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419 Background: A predictive biomarker for resistance to trastuzumab in HER2 positive oesophago-gastric cancer would refine patient selection. Our preclinical studies suggest that patients with HIGH baseline plasma miR-148a-3p levels will experience shorter Overall Survival (OS), Progression Free Survival (PFS), and worse Progression Free Rates (PFR) than those with LOW plasma miR-148a-3p levels. Methods: This sub-study is a prospective biomarker analysis of baseline plasma samples for HER2 positive advanced oesophago-gastric cancer patients registered within Arm B1 of the Phase 2 open label, multicentre, randomised PLATFORM trial (NCT02678182). All HER2 positive patients assessable for clinical response and miR signatures were included. Copies of miR-148a-3p and miR-16 per ml of plasma were quantified using Digital Droplet Polymerase Chain Reaction (ddPCR). OS as primary endpoint for miR-148a-3p LOW (≤median) versus HIGH (>median) was analysed using Kaplan-Meier curves and Cox model regression. Secondary endpoints were PFS and PFR. OS and PFS are from start of 1st line therapy; PFR are from start of maintenance trastuzumab. Sensitivity analysis normalised miR-148a-3p to miR-16. Results: Of 63 patients with analysable lab samples and available survival data, normalisation was possible for 41 patients. Median follow-up was 38 months. There was no statistically significant relationship between OS and miR-148-3p copies/μl of ddPCR reaction LOW versus HIGH (n= 62, Hazard Ratio (HR) 0.98, p=0.933), PFS (n=62, HR 1.08, p=0.759) or PFR (n=31, Odds Radio (OR) 0.67, p=0.577). Normalised miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in PFR at 3 months (n=23, OR=0.11, p=0.027) but no difference in OS or PFS. A model adjusting for primary tumour site, metastatic disease and number of sites demonstrated a statistically significant difference in PFR at 3 months (aOR=0.03, p=0.029). Conclusions: Patients with HIGH NmiR-148-3p have 0.03 times the odds of being progression-free at 3 months than patients with LOW NmiR-148a-3p in this population, when adjusted for key factors. Limitations include small sample size and normalisation. Clinical trial information: NCT02678182 . [Table: see text]

522 Background: Most patients with pancreatic cancer (PC) and biliary tract cancer (BTC) present with advanced disease. In confirmed cases, circulating tumour DNA (ctDNA) may be detected through liquid biopsy in 80-90%. Obtaining a diagnostic biopsy can be technically challenging, require complex invasive procedures and may not be feasible due to comorbidity. Reduction in capacity of aerosol generating diagnostic procedures in many healthcare systems due to COVID19 has highlighted the unmet need for simple, non-invasive diagnostic tools. We piloted the use of ctDNA to support the diagnostic pathway in patients with suspected cancer across 6 tumour types, here we present its use in PC/BTC. Methods: This single centre prospective cohort pilot trial was conducted at the Royal Marsden from June 2020 to August 2021. 16 patients were planned each in the PC and BTC cohorts. Eligibility included radiologically suspicious PC/BTC without histological diagnosis, patients with prior non-diagnostic biopsy and inaccessible tumours. Liquid biopsy for ctDNA was collected for plasma based next generation sequencing, using a custom 59 gene panel of common variants in PC/BTC tumours, including analysis for somatic, copy number and structural variants. Clonal haematopoiesis of indeterminate potential (CHIP) and germline variants were identified and subtracted. A molecular tumour board (MTB) reviewed results for interpretation and clinical context. Primary outcome was the proportion of patients with a ctDNA result consistent with a diagnosis of malignancy following MTB discussion. Results: 32 patients with suspected PC (n= 16) and BTC (n=16) were recruited. Baseline characteristics are shown in table. ctDNA was detected in 69% and 56% of patients with suspected PC and BTC respectively. MTB discussion confirmed all variants detected were consistent with a diagnosis of malignancy. At the time of data cut off, 23 patients had a subsequent biopsy. The sensitivity and specificity of ctDNA as a diagnostic tool was 80% (90% CI 49.3-96.3) and 100% (90% CI 36.8-100) for PC respectively, and 100% (90% CI 60.7-100) and 75% (90% CI 24.9-98.7) for BTC respectively. There were 2 false negatives in the PC cohort subsequently diagnosed with PC, and 1 false positive in the BTC cohort subsequently diagnosed with oesophageal cancer. Conclusions: ctDNA can be used to support a diagnosis of cancer in patients with radiologically suspected PC/BTC. A blood first, tissue second strategy in the diagnosis of PC/BTC could improve diagnostic efficiency, speed, and add resilience to the current diagnostic pathway. Clinical trial information: NCT04566614. [Table: see text]

57 Background: Real world data is a valuable research resource but manual data collection is time consuming and labour intensive. As there is no consensus on the prognostic role of TP53 and PIK3CA mutations in mCRC, we assessed the feasibility of using SQL, a programming language, to derive data from routine electronic clinical notes to investigate the prognostic impact of TP53 and PIK3CA mutations in mCRC. Methods: A cohort of patients (pts) diagnosed with metastatic or recurrent colorectal cancer as per ICD-10 classification from January 2015 to December 2017 and managed at the Royal Marsden Hospital were identified using SQL algorithms developed in-house. Baseline demographics, histopathological and molecular characteristics and death dates were derived from the Electronic Patient Record and extracted in a structured format for statistical analysis. Mutational analysis of TP53 and PIK3CA were performed with standard of care KRAS, NRAS and BRAF testing using next generation sequencing. Overall survival (OS) according to TP53 or PIK3CA mutational status was estimated using the Kaplan-Meier method. Uni- and multivariate Cox regression included KRAS, NRAS, BRAF, sidedness and mismatch repair (MMR) status. Association between TP53 or PIK3CA and MMR status was tested by the Chi squared test. Results: A total of 367 mCRC pts were identified; 10 were excluded due to ineligibility or inadequate data availability. Based on a final dataset of 357 pts, 342 and 354 pts had TP53 and PIK3CA results available. The incidence of TP53 mutations was 75% (n = 257/342) and PIK3CA 16% (n = 55/354). Co-mutations with KRAS, NRAS and BRAF were seen (Table). The overall median follow-up was 42.3 and 42.7 months for TP53 and PIK3CA respectively. There was no difference in OS between TP53 mutant (MT) and wild type (WT) pts (22.0 vs. 22.8 months, p = 0.96) and between PIK3CA MT and WT pts (21.7 vs. 22.4 months, p = 0.49). Right sided and BRAF MT tumours were associated with poorer survival than left sided and BRAF WT tumours when all other factors were constant for TP53 (p

Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed the outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p 0.05) among patients with KRAS wild-type compared to those with KRAS exon 2 mutant tumours. No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF-1 in colon compared to rectal cancers (p = 0.06). Albeit limited by the small sample size, this study does not appear to support a potential role for anti-IGF-1R agents in KRAS exon 2 mutant CRC. Data on IGF-1R, IGF-1 and IGF-2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway.

A tridentate nitrogen-sulfur Schiff base, 3-methylbenzyl 2-(6-methylpyridin-2-ylmethylene)hydrazine carbodithioate (6mpyS3M), was synthesized by condensation of 6-methylpyridine-2-aldehyde with S-3-methylbenzyldithiocarbazate. It crystallized in space group P 21/n. It displayed intermolecular N–H···N hydrogen bonding between the α-nitrogen and the pyridyl nitrogen. The thione sulfur is in a trans position with respect to the 6-methylpyridine fragment across the C–N bond but adopts a cis position with the 3-methylbenzyl fragment through the C–S bond. Octahedral complexes containing two 6mpyS3M ligands were prepared with Cu(II), Ni(II), Zn(II) and Cd(II). 6mpyS3M and its metal complexes were assayed against selected microbes and two breast cancer cell lines. 6mpyS3M was strongly active against both cancer cell lines. Its metal complexes showed high selectivity with Cu(II), Ni(II) and Zn(II) complexes strongly active against only one of the cancer cell lines, whereas the Cd(II) complex was strongly active only against the other. Only Cu(II) and Cd(II) complexes were active against some of the bacteria.

The “countermajoritarian difficulty,” first formulated by Alexander Bickel almost fifty years ago, has been a profoundly influential starting point for those who critically examine the relationship between democracy and constitutional judicial review. However, the inadequacies of this framework are manifest. This framework rests, first, on unwarranted empirical assumptions about the “majoritarianism” of legislative action and the “countermajoritarianism” of courts. It also rests on unwarranted theoretical assumptions about the relationship between democracy and majoritarianism. Virtually all sophisticated approaches to democratic theory do not simply equal democracy with majoritarianism, although this is often forgotten when discussing judicial review. Using the “democracy-against-domination” approach, we assess the democratic status of judicial review, and conclude that judicial review has the potential to make a modest and contingent positive contribution to democracy.

Using the Method of Constant Stimuli, difference limens were obtained for lifted weights of 50 to 200 gm. 184 college students were assigned to one of four experimental conditions resulting from the combination of two modes of stimulus presentation with whether the preferred or non-preferred hand was used to judge the standard weight. Simultaneous interhand judgments produced significantly larger Weber Ratios and more variable Constant Errors than were produced by Successive intrahand presentation. This was contrary to earlier work in the visual modality indicating that simultaneous stimulus presentation produced more sensitive discrimination than did successive. The results are interpreted in terms of the neural organization of tactile input.

Foundation design for offshore structures in areas where wave-induced bottom pressures cause submarine mud slides requires a knowledge of the potential depth of slide and of the magnitude and distribution of soil movements below the slide. Several methods have been developed to evaluate the stability of the seafloor due to wave-induced bottom pressures. These methods are reviewed and an improved procedure is presented. This procedure makes use of finite element analysis and combines in a rational manner oceanographic information on wave statistics with stress-strain behavior of soils under cyclic load conditions in order to evaluate the effects of a given storm history on the behavior of submarine sediments.