Colorectal cancer risk stratification using a polygenic risk score in symptomatic primary care patients-a UK Biobank retrospective cohort study.

Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide. Accurate cancer risk assessment approaches could increase rates of early CRC diagnosis, improve health outcomes for patients and reduce pressure on diagnostic services. The faecal immunochemical test (FIT) for blood in stool is widely used in primary care to identify symptomatic patients with likely CRC. However, there is a 6-16% noncompliance rate with FIT in clinic and ~90% of patients over the symptomatic 10 µg/g test threshold do not have CRC. A polygenic risk score (PRS) quantifies an individual's genetic risk of a condition based on many common variants. Existing PRS for CRC have so far been used to stratify asymptomatic populations. We conducted a retrospective cohort study of 50,387 UK Biobank participants with a CRC symptom in their primary care record at age 40+. A PRS based on 201 variants, 5 genetic principal components and 22 other risk factors and markers for CRC were assessed for association with CRC diagnosis within 2 years of first symptom presentation using logistic regression. Associated variables were included in an integrated risk model and trained in 80% of the cohort to predict CRC diagnosis within 2 years. An integrated risk model combining PRS, age, sex, and patient-reported symptoms was predictive of CRC development in a testing cohort (receiver operating characteristic area under the curve, ROCAUC: 0.76, 95% confidence interval: 0.71-0.81). This model has the potential to improve early diagnosis of CRC, particularly in cases of patient noncompliance with FIT.

The Clinical Value of Pre-Diagnostic Thrombocytosis for the Detection of Lung Cancer in Primary Care.

Thrombocytosis is a risk marker for lung cancer in primary care. We investigated whether thrombocytosis presents pre-diagnostically for all the histological subtypes of lung cancer and its association with the stage at diagnosis. A matched cohort study used English electronic primary care data linked to the national cancer registry. Patients diagnosed with lung cancer aged ≥40 years with no prior history of malignancy were matched by age, sex, and general practice to five controls without lung cancer. Multivariable logistic regression models quantified the incidence of pre-diagnostic thrombocytosis and advanced-stage diagnoses, adjusting for COPD diagnosis, smoking status, and anti-platelet drug prescriptions. A total of 9504 cases were matched to 45,647 controls, consisting of 3260 (34%) adenocarcinomas (ADC), 2020 (21%) squamous cell carcinomas (SCC), 70 (<1%) large-cell carcinomas (LCC), and 1089 (12%) small-cell lung cancers (SCLC). The patients with lung cancer were 8.9 (95% CI 8.0-9.9) times more likely to exhibit pre-diagnostic thrombocytosis than the controls. The odds ratios were highest for the comparison between SCC and ADC (1.8, 95% CI 1.5-2.1). Thrombocytosis is associated with advanced-stage ADC and SCC but presented equally for early- and advanced-stage SCLC. Pre-diagnostic thrombocytosis may aid in the detection of all the histological subtypes in primary care.

Association between patient ethnicity and prostate cancer diagnosis following a prostate-specific antigen test: a cohort study of 730,000 men in primary care in the UK.

BACKGROUND: Black men have higher prostate-specific antigen (PSA) levels and higher prostate cancer incidence and mortality than White men, while Asian men tend to have lower prostate cancer incidence and mortality than White men. Much of the evidence comes from the USA, and information from UK populations is limited. METHODS: This retrospective cohort study used data on patients registered at general practices in England contributing to the Clinical Practice Research Datalink (CPRD) Aurum dataset. Those eligible were men aged 40 and over with a record of ethnicity and a PSA test result recorded between 2010 and 2017 with no prior cancer diagnosis. The aim was to assess the incidence of prostate cancer following a raised PSA test result in men from different ethnic groups. Additionally, incidence of advanced prostate cancer was investigated. Cancer incidence was estimated from multi-level logistic regression models adjusting for potential confounding factors. RESULTS: 730,515 men with a PSA test were included (88.9% White). Black men and men with mixed ethnicity had higher PSA values, particularly for those aged above 60 years. In the year following a raised PSA result (using age-specific thresholds), Black men had the highest prostate cancer incidence at 24.7% (95% CI 23.3%, 26.2%); Asian men had the lowest at 13.4% (12.2%, 14.7%); incidence for White men was 19.8% (19.4%, 20.2%). The peak incidence of prostate cancer for all groups was in men aged 70-79. Incidence of prostate cancer diagnosed at an advanced stage was similar between Black and White men. CONCLUSIONS: More prostate cancer was diagnosed in Black men with a raised PSA result, but rates of advanced prostate cancer were not higher in this group. In this large primary care-based cohort, the incidence of prostate cancer in men with elevated PSA levels increases with increasing age, even when using age-adjusted thresholds, with Black men significantly more likely to be diagnosed compared to White or Asian men. The incidence of advanced stage prostate cancer at diagnosis was similar for Black and White men with a raised PSA result, but lower for Asian men.

Colorectal cancer in symptomatic patients: How to improve the diagnostic pathway.

Even in countries with national screening programmes for colorectal cancer, most cancers are identified after the patient has developed symptoms. The patients present these symptoms usually to primary care, or in some countries to specialist care. In either healthcare setting, the clinician has to consider cancer to be a possibility, then to perform triage investigations, followed by definitive investigation, usually by colonoscopy. This apparently simple pathway is not simple: most symptoms of colorectal cancer are more likely to represent benign disease than cancer, and each of these stages represents selection of patients into a higher-risk pool. This article summarises a symptom-based approach to selection and initial investigation of such patients in primary care. Some special groups need particular attention, including the younger patient, those with an inherited predisposition to cancer, and those with co-morbidities.

Applying a genetic risk score for prostate cancer to men with lower urinary tract symptoms in primary care to predict prostate cancer diagnosis: a cohort study in the UK Biobank.

BACKGROUND: Prostate cancer is highly heritable, with >250 common variants associated in genome-wide association studies. It commonly presents with non-specific lower urinary tract symptoms that are frequently associated with benign conditions. METHODS: Cohort study using UK Biobank data linked to primary care records. Participants were men with a record showing a general practice consultation for a lower urinary tract symptom. The outcome measure was prostate cancer diagnosis within 2 years of consultation. The predictor was a genetic risk score of 269 genetic variants for prostate cancer. RESULTS: A genetic risk score (GRS) is associated with prostate cancer in symptomatic men (OR per SD increase = 2.12 [1.86-2.41] P = 3.5e-30). An integrated risk model including age and GRS applied to symptomatic men predicted prostate cancer (AUC 0.768 [0.739-0.796]). Prostate cancer incidence was 8.1% (6.7-9.7) in the highest risk quintile. In the lowest quintile, prostate cancer incidence was <1%. CONCLUSIONS: This study is the first to apply GRS in primary care to improve the triage of symptomatic patients. Men with the lowest genetic risk of developing prostate cancer could safely avoid invasive investigation, whilst those identified with the greatest risk could be fast-tracked for further investigation. These results show that a GRS has potential application to improve the diagnostic pathway of symptomatic patients in primary care.

Diagnostic performance of a faecal immunochemical test for patients with low-risk symptoms of colorectal cancer in primary care: an evaluation in the South West of England.

BACKGROUND: The faecal immunochemical test (FIT) was introduced to triage patients with low-risk symptoms of possible colorectal cancer in English primary care in 2017, underpinned by little primary care evidence. METHODS: All healthcare providers in the South West of England (population 4 million) participated in this evaluation. 3890 patients aged ≥50 years presenting in primary care with low-risk symptoms of colorectal cancer had a FIT from 01/06/2018 to 31/12/2018. A threshold of 10 µg Hb/g faeces defined a positive test. RESULTS: Six hundred and eighteen (15.9%) patients tested positive; 458 (74.1%) had an urgent referral to specialist lower gastrointestinal (GI) services within three months. Forty-three were diagnosed with colorectal cancer within 12 months. 3272 tested negative; 324 (9.9%) had an urgent referral within three months. Eight were diagnosed with colorectal cancer within 12 months. Positive predictive value was 7.0% (95% CI 5.1-9.3%). Negative predictive value was 99.8% (CI 99.5-99.9%). Sensitivity was 84.3% (CI 71.4-93.0%), specificity 85.0% (CI 83.8-86.1%). The area under the ROC curve was 0.92 (CI 0.86-0.96). A threshold of 37 µg Hb/g faeces would identify patients with an individual 3% risk of cancer. CONCLUSIONS: FIT performs exceptionally well to triage patients with low-risk symptoms of colorectal cancer in primary care; a higher threshold may be appropriate in the wake of the COVID-19 crisis.

The association between thrombocytosis and subtype of lung cancer: a systematic review and meta-analysis.

BACKGROUND: Thrombocytosis is associated with poor lung cancer prognosis and has recently been identified as having a high positive predictive value in lung cancer detection. Lung cancer has multiple histological and genetic subtypes and it is not known whether platelet levels differ across these subtypes, or whether thrombocytosis is predictive of a particular subtype. METHODS: PubMed and Embase were systematically searched for studies that reported pre-treatment platelet count, as either averages or proportion of patients with thrombocytosis, by subtype of lung cancer using a pre-specified search strategy. The Newcastle-Ottowa scale was used to assess study quality and risk of bias. Suitable studies were synthesised in meta-analyses and subgroup analyses examined for differences across subtypes. RESULTS: The prevalence of pre-treatment thrombocytosis across all lung cancer patients was 27% (95% CI: 17% to 37%). By subtype, this was 22% (95% CI: 7% to 41%) for adenocarcinoma, 28% (95% CI: 15% to 43%) for squamous cell carcinoma (SCC), 36% (95% CI: 13% to 62%) for large cell carcinoma (LCC), and 30% (95% CI: 8% to 58%) for small cell lung cancer (SCLC). The pooled mean platelet count for lung cancer patients was 289×109/L (95% CI: 268 to 311). By subtype, this was 282×109/L (95% CI: 259 to 306) for adenocarcinoma, 297×109/L (95% CI: 238 to 356) for SCC, 290×109/L (95% CI: 176 to 404) for LCC, and 293×109/L (95% CI: 244 to 342) for SCLC. There was no difference in thrombocytosis prevalence (P=0.76) or mean platelet count (P=0.96) across the subtypes. CONCLUSIONS: These findings suggest thrombocytosis is no more indicative of one lung cancer subtype over another. We therefore conclude a high platelet count is likely to be generic across all lung cancer subtypes.

Faecal immunochemical test to triage patients with abdominal symptoms for suspected colorectal cancer in primary care: review of international use and guidelines.

BACKGROUND: Recently, faecal immunochemical tests (FITs) have been introduced for investigation of primary care patients with low-risk symptoms of colorectal cancer (CRC), but recommendations vary across the world. This systematic review of clinical practice guidelines aimed to determine how FITs are used in symptomatic primary care patients and the underpinning evidence for these guidelines. METHODS: MEDLINE, Embase and TRIP databases were systematically searched, from 1 November 2008 to 1 November 2018 for guidelines on the assessment of patients with symptoms suggestive of CRC. Known guideline databases, websites and references of related literature were searched. The following questions were addressed: (i) which countries use FIT for symptomatic primary care patients; (ii) in which populations is FIT used; (iii) what is the cut-off level used for haemoglobin in the faeces (FIT) and (iv) on what evidence are FIT recommendations based. RESULTS: The search yielded 2433 publications; 25 covered initial diagnostic assessment of patients with symptoms of CRC in 15 countries (Asia, n = 1; Europe, n = 13; Oceania, n = 4; North America, n = 5; and South America, n = 2). In three countries (Australia, Spain and the UK), FIT was recommended for patients with abdominal symptoms, unexplained weight loss, change in bowel habit or anaemia despite a low level of evidence in the symptomatic primary care patient population. CONCLUSIONS: Few countries recommend FITs in symptomatic patients in primary care either because of limited evidence or because symptomatic patients are directly referred to secondary care without triage. These results demonstrate a clear need for research on FIT in the symptomatic primary care population.

Cancer incidence in patients with a high normal platelet count: a cohort study using primary care data.

Background: A platelet count >400 × 109/l (i.e. thrombocytosis) is a recently discovered risk marker of cancer. The risk of undiagnosed cancer in patients with thrombocytosis is 11.6% for men and 6.2% for women, well above the 3% risk threshold set by National Institute for Health and Care Excellence (NICE) for cancer investigation. Patients with a platelet count at the upper end of the normal range (325-400 × 109/l) could be at increased risk of undiagnosed malignancy. Objective: To quantify the risk of an undiagnosed cancer in patients with a platelet count at the upper end of the normal range. Methods: A primary care-based cohort study using Clinical Practice Research Datalink (CPRD) data from 2000 to 2013. The study sample comprised 2704 individuals stratified by platelet count: 325-349 × 109/l; 350-374 × 109/l; 375-399 × 109/l. Incident cancer diagnoses in the year following that platelet count were obtained from patient records. Results: Cancer incidence rose with increasing platelet count: 2.6% [95% confidence interval (CI) 1.9 to 3.6] in subjects with a count of 325-349 × 109/l, 3.7% (95% CI 2.5 to 5.3) in subjects with a count of 350-374 × 109/l and 5.1% (95% CI 3.4 to 7.5) in those with a count of 375-399 × 109/l. Colorectal cancer was most commonly diagnosed in all three groups. Cancer incidence was consistently higher in males than in females. Conclusion: These results suggest that clinicians should consider cancer in patients with a platelet count >375 × 109/l, review reasons for testing and any additional reported symptoms. Until these results are replicated on a larger scale, recommendations for clinical action cannot be made.

How useful is thrombocytosis in predicting an underlying cancer in primary care? a systematic review.

BACKGROUND: Although the association between raised platelet count (thrombocytosis) and cancer has been reported in primary and secondary care studies, UK GPs are unaware of it, and it is insufficiently evidenced for laboratories to identify and warn of it. This systematic review aimed to identify and collate evidence from studies that have investigated thrombocytosis as an early marker of cancer in primary care. METHODS: EMBASE (OvidSP), Medline (Ovid), Web of Science and The Cochrane Library were searched for relevant studies. Eligible studies had reported estimates of the association between thrombocytosis and cancer, in adults aged ≥40 in a primary care setting. Raw data from included studies were used to calculate positive predictive values and likelihood ratios (LRs) for cancer. RESULTS: Nine case-control studies were identified. Study quality was judged to be high. Included studies reported on the following cancer sites: colorectal, lung, ovary, bladder, kidney, pancreas, oesophago-gastric, uterus and breast. LRs indicated that thrombocytosis was a predictor of cancer in all sites except breast. In a consulting population, thrombocytosis is most highly predictive of lung and colorectal cancer. CONCLUSIONS: These results suggest that patients with thrombocytosis in primary care have an increased risk of cancer, and that some, but not all, cancers have raised platelets as an early marker. This finding is expected to be of use in primary care, for GPs receiving blood test results unexpectedly showing high platelet counts. Further research is needed to identify the cancers that are most strongly associated with thrombocytosis.

Allergy education in otolaryngology residency: a survey of program directors and residents.

BACKGROUND: The purpose of this study was to survey program directors of the accredited otolaryngology residency programs and resident attendees of the 2013 American Academy of Otolaryngic Allergy (AAOA) Basic/MOC Course regarding resident education and participation as well as assessment of competency in otolaryngic allergy and immunotherapy. METHODS: A multiple-choice questionnaire was sent to all accredited otolaryngology residency training programs in the United States as part of resident attendance at the 2013 AAOA CORE Basic/MOC Course. Following this, a similar multiple-choice survey was sent to all resident attendees from the programs that responded positively. RESULTS: Program directors reported that 73% of their academic institutions offer allergy testing and immunotherapy. More PDs than residents indicated that residents participate in allergy practice and perform/interpret skin testing and in vitro testing, and more residents (85%) than program directors (63%) reported inadequate or no allergy training. Program directors and residents equally indicated that residents do not calculate immunotherapy vial formulations or administer immunotherapy injections. The majority of program directors indicated that resident competency in allergy was assessed through direct observation, whereas residents more commonly perceived that no assessment of competency was being performed for any portion of allergy practice. CONCLUSION: This survey demonstrates a discrepancy between program directors and residents regarding resident involvement and adequacy of training in the allergy practice. Although the majority of otolaryngology residencies report offering otolaryngic allergy services and education, the vast majority of residents report inadequate allergy training and less participation in an allergy practice compared to the majority of program directors.

HCV NS5B polymerase inhibitors 2: Synthesis and in vitro activity of (1,1-dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives.

(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives have been investigated as potential anti-HCV drugs. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.

Successful cryopreservation of mouse oocytes by using low concentrations of trehalose and dimethylsulfoxide.

Sugars such as trehalose, sucrose, and glucose are effectively used by a variety of animals (e.g., brine shrimp, tardigrades, some frogs, and insects), as well as by bacteria, yeasts, and plant seeds to survive freezing and extreme drying. The objective of this study was to examine the potential application of sugars to mammalian oocyte cryopreservation. To this end, we used trehalose, a nonreducing disaccharide, and mouse metaphase II oocytes as models. Our experiments show that extracellular trehalose alone affords some protection at high subzero temperatures (e.g., -15 degrees C), which diminishes with further cooling of the oocytes to -30 degrees C and below. When present both intracellularly and extracellularly, trehalose dramatically improves the cryosurvival with increasing extracellular concentrations to 0.5 M, even after cooling to -196 degrees C. Furthermore, the combination of intracellular and extracellular trehalose with small amounts of a conventional penetrating cryoprotectant (i.e., 0.5 M dimethylsulfoxide) provide high survival, fertilization, and embryonic development rates statistically similar to untreated controls. When transferred to foster mothers, cryopreserved oocytes give rise to healthy offspring showing the proof of principle. Our experiments with differential scanning calorimetry indicate that when cooled using the same cryopreservation protocol, the mixture of 0.5 M trehalose and cryopreservation medium undergoes glass transition at high subzero temperatures, which further substantiates the use of sugars as intracellular and extracellular cryoprotectants. Taken together, our results are in agreement with the survival schemes in nature and demonstrate the successful use of sugars in cryopreservation of mammalian oocytes.