech stimuli by older adults reviewed, the following findings emerged: (1) the three most frequently studied behavioral measures were gap detection, temporal discrimination, and temporal-order discrimination or identification; (2) hearing loss was seldom a significant factor; and (3) negative effects of age were almost always observed.For 18 studies reviewed that made use of test batteries and medium-to-large sample sizes, the following findings emerged: (1) all studies included speech-based measures of auditory processing; (2) 4 of the 18 studies included nonspeech stimuli; (3) for the speech-based measures, monaural speech in a competing-speech background, dichotic speech, and monaural time-compressed speech were investigated most frequently; (4) the most frequently used tests were the Synthetic Sentence Identification (SSI) test with Ipsilateral Competing Message (ICM), the Dichotic Sentence Identification (DSI) test, and time-compressed speech; (5) many of these studies using speech-based measures reported significant effects of age, but most of these studies were confounded by declines in hearing, cognition, or both; (6) for nonspeech auditory-processing measures, the focus was on measures of temporal processing in all four studies; (7) effects of cognition on nonspeech measures of auditory processing have been studied less frequently, with mixed results, whereas the effects of hearing loss on performance were minimal due to judicious selection of stimuli; and (8) there is a paucity of observational studies using test batteries and longitudinal designs. Conclusions: Based on this review of the scientific literature, there is insufficient evidence to confirm the existence of central presbycusis as an isolated entity. On the other hand, recent evidence has been accumulating in support of the existence of central presbycusis as a multifactorial condition that involves age- and/or disease-related changes in the auditory system and in the brain. Moreover, there is a clear need for additional research in this area.

Purpose: GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted. Experimental Design: GSK461364 was administered in escalating doses to patients with solid malignancies by two schedules, either on days 1, 8, and 15 of 28-day cycles (schedule A) or on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (schedule B). Assessments included pharmacokinetic and pharmacodynamic profiles, as well as marker expression studies in pretreatment tumor biopsies. Results: Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Dose-limiting toxicities (DLT) in schedule A at 300 mg (2 of 7 patients) and 225 mg (1 of 8 patients) cohorts included grade 4 neutropenia and/or grade 3–4 thrombocytopenia. In schedule B, DLTs of grade 4 pulmonary emboli and grade 4 neutropenia occurred at 7 or more days at 100 mg dose level. Venous thrombotic emboli (VTE) and myelosuppression were the most common grade 3–4, drug-related events. Pharmacokinetic data indicated that AUC (area under the curve) and Cmax (maximum concentration) were proportional across doses, with a half-life of 9 to 13 hours. Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 (pHH3) following drug administration. A best response of prolonged stable disease of more than 16 weeks occurred in 6 (15%) patients, including 4 esophageal cancer patients. Those with prolonged stable disease had greater expression of Ki-67, pHH3, and Plk1 in archived tumor biopsies. Conclusions: The final recommended phase II dose for GSK461364 was 225 mg administered intravenously in schedule A. Because of the high incidence (20%) of VTE, for further clinical evaluation, GSK461364 should involve coadministration of prophylactic anticoagulation. Clin Cancer Res; 17(10); 3420–30. ©2011 AACR.

Purpose: A phase I study to define toxicity and recommend a phase II dose of the HSP90 inhibitor alvespimycin (17-DMAG; 17-dimethylaminoethylamino-17-demethoxygeldanamycin). Secondary endpoints included evaluation of pharmacokinetic profile, tumor response, and definition of a biologically effective dose (BED). Patients and Methods: Patients with advanced solid cancers were treated with weekly, intravenous (i.v.) 17-DMAG. An accelerated titration dose escalation design was used. The maximum tolerated dose (MTD) was the highest dose at which ≤1/6 patients experienced dose limiting toxicity (DLT). Dose de-escalation from the MTD was planned with mandatory, sequential tumor biopsies to determine a BED. Pharmacokinetic and pharmacodynamic assays were validated prior to patient accrual. Results: Twenty-five patients received 17-DMAG (range 2.5–106 mg/m2). At 106 mg/m2 of 17-DMAG 2/4 patients experienced DLT, including one treatment-related death. No DLT occurred at 80 mg/m2. Common adverse events were gastrointestinal, liver function changes, and ocular. Area under the curve and mean peak concentration increased proportionally with 17-DMAG doses 80 mg/m2 or less. In peripheral blood mononuclear cells significant (P < 0.05) HSP72 induction was detected (≥20 mg/m2) and sustained for 96 hours (≥40 mg/m2). Plasma HSP72 levels were greatest in the two patients who experienced DLT. At 80 mg/m2 client protein (CDK4, LCK) depletion was detected and tumor samples from 3 of 5 patients confirmed HSP90 inhibition. Clinical activity included complete response (castration refractory prostate cancer, CRPC 124 weeks), partial response (melanoma, 159 weeks), and stable disease (chondrosarcoma, CRPC, and renal cancer for 28, 59, and 76 weeks, respectively). Couclusions: The recommended phase II dose of 17-DMAG is 80 mg/m2 weekly i.v. Clin Cancer Res; 17(6); 1561–70. ©2011 AACR.

Background: The CXC-chemokine expression is linked with colorectal cancer (CRC) progression but their significance in resected CRC is unclear. We explored the prognostic impact of such expression in stage II and III CRC. Methods: Tissue microarrays were constructed from stage II and III CRC biopsies (n=254), and the expression of CXCL1 and CXCL8, and their receptors CXCR1 and CXCR2, in malignant and adjacent normal tissue was graded by immunohistochemistry and was correlated with prognostic factors. Results: Expression of CXCL1, CXCR1 and CXCR2 was elevated in tumour epithelium relative to normal adjacent tissue (P

Studies of the fat mass and obesity-associated (FTO) gene provide compelling evidence of genetic variation in the general population that influences fat levels and obesity risk. Studies of the interaction between genetic and environmental factors such as physical activity (PA) will promote the understanding of how lifestyle can modulate genetic contributions to obesity. In this study, we investigated the effect of FTO genotype, and interactions with PA or energy intake, in young children and adolescents. In all, 1-5-year-old children from the Growth, Exercise and Nutrition Epidemiological Study in preSchoolers (GENESIS) study (N=1980) and 11-18-year-old Greek adolescents (N=949) were measured for adiposity-related phenotypes and genotyped at the FTO single-nucleotide polymorphism (SNP) marker, rs17817449. Adolescents were classified as physically active or inactive based on self-reported levels of PA. In adolescents, FTO genotype influenced weight (P=0.001) and BMI (P=0.007). There was also a significant SNP(*)PA(*)gender interaction (P=0.028) on BMI, which reflected the association between FTO genotype and BMI in males (P=0.016), but not females (P=0.15), and significant SNP(*)PA interaction in males (P=0.007), but not females (P=0.74). The FTO genotype effect was more pronounced in inactive than active males. Inactive males homozygous for the G allele had a mean BMI 3 kg/m(2) higher than T carriers (P=0.008). In the GENESIS study, no significant association between FTO genotype and adiposity was found. The present findings highlight PA as an important factor modifying the effect of FTO genotype.

Introduction: 40-45% of patients with High Grade Serous Ovarian Cancer (HGSOC) will eventually relapse with platinum resistant disease. Tothill et al and TCGA are two independent gene expression datasets which have demonstrated the presence of a mesenchymal molecular subgroup, characterised by upregulation of angiogenesis regulating genes. Angiogenesis is known to be an integral pathological feature of HGSOC and anti-angiogenics have dominated the field of drug development in EOC. However, despite this, anti-angiogenic agents have failed to demonstrate a significant impact on overall survival (OS) benefit. In this study, we asked if platinum resistance could be associated with an improved response to anti-angiogenic agents and what the underlying biological rationale for this could be. Methods: A meta-analysis of 14 phase II and III clinical trials in EOC were used to investigate the association between platinum resistance and response to anti-angiogenic agents. In addition, we analysed gene expression in 12 matched pre- and post-chemotherapy EOC samples. Novel isogenic cisplatin-resistant HGSOC cell lines were established to study the development of an angiogenic phenotype. Further studies were performed in novel ascites-derived primary cell lines from HGSOC patients with known outcomes following platinum-based chemotherapy. Result: In the clinical trial meta-analysis, an OS benefit for antiangiogenics was observed in platinum-resistant disease (p=0.029), whilst platinum-sensitive EOC only derived progression free survival (PFS) (p= Discussion: We have demonstrated that previous platinum therapy for EOC is associated with an increase in tumor PDGFα and VEGF-A expression, correlating with a response to anti-angiogenic therapies. This data suggests that platinum therapy resistance may inform the selection of EOC patients for novel antiangiogenic therapies in future clinical trials. Citation Format: Aya El Helali, Nuala McCabe, Christopher Steele, Lara Dura Perez, Christina L. O'Neill, Naomi Dickson, Niamh McGivern, Caolan Harkin, Andrena McCavigan, Reinhold J. Medina, Laura A. Knight, Stephen McQuaid, Jacqueline A. James, Caroline O. Michie, Charlie Gourley, W Glenn McCluggage, Denis P. Harkin, Richard H. Wilson, Alan W. Stitt, Richard D. Kennedy. Platinum resistance in epithelial ovarian cancer is dependent on a PDGFR alpha-VEGF-A signalling mechanism that activates downstream angiogenesis pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 7.

Introduction. Triple negative breast cancer (TNBC) makes up 15% of breast cancers and is associated with poor prognosis. TNBC treatment remains hampered by early visceral metastasis and lymph node involvement at the time of diagnosis and limited effective therapeutic options. Advances in treatment that translate to significant improvements in outcome have been painstakingly incremental, despite advances in research technologies and TNBC subtyping. We have identified deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) as a critical gatekeeper that protects tumor DNA from the genotoxic misincorporation of uracil during treatment with anthracyclines that are commonly used in the FEC chemotherapy regimen. dUTPase catalyses the hydrolytic dephosphorylation of deoxyuridine triphosphate (dUTP) to deoxyuridine monophosphate (dUMP). This reaction has the dual function of providing dUMP for thymidylate synthase (TS) as part of the thymidylate biosynthesis pathway and of maintaining low intracellular dUTP pools. This is crucial as DNA polymerase cannot distinguish between dUTP and deoxythymidylate triphosphate (dTTP), leading to dUTP misincorporated into DNA. dUTPase is being evaluated as a target in cancer therapy alongside TS-targeted therapies and uracil misincorporation is believed to be a potential mechanism of cytotoxicity. Hypothesis: Targeting dUTPase and inducing uracil misincorporation during the repair of DNA damage induced by anthracyclines represents a novel strategy to induce TNBC cell lethality. Methods. Inhibition of dUTPase (DUTi) was carried out using SMARTpool siRNA or small molecule inhibition. The effect of DUTi in combination with anthracyclines was determined by growth inhibition and clonogenics assays. DNA damage was assessed by Western blot, immune-fluorescent foci detection, and flow cytometry. Nucleotide metabolites were quantified by LC/MS. Results. DUTi significantly sensitised TNBC cell lines to doxorubicin and epirubicin. In the MDA-MB-231 cancer cells, loss of dUTPase expression resulted in a synergistic 80% reduction in survival compared to 0.075µM doxorubicin alone at 40%. This decrease in survival correlated with increased activation of proteins involved in DNA damage response, including γ-H2AX(Ser139), a marker for dsDNA breaks. We anticipate that quantification of nucleotides will show an imbalance of dUTP:dTTP, subsequently leading to uracil misincorporation and resulting cell death. Discussion. These results suggest that repair of anthracycline-induced DNA damage requires dUTPase to prevent uracil misincorporation and that inhibition of dUTPase is a potential novel strategy to enhance the efficacy of anthracyclines. This shows the potential advantage of a dUTPase inhibitor being added to current chemotherapy regimens for TNBC. Future work will elucidate the mechanism of sensitisation and in vivo translation of combination therapy for TNBC. Citation Format: Craig Davison, Olivier P. Chevallier, Catherine Knowlson, Melanie McKechnie, Robbie Carson, Jaime Esteve, Richard Wilson, Robert D. Ladner, Melissa J. LaBonte (Wilson). Imbalanced nucleotide metabolism sensitizes breast cancer cells to anthracyclines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3836.

Purpose: We previously found that cellular FLICE-inhibitory protein (c-FLIP), caspase 8, and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) receptor 2 (DR5) are major regulators of cell viability and chemotherapy-induced apoptosis in colorectal cancer. In this study, we determined the prognostic significance of c-FLIP, caspase 8, TRAIL and DR5 expression in tissues from patients with stage II and III colorectal cancer.Experimental Design: Tissue microarrays were constructed from matched normal and tumor tissue derived from patients (n = 253) enrolled in a phase III trial of adjuvant 5-fluorouracil–based chemotherapy versus postoperative observation alone. TRAIL, DR5, caspase 8, and c-FLIP expression levels were determined by immunohistochemistry.Results: Colorectal tumors displayed significantly higher expression levels of c-FLIP (P < 0.001), caspase 8 (P = 0.01), and DR5 (P < 0.001), but lower levels of TRAIL (P < 0.001) compared with matched normal tissue. In univariate analysis, higher TRAIL expression in the tumor was associated with worse overall survival (P = 0.026), with a trend to decreased relapse-free survival (RFS; P = 0.06), and higher tumor c-FLIP expression was associated with a significantly decreased RFS (P = 0.015). Using multivariate predictive modeling for RFS in all patients and including all biomarkers, age, treatment, and stage, we found that the model was significant when the mean tumor c-FLIP expression score and disease stage were included (P < 0.001). As regards overall survival, the overall model was predictive when both TRAIL expression and disease stage were included (P < 0.001).Conclusions: High c-FLIP and TRAIL expression may be independent adverse prognostic markers in stage II and III colorectal cancer and might identify patients most at risk of relapse. Clin Cancer Res; 16(13); 3442–51. ©2010 AACR.

Background: The most common complaint of adults with hearing loss is understanding speech in noise. One class of masker that may be particularly useful in the assessment of speech-in-noise abilities is interrupted noise. Interrupted noise usually is a continuous noise that has been multiplied by a square wave that produces alternating intervals of noise and silence. Wilson and Carhart found that spondaic word thresholds for listeners with normal hearing were 28 dB lower in an interrupted noise than in a continuous noise, whereas listeners with hearing loss experienced only an 11 dB difference. Purpose: The purpose of this series of experiments was to determine if a speech-in-interrupted-noise paradigm differentiates better (1) between listeners with normal hearing and listeners with hearing loss and (2) among listeners with hearing loss than do traditional speech-in-continuous-noise tasks. Research Design: Four descriptive/quasi-experimental studies were conducted. Study Sample: Sixty young adults with normal hearing and 144 older adults with pure-tone hearing losses participated. Data Collection and Analysis: A 4.3 sec sample of speech-spectrum noise was constructed digitally to form the 0 interruptions per second (ips; continuous) noise and the 5, 10, and 20 ips noises with 50% duty cycles. The noise samples were mixed digitally with the Northwestern University Auditory Test No. 6 words at selected signal-to-noise ratios and recorded on CD. The materials were presented through an earphone, and the responses were recorded and analyzed at the word level. Similar techniques were used for the stimuli in the remaining experiments. Results: In Experiment 1, using 0 ips as the reference condition, the listeners with normal hearing achieved 34.0, 30.2, and 28.4 dB escape from masking for 5, 10, and 20 ips, respectively. In contrast, the listeners with hearing loss only achieved 2.1 to 2.4 dB escape from masking. Experiment 2 studied the 0 and 5 ips conditions on 72 older listeners with hearing loss, who were on average 13 yr younger and more varied in their hearing loss than the listeners in Experiment 1. The mean escape from masking in Experiment 2 was 7 dB, which is 20–25 dB less than the escape achieved by listeners with normal hearing. Experiment 3 examined the effects that duty cycle (0–100% in 10% steps) had on recognition performance in the 5 and 10 ips conditions. On the 12 young listeners with normal hearing, (1) the 50% correct point increased almost linearly between the 0 and 60% duty cycles (slope = 4.2 dB per 10% increase in duty cycle), (2) the slope of the function was steeper between 60 and 80% duty cycles, and (3) about the same masking was achieved for the 80–100% duty cycles. The data from the listeners with hearing loss were inconclusive. Experiment 4 varied the interburst ratios (0, –6, –12, –24, –48, and –∞ dB) of 5 ips noise and evaluated recognition performance by 24 young adults. The 50% points were described by a linear regression (R 2 = 0.98) with a slope of 0.55 dB/dB. Conclusion: The current data indicate that interrupted noise does provide a better differentiation both between listeners with normal hearing and listeners with hearing loss and among listeners with hearing loss than is provided by continuous noise.

Background: There is a significant body of in vitro evidence and pre-clinical data which demonstrates that aspirin inhibits the growth of tumours and prevents the development of metastases[1]. A recent meta-analysis using individual patient data from randomized trials evaluating the cardiovascular effects of aspirin reports a reduction in cancer deaths after 5 years (hazard ratio 0.46, 95% confidence interval 0.27-0.77)[2]. Effects on risk of metastases and death following a cancer diagnosis have also been observed[3]. An analysis of the Nurses’ Health Study found that aspirin use following a diagnosis of stage I-III breast cancer was associated with a lower risk of breast cancer death (for those taking aspirin 2-5 times per week, relative risk 0.27, 95% confidence interval 0.15-0.47)[4]. Concerns over toxicity have limited the use of aspirin as a primary prevention agent against cancer. In the adjuvant setting the benefit:risk ratio will be different with higher morbidity and mortality from recurrent cancer potentially outweighing the risks associated with regular aspirin use. The Add-Aspirin trials will investigate whether regular aspirin use after curative treatment for localised malignancy can prevent tumour recurrence and prolong survival. As an inexpensive drug with a potential therapeutic role in several common cancers, aspirin could have a huge impact on the global cancer burden. Trial design: Multicentre, international, phase III, double-blind, placebo-controlled randomized trial in patients with early breast cancer. Participants will be randomised to enteric-coated aspirin 100mg, aspirin 300mg or matching placebo daily for at least 5 years. Parallel trials based on a common infrastructure will be conducted in colorectal, gastro-oesophageal and prostate cancer. Eligibility criteria: Patients who have undergone primary therapy, including curative surgery and appropriate neoadjuvant/adjuvant therapies for histologically confirmed invasive breast cancer which is node positive or node negative with high-risk features. Patients who have already participated in other primary treatment trials may be eligible subject to agreement from the trial management groups. Specific aims: The primary outcome will be disease-free survival. Secondary endpoints include overall survival, toxicity, cardiac morbidity and assessment of overall healthcare benefits. Translational work will investigate mechanisms of action and biomarkers for toxicity and treatment efficacy (including PIK3CA mutation status and COX-2 expression). Statistical methods: Approximately 3100 patients will be needed to test for a 4% improvement in DFS associated with aspirin use. [1] Langley RE et al. Br J Cancer. 2011;105(8):1107-13. [2] Rothwell PM et al. Lancet. 2011;377(9759):31-41. [3] Rothwell PM et al. Lancet. 2012;379(9826):1591-601. [4] Holmes MD et al. J Clin Oncol 2010;28(9):1467-72. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-4-01.

Purpose: P-glycoprotein (Pgp) antagonists have had unpredictable pharmacokinetic interactions requiring reductions of chemotherapy. We report a phase I study using tariquidar (XR9576), a potent Pgp antagonist, in combination with vinorelbine. Experimental Design: Patients first received tariquidar alone to assess effects on the accumulation of 99mTc-sestamibi in tumor and normal organs and rhodamine efflux from CD56+ mononuclear cells. In the first cycle, vinorelbine pharmacokinetics was monitored after the day 1 and 8 doses without or with tariquidar. In subsequent cycles, vinorelbine was administered with tariquidar. Tariquidar pharmacokinetics was studied alone and with vinorelbine. Results: Twenty-six patients were enrolled. Vinorelbine 20 mg/m2 on day 1 and 8 was identified as the maximum tolerated dose (neutropenia). Nonhematologic grade 3/4 toxicities in 77 cycles included the following: abdominal pain (4 cycles), anorexia (2), constipation (2), fatigue (3), myalgia (2), pain (4) and dehydration, depression, diarrhea, ileus, nausea, and vomiting, (all once). A 150-mg dose of tariquidar: (1) reduced liver 99mTc-sestamibi clearance consistent with inhibition of liver Pgp; (2) increased 99mTc-sestamibi retention in a majority of tumor masses visible by 99mTc-sestamibi; and (3) blocked Pgp-mediated rhodamine efflux from CD56+ cells over the 48 hours examined. Tariquidar had no effects on vinorelbine pharmacokinetics. Vinorelbine had no effect on tariquidar pharmacokinetics. One patient with breast cancer had a minor response, and one with renal carcinoma had a partial remission. Conclusions: Tariquidar is a potent Pgp antagonist, without significant side effects and much less pharmacokinetic interaction than previous Pgp antagonists. Tariquidar offers the potential to increase drug exposure in drug-resistant cancers.

We sought to characterise whether dexamethasone (DEX) may enhance tumour response to docetaxel in in vitro and in vivo models of metastatic prostate cancer (CaP). In vitro experiments conducted on PC3 and human bone marrow endothelial cells (hBMECs) determined that administration of DEX (10 nM) reduced constitutive nuclear factor-kappaB (NF-kappaB) activity, decreasing interleukin (IL)-8, CXCL1 and VEGF gene expression in PC3 cells. Dexamethasone also attenuated docetaxel-induced NF-kappaB and activator protein-1 transcription and reduced docetaxel-promoted expression/secretion of IL-8 and CXCL1 in PC3 and hBMECs. Although DEX failed to enhance docetaxel cytotoxicity on PC3 cells, DEX potentiated the antiangiogenic activity of docetaxel in vitro, further reducing vessel area and vessel length in developing endothelial tubes (P0.05). Docetaxel had a potent antiangiogenic activity in the dorsal skin flap-implanted PC3 tumours in vivo. Small blood vessel formation was further suppressed in tumours co-treated with docetaxel and DEX, substantiated by an increased average vessel diameter and segment length and a decreased number of branch points in the residual tumour vasculature (P0.001). Our data show that DEX potentiates the antiangiogenic activity of docetaxel, suggesting a putative mechanism for the palliative and survival benefits of these agents in metastatic CaP.

OSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma.A 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity.Fourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients.The recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).

The functional allele (577R) of ACTN3, which encodes human alpha-actinin-3, has been reported to be associated with elite athletic status and with response to resistance training, while the nonfunctional allele (577X) has been proposed as a candidate metabolically thrifty allele. In a study of 992 adolescent Greeks, we show that there is a significant association (P=0.003) between the ACTN3 R577X polymorphism and 40 m sprint time in males that accounts for 2.3% of phenotypic variance, with the 577R allele contributing to faster times in an additive manner. The R577X polymorphism is not associated with other power phenotypes related to 40 m sprint, nor with an endurance phenotype. Furthermore, the polymorphism is not associated with obesity-related phenotypes in our population, suggesting that the 577X allele is not a thrifty allele, and thus the persistence of this null allele must be explained in other terms.