A let-7 microRNA-binding site polymorphism in 3'-untranslated region of KRAS gene predicts response in wild-type KRAS patients with metastatic colorectal cancer treated with cetuximab monotherapy

PURPOSE: recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3' untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy.

PATIENTS AND METHODS: the presence of KRAS let-7 lcs6 polymorphism was evaluated in 130 mCRC patients who were enrolled in a phase II study of cetuximab monotherapy (IMCL-0144). Genomic DNA was extracted from dissected formalin-fixed paraffin-embedded tumor tissue, KRAS mutation status and polymorphism were assessed using direct sequencing and PCR restriction fragment length polymorphism technique.

RESULTS: KRAS let-7 lcs6 polymorphism was found to be related to object response rate (ORR) in mCRC patients whose tumors had KRASwt. The 12 KRASwt patients harboring at least a variant G allele (TG or GG) had a 42% ORR compared with a 9% ORR in 55 KRASwt patients with let-7 lcs6 TT genotype (P = 0.02, Fisher's exact test). KRASwt patients with TG/GG genotypes had trend of longer median progression-free survival (3.9 versus 1.3 months) and OS (10.7 versus 6.4 months) compared to those with TT genotypes.

CONCLUSIONS: these results are the first to indicate that the KRAS 3'UTR polymorphism may predict for cetuximab responsiveness in KRASwt mCRC patients, which warrants validation in other clinical trials.

Association of common gene variants in the WNT/β-catenin pathway with colon cancer recurrence

Wnt/β-catenin signaling has a central role in the development and progression of most colon cancers (CCs). Germline variants in Wnt/β-catenin pathway genes may result in altered gene function and/or activity, thereby causing inter-individual differences in relation to tumor recurrence capacity and chemoresistance. We investigated germline polymorphisms in a comprehensive panel of Wnt/β-catenin pathway genes to predict time to tumor recurrence (TTR) in patients with stage III and high-risk stage II CC. A total of 234 patients treated with 5-fluorouracil-based chemotherapy were included in this study. Whole-blood samples were analyzed for putative functional germline polymorphisms in SFRP3, SFRP4, DKK2, DKK3, Axin2, APC, TCF7L2, WNT5B, CXXC4, NOTCH2 and GLI1 genes by PCR-based restriction fragment-length polymorphism or direct DNA sequencing. Polymorphisms with statistical significance were validated in an independent study cohort. The minor allele of WNT5B rs2010851 T>G was significantly associated with a shorter TTR (10.7 vs 4.9 years; hazard ratio: 2.48; 95% CI, 0.96-6.38; P=0.04) in high-risk stage II CC patients. This result remained significant in multivariate Cox's regression analysis. This study shows that the WNT5B germline variant rs2010851 was significantly identified as a stage-dependent prognostic marker for CC patients after 5-fluorouracil-based adjuvant therapy.

Pharmacogenetic angiogenesis profiling for first-line Bevacizumab plus oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer

PURPOSE: There is substantial germline genetic variability within angiogenesis pathway genes, thereby causing interindividual differences in angiogenic capacity and resistance to antiangiogenesis therapy. We investigated germline polymorphisms in genes involved in VEGF-dependent and -independent angiogenesis pathways to predict clinical outcome and tumor response in metastatic colorectal cancer (mCRC) patients treated with bevacizumab and oxaliplatin-based chemotherapy.

EXPERIMENTAL DESIGN: A total of 132 patients treated with first-line bevacizumab and FOLFOX or XELOX were included in this study. Genomic DNA was isolated from whole-blood samples by PCR-RFLP or direct DNA sequencing. The endpoints of the study were progression-free survival (PFS), overall survival (OS), and response rate (RR).

RESULTS: The minor alleles of EGF rs444903 A>G and IGF-1 rs6220 A>G were associated with increased OS and remained significant in multivariate Cox regression analysis (HR: 0.52; 95% CI: 0.31-0.87; adjusted P = 0.012 and HR: 0.60; 95% CI: 0.36-0.99; adjusted P = 0.046, respectively). The minor allele of HIF1α rs11549465 C>T was significantly associated with increased PFS but lost its significance in multivariate analysis. CXCR1 rs2234671 G>C, CXCR2 rs2230054 T>C, EGFR rs2227983 G>A, and VEGFR-2 rs2305948 C>T predicted tumor response, with CXCR1 rs2234671 G>C remaining significant in multiple testing (P(act) = 0.003).

CONCLUSION: In this study, we identified common germline variants in VEGF-dependent and -independent angiogenesis genes predicting clinical outcome and tumor response in patients with mCRC receiving first-line bevacizumab and oxaliplatin-based chemotherapy.

Human papillomavirus: a strong case for vaccinating boys

In the UK, human papilloma virus vaccination is restricted on the NHS to girls and only recently been recommended for men who have sex with men. The restriction is based largely on cost-effectiveness. In this article, Gillian Prue sets out the compelling case for vaccinating all boys. On page 10, Peter Baker describes HPV Action’s campaign for gender-neutral HPV vaccination.

Improving E-Assessment Systems With A focus On Adaptive Feedback And Marking

Institutions involved in the provision of tertiary education across Europe are feeling the pinch. European universities, and other higher education (HE) institutions, must operate in a climate where the pressure of government spending cuts (Garben, 2012) is in stark juxtaposition to the EU’s strategy to drive forward and maintain a growth of student numbers in the sector (eurostat, 2015).

In order to remain competitive, universities and HE institutions are making ever-greater use of electronic assessment (E-Assessment) systems (Chatzigavriil et all, 2015; Ferrell, 2012). These systems are attractive primarily because they offer a cost-effect and scalable approach for assessment. In addition to scalability, they also offer reliability, consistency and impartiality; furthermore, from the perspective of a student they are most popular because they can offer instant feedback (Walet, 2012).

There are disadvantages, though.

First, feedback is often returned to a student immediately on competition of their assessment. While it is possible to disable the instant feedback option (this is often the case during an end of semester exam period when assessment scores must be can be ratified before release), however, this option tends to be a global ‘all on’ or ‘all off’ configuration option which is controlled centrally rather than configurable on a per-assessment basis.

If a formative in-term assessment is to be taken by multiple groups of
students, each at different times, this restriction means that answers to each question will be disclosed to the first group of students undertaking the assessment. As soon as the answers are released “into the wild” the academic integrity of the assessment is lost for subsequent student groups.

Second, the style of feedback provided to a student for each question is often limited to a simple ‘correct’ or ‘incorrect’ indicator. While this type of feedback has its place, it often does not provide a student with enough insight to improve their understanding of a topic that they did not answer correctly.

Most E-Assessment systems boast a wide range of question types including Multiple Choice, Multiple Response, Free Text Entry/Text Matching and Numerical questions. The design of these types of questions is often quite restrictive and formulaic, which has a knock-on effect on the quality of feedback that can be provided in each case.

Multiple Choice Questions (MCQs) are most prevalent as they are the most prescriptive and therefore most the straightforward to mark consistently. They are also the most amenable question types, which allow easy provision of meaningful, relevant feedback to each possible outcome chosen.
Text matching questions tend to be more problematic due to their free text entry nature. Common misspellings or case-sensitivity errors can often be accounted for by the software but they are by no means fool proof, as it is very difficult to predict in advance the range of possible variations on an answer that would be considered worthy of marks by a manual marker of a paper based equivalent of the same question.

Numerical questions are similarly restricted. An answer can be checked for accuracy or whether it is within a certain range of the correct answer, but unless it is a special purpose-built mathematical E-Assessment system the system is unlikely to have computational capability and so cannot, for example, account for “method marks” which are commonly awarded in paper-based marking.

From a pedagogical perspective, the importance of providing useful formative feedback to students at a point in their learning when they can benefit from the feedback and put it to use must not be understated (Grieve et all, 2015; Ferrell, 2012).

In this work, we propose a number of software-based solutions, which will overcome the limitations and inflexibilities of existing E-Assessment systems.

Fetal umbilical artery Doppler pulsatility index and childhood neurocognitive outcome at 12 years

OBJECTIVE: To determine whether an elevated fetal umbilical artery Doppler (UAD) pulsatility index (PI) at 28 weeks' gestation, in the absence of fetal growth restriction (FGR) and prematurity, is associated with adverse neurocognitive outcome in children aged 12 years.

METHODS: Prospective cohort study, comparing children with a normal fetal UAD PI (<90th centile) (n=110) and those with an elevated PI (≥90th centile) (n=40). UAD was performed at 28, 32 and 34 weeks gestation. At 12 years of age, all children were assessed under standardised conditions at Queen's University, Belfast, UK to determine cognitive and behavioural outcomes using the British Ability Score-II and Achenbach Child Behavioural Checklist Parent Rated Version under standardised conditions. Regression analysis was performed, controlling for confounders such as gender, socioeconomic status and age at assessment.

RESULTS: The mean age of follow-up was 12.4 years (±0.5 SD) with 44% of children male (n=63). When UAD was assessed at 28 weeks, the elevated fetal UAD group had lower scores in cognitive assessments of information processing and memory. Parameters included (1) recall of objects immediate verbal (p=0.002), (2) delayed verbal (p=0.008) and (3) recall of objects immediate spatial (p=0.0016). There were no significant differences between the Doppler groups at 32 or 34 weeks' gestation.

CONCLUSIONS: An elevated UAD PI at 28 weeks' gestation in the absence of FGR or prematurity is associated with lower scores of declarative memory in children aged 12 years. A potential explanation for this is an element of placental insufficiency in the presence of the appropriately grown fetus, which affects the development of the fetal hippocampus and information processing and memory long-term. These findings, however, had no impact on overall academic ability, mental processing and reasoning or overall behavioural function.