Referral challenges for early-onset colorectal cancer: a qualitative study in UK primary care.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC) in adults aged <50 years has increased in several Western nations. National surveys have highlighted significant barriers to accessing timely care for patients with EOCRC, which may be contributing to a late stage of presentation in this population group. AIM: To explore awareness of the increasing incidence of EOCRC, and to understand the potential barriers or facilitators faced by GPs when referring younger adults to secondary care with features indicative of EOCRC. DESIGN & SETTING: Qualitative methodology, via virtual semi-structured interviews with 17 GPs in Northern Ireland. METHOD: Reflective thematic analysis was conducted with reference to Braun and Clarke's framework. RESULTS: Three main themes were identified among participating GPs: awareness, diagnostic, and referral challenges. Awareness challenges focused on perceptions of EOCRC being solely associated with hereditary cancer syndromes, and colorectal cancer being a condition of older adults. Key diagnostic challenges centred around the commonality of lower gastrointestinal complaints and overlap in EOCRC symptoms with benign conditions. Restrictions in age-based referral guidance and a GP 'guilt complex' surrounding over-referral to secondary care summarised the referral challenges. Young females were perceived as being particularly disadvantaged with regard to delays in diagnosis. CONCLUSION: This novel research outlines potential reasons for the diagnostic delays seen in patients with EOCRC from a GP perspective, and highlights many of the complicating factors that contribute to the diagnostic process.

Is qFIT a useful tool in prioritising symptomatic patients referred with suspect colorectal cancer in the COVID-19 era?

Background: The COVID-19 pandemic is an evolving healthcare challenge causing secondary disruption of cancer services. Quantitative Faecal Immunochemical Testing (qFIT) has been established as a screening method in asymptomatic patients. We aim to assess its utility as a triage tool to prioritise investigations in symptomatic patients with suspected colorectal cancer. Methods: At the commencement of the COVID-19 pandemic a database was established to include patients awaiting red flag outpatient consultation or colonic investigations and new red flag referrals from March to June 2020. Patients were supplied with qFIT kits and returned results categorised into 3 priority groups according to the qFIT value. Group 1 >150µg Hb/g, Group 2 ≥10 to ≤150µg Hb/g and Group 3 <10µg Hb/g. Subsequent colonic evaluation was offered by colonoscopy or cross-sectional imaging with urgency determined by qFIT priority group. When identified colorectal cancer, inflammatory bowel disease or high-risk polyps were recorded as "significant colorectal pathology." Findings: Three hundred and seventeen patients were identified with data analysed on 290 patients. Colorectal malignancy was identified in 17 patients; 94% of these patients were in Group 1. A qFIT result >150 µg Hb/g had a sensitivity and specificity for colorectal cancer of 94.12% (95% CI 71.31-99.85) and 91.21% (95% CI 87.20-94.29) respectively. No malignancy was detected in Priority Group 3; negative predictive value of 100% (95% CI 98.06-100). Conclusions: In symptomatic, suspect lower GI cancer patients qFIT is a useful adjunct for prioritising patients and can be used to determine the urgency of colorectal investigations.

The Value of Quantitative Faecal Immunochemical Testing as a Prioritisation Tool for the Endoscopic Investigation of Patients With Iron Deficiency.

Difficulty in providing endoscopy for patients with iron deficiency anaemia (IDA) during the COVID-19 pandemic has highlighted the requirement for a prioritisation tool. We aimed to test the validity of qFIT as a prioritisation tool in patients with iron deficiency and its ability to identify patients with advanced neoplastic lesions (ANLs). Data collected from patients referred with biochemically proven iron deficiency (ferritin ≤ 15 µg/L) and synchronous qFIT who underwent full gastrointestinal investigation within NHS Greater Glasgow and Clyde was analysed retrospectively. Patients who did not undergo full investigation, defined as gastroscopy and colonoscopy or CT colonography, were excluded. ANLs were defined as defined as upper GI cancer, colorectal adenoma ≥ 1 cm or colorectal cancer. Area under the curve (AUC) analysis was performed on qFIT results and outcome, defined as the presence of an ANL. AUC analysis guided cut-off scores for qFIT. Patients with a qFIT of <10, 10-200, >200, were allocated a score of 1, 2, and 3, respectively. A total of 575 patients met criteria for inclusion into the study. Overall, qFIT results strongly predicted the presence of ANLs (AUC 0.87, CI 0.81-0.92; P < 0.001). The prevalence of ANLs in patients with scores 1-3 was 1.2, 13.5, and 38.9% respectfully. When controlled for other significant variables, patients with a higher qFIT score were statistically more likely to have an ANL (qFIT score = 2; OR 12.8; P < 0.001, qFIT score = 3, OR 50.0; P < 0.001). A negative qFIT had a high NPV for the presence of ANLs (98.8%, CI 97.0-99.5%). These results strongly suggest that qFIT has validity as a prioritisation tool in patients with iron deficiency; both allowing for a more informed decision of investigation of patients with very low risk of malignancy, and in identifying higher risk patients who may benefit from more urgent endoscopy.

Exploring ligand dynamics in protein crystal structures with ensemble refinement.

Understanding the dynamics of ligands bound to proteins is an important task in medicinal chemistry and drug design. However, the dominant technique for determining protein-ligand structures, X-ray crystallography, does not fully account for dynamics and cannot accurately describe the movements of ligands in protein binding sites. In this article, an alternative method, ensemble refinement, is used on six protein-ligand complexes with the aim of understanding the conformational diversity of ligands in protein crystal structures. The results show that ensemble refinement sometimes indicates that the flexibility of parts of the ligand and some protein side chains is larger than that which can be described by a single conformation and atomic displacement parameters. However, since the electron-density maps are comparable and Rfree values are slightly increased, the original crystal structure is still a better model from a statistical point of view. On the other hand, it is shown that molecular-dynamics simulations and automatic generation of alternative conformations in crystallographic refinement confirm that the flexibility of these groups is larger than is observed in standard refinement. Moreover, the flexible groups in ensemble refinement coincide with groups that give high atomic displacement parameters or non-unity occupancy if optimized in standard refinement. Therefore, the conformational diversity indicated by ensemble refinement seems to be qualitatively correct, indicating that ensemble refinement can be an important complement to standard crystallographic refinement as a tool to discover which parts of crystal structures may show extensive flexibility and therefore are poorly described by a single conformation. However, the diversity of the ensembles is often exaggerated (probably partly owing to the rather poor force field employed) and the ensembles should not be trusted in detail.

Adapting a 2-week-wait colorectal service in the pandemic using the quantitative faecal immunochemical test.

The coronavirus pandemic has brought about an economic and healthcare crisis. This has resulted in delays in virtually all areas of patient care and has forced clinicians to review and adapt their processes, in order to ensure patients continue to have access to timely and effective services. In the author's local Trust, this manifested in altered protocols, developed in order to maintain patient and staff safety while conducting invasive and potentially virus-spreading investigations. A new (temporary) standard operating procedure was developed in conjunction with Cancer Alliance South West to introduce the quantitative faecal immunochemical test (qFIT) as an indicator for diagnostic testing after the majority of diagnostic services were suspended or drastically reduced. Patients would then have their investigation(s) deferred on the basis of a negative result (<10 mcg Hb/g). This cohort (n=120) were revisited once diagnostic services were resumed and referred for CT examination. Audits carried out on the data showed that nine cancers had been identified in the negative qFIT population (lung, prostate, breast, bladder, small bowel carcinoid, oesophageal and three occurrences of caecal carcinoma. This article provides an overview of the experiences and outcomes of a colorectal 2-week-wait service in response to this global pandemic and how this experience will shape the service in the future.

Short-term outcomes of a COVID-adapted triage pathway for colorectal cancer detection.

AIM: The dramatic curtailment of endoscopy and CT colonography capacity during the coronavirus pandemic has adversely impacted timely diagnosis of colorectal cancer (CRC). We describe a rapidly implemented COVID-adapted diagnostic pathway to mitigate risk and maximize cancer diagnosis in patients referred with symptoms of suspected CRC. METHOD: The 'COVID-adapted pathway' integrated multiple quantitative faecal immunochemical tests (qFIT) to enrich for significant colorectal disease with judicious use of CT with oral contrast to detect gross pathology. Patients reporting 'high-risk' symptoms were triaged to qFIT+CT and the remainder underwent an initial qFIT to inform subsequent investigation. Demographic and clinical data were prospectively collected. Outcomes comprised cancer detection frequency. RESULTS: Overall, 422 patients (median age 64 years, 220 women) were triaged using this pathway. Most (84.6%) were referred as 'urgent suspicious of cancer'. Of the 422 patients, 202 (47.9%) were triaged to CT and qFIT, 211 (50.0%) to qFIT only, eight (1.9%) to outpatient clinic and one to colonoscopy. Fifteen (3.6%) declined investigation and seven (1.7%) were deemed unfit. We detected 13 cancers (3.1%), similar to the mean cancer detection rate from all referrals in 2017-2019 (3.3%). Compared with the period 1 April-31 May in 2017-2019, we observed a 43% reduction in all primary care referrals (1071 referrals expected reducing to 609). CONCLUSION: This COVID-adapted pathway mitigated the adverse effects on diagnostic capacity and detected cancer at the expected rate within those referred. However, the overall reduction in the number of referrals was substantial. The described risk-mitigating measures could be a useful adjunct whilst standard diagnostic services remain constrained due to the ongoing pandemic.

New horizons in iron deficiency anaemia in older adults.

Iron deficiency anaemia (IDA) is common in older adults and associated with a range of adverse outcomes. Differentiating iron deficiency from other causes of anaemia is important to ensure appropriate investigations and treatment. It is possible to make the diagnosis reliably using simple blood tests. Clinical evaluation and assessment are required to help determine the underlying cause and to initiate appropriate investigations. IDA in men and post-menopausal females is most commonly due to occult gastrointestinal blood loss until proven otherwise, although there is a spectrum of underlying causative pathologies. Investigation decisions should take account of the wishes of the patient and their competing comorbidities, individualising the approach. Management involves supplementation using oral or intravenous (IV) iron then consideration of treatment of the underlying cause of deficiency. Future research areas are outlined including the role of Hepcidin and serum soluble transferrin receptor measurement, quantitative faecal immunochemical testing, alternative dosing regimens and the potential role of IV iron preparations.

Atomic resolution experimental phase information reveals extensive disorder and bound 2-methyl-2,4-pentanediol in Ca(2+)-calmodulin.

Calmodulin (CaM) is the primary calcium signaling protein in eukaryotes and has been extensively studied using various biophysical techniques. Prior crystal structures have noted the presence of ambiguous electron density in both hydrophobic binding pockets of Ca(2+)-CaM, but no assignment of these features has been made. In addition, Ca(2+)-CaM samples many conformational substates in the crystal and accurately modeling the full range of this functionally important disorder is challenging. In order to characterize these features in a minimally biased manner, a 1.0 Å resolution single-wavelength anomalous diffraction data set was measured for selenomethionine-substituted Ca(2+)-CaM. Density-modified electron-density maps enabled the accurate assignment of Ca(2+)-CaM main-chain and side-chain disorder. These experimental maps also substantiate complex disorder models that were automatically built using low-contour features of model-phased electron density. Furthermore, experimental electron-density maps reveal that 2-methyl-2,4-pentanediol (MPD) is present in the C-terminal domain, mediates a lattice contact between N-terminal domains and may occupy the N-terminal binding pocket. The majority of the crystal structures of target-free Ca(2+)-CaM have been derived from crystals grown using MPD as a precipitant, and thus MPD is likely to be bound in functionally critical regions of Ca(2+)-CaM in most of these structures. The adventitious binding of MPD helps to explain differences between the Ca(2+)-CaM crystal and solution structures and is likely to favor more open conformations of the EF-hands in the crystal.