Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, Ktrans (R:−0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.

BackgroundMalignant bowel obstruction (MBO) is a common cause of morbidity and mortality in women diagnosed with ovarian cancer. Earlier detection of MBO may improve patient outcomes. There are currently no screening tools to assist detection.AimWe report a screening questionnaire that can be used to detect MBO, and how the severity score for key clinical symptoms correlate with radiological evidence of MBO from ovarian cancer.DesignA case–control study in which patients with relapsed, metastatic ovarian cancer were asked to answer 10 questions related to key clinical symptoms associated with intestinal obstruction. The study group included women with CT-confirmed MBO, whereas the control group had no evidence of MBO. Patients scored each question according to severity from 1 (least severe) to 5 (most severe).Setting/participantsBetween 1 June and 31 December 2016, 37 women completed the screening questionnaire.ResultsPatients in the study group (n=17) reported significantly higher (ie, more severe) scores for abdominal pain, nausea, vomiting and constipation. In contrast, differences in severity scores between groups did not differ significantly in response to questions regarding abdominal swelling, borborygmi, diarrhoea or loss of appetite. All patients in the study group more frequently stated that their symptoms had deteriorated within the 2 months prior to completing the questionnaire.ConclusionHere we report the key clinical symptoms associated with radiologically-confirmed MBO in relapsed, metastatic ovarian cancer. We recommend healthcare practitioners focus on these specific symptoms during patient consultations in order to improve risk stratification of MBO.

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Background We aimed to assess the safety, tolerability and pharmacokinetics of a novel anti-angiogenic peptide. Methods We used an open-label, multicentre, dose-escalation Phase I trial design in patients with solid tumours. ALM201 was administered subcutaneously once daily for 5 days every week in unselected patients with solid tumours. Results Twenty (8 male, 12 female) patients with various solid tumours were treated (18 evaluable for toxicity) over eight planned dose levels (10–300 mg). ALM201 was well-tolerated at all dose levels without CTCAE grade 4 toxicities. Adverse events were predominantly grades 1–2, most commonly, localised injection-site reactions (44.4%), vomiting (11%), fatigue (16.7%), arthralgia (5.6%) and headache (11%). Thrombosis occurred in two patients at the 100 mg and 10 mg dose levels. The MTD was not reached, and a recommended Phase II dose (RP2D) based on feasibility was declared. Plasma exposure increased with dose (less than dose-proportional at the two highest dose levels). No peptide accumulation was evident. The median treatment duration was 11.1 (range 3–18) weeks. Four of 18 evaluable patients (22%) had stable disease. Conclusions Doses up to 300 mg of ALM201 subcutaneously are feasible and well-tolerated. Further investigation of this agent in selected tumour types/settings would benefit from patient-selection biomarkers.

The data suggest that international survival statistics are achieved in UK regional cancer centres.

Background Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. Methods A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). Results Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01–1.20, p = 0.025). Conclusions In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

histologically validated to provide information on the microstructure of the myocardium. [1][2][3] There is a standard helical myocyte arrangement in the situs solitus (SS) heart, as viewed from the apex; left-handed in the epicardium, circumferential in the mesocardium and right-handed in the endocardium. This generates the opposing basal clockwise rotation and apical anticlockwise rotation necessary for torsion. 4 However in situs inversus totalis (SIT) there is mirror image arrangement of the visceral organs. There are no histological studies assessing how myocardial microstructure is affected in SIT. DT-CMR offers a unique opportunity to evaluate the microstructural abnormalities in SIT. Methods 12 SIT patients and 12 matched healthy volunteers were scanned in a 3T Siemens Skyra scanner. DT-CMR was performed at peak systole in the short axis at base, mid and apex. 2 people had whole heart tractography. A STEAM sequence with bmain=600 s/mm 2 and bref=150 s/mm 2 was used, as previously described.3 Strain and torsion assessment was performed using DENSE5. Results Patients were age and sex-matched (SIT 39.5 and SS 34.5 years, 3/12 male). Myocyte organisation at base, mid and apex was significantly different in SIT hearts compared to the SS hearts. Figure 1 shows example tractography. In SS, the endocardial positive helix angle (HA) progressed to a negative HA in the epicardium. In SIT hearts this pattern was inverted at the base and approached normal at the apex, with a midventricular transition zone.Mid-ventricular peak radial and circumferential strain were reduced in SIT (0.4±0.16 vs 0.56±0.16, p=0.02, and À0.16 ±0.02 vs À0.18±0.01 p=0.04 respectively). Peak absolute torsion was reduced in SIT 3.6°[3.6°] vs 8.0° [3.5°]. Conclusion This is the first human DT-CMR study of SIT hearts. We demonstrate that the SIT heart has an inverted myocyte orientation at the base that approaches normal towards the apex. Peak absolute torsion is reduced. Peak radial and circumferential strain are also reduced at the midventricle. The deranged microstructure in SIT has functional effects, the long-term outcomes of which require further study. Background Cancer survivorship is an international priority and mortality from cardiac damage is one of the greatest concerns. Anthracycline chemotherapy is cardiotoxic but remains highly effective against cancer. Methods This translational project involved the development of a pre-clinical rat model of progressive anthracycline-induced cardiotoxicity (1.25mg/m 2 doxorubicin weekly for 8 doses) and a concurrent clinical study of 30 cancer patients receiving 6 cycles of curative anthracycline therapy (doxorubicin 50mg/ m 2 ). A bespoke cardiac magnetic resonance imaging (CMR) protocol was developed which included longitudinal T1 REFERENCES1. Reese TG, Weisskoff RM, Smith RN, et al. Imaging myocardial fibre architecture inAbstract 18 Figure 1 Tractography of a SIT and SS heart.

Background: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to firstly define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers.Methods: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS).Results: 20 patients were recruited to the study. Results showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. Across all patients, the MRI perfusion parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p=0.025).Conclusions: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecular targeted therapies such as anti-angiogenic agents.