The presenting symptom signatures of incident cancer: evidence from the English 2018 National Cancer Diagnosis Audit.

BACKGROUND: Understanding relationships between presenting symptoms and subsequently diagnosed cancers can inform symptom awareness campaigns and investigation strategies. METHODS: We used English National Cancer Diagnosis Audit 2018 data for 55,122 newly diagnosed patients, and examined the relative frequency of presenting symptoms by cancer site, and of cancer sites by presenting symptom. RESULTS: Among 38 cancer sites (16 cancer groups), three classes were apparent: cancers with a dominant single presenting symptom (e.g. melanoma); cancers with diverse presenting symptoms (e.g. pancreatic); and cancers that are often asymptomatically detected (e.g. chronic lymphocytic leukaemia). Among 83 symptoms (13 symptom groups), two classes were apparent: symptoms chiefly relating to cancers of the same body system (e.g. certain respiratory symptoms mostly relating to respiratory cancers); and symptoms with a diverse cancer site case-mix (e.g. fatigue). The cancer site case-mix of certain symptoms varied by sex. CONCLUSION: We detailed associations between presenting symptoms and cancer sites in a large, representative population-based sample of cancer patients. The findings can guide choice of symptoms for inclusion in awareness campaigns, and diagnostic investigation strategies post-presentation when cancer is suspected. They can inform the updating of clinical practice recommendations for specialist referral encompassing a broader range of cancer sites per symptom.

Stage-specific risk of colon and rectal cancer in patients presenting with rectal bleeding or change in bowel habit in primary care: A population-based cohort study.

INTRODUCTION: Rectal bleeding and change in bowel habit are red-flag symptoms for colon and rectal cancer but how they relate to advanced stage disease is not adequately understood. METHODS: We analysed primary care electronic health records data on patients aged 30-99 years. Using logistic regression, we first examined the risk of colon and rectal cancer within 12 months in patients presenting with change in bowel habit and rectal bleeding, and then the risk of advanced stage at diagnosis within cancer cases. We combined the results to estimate risk of advanced stage colon and rectal cancers at diagnosis. RESULTS: For both symptoms and sexes, risk of cancer (overall and by stage) increased with increasing age. We illustrate the findings for persons at the highest age-specific observed risk (typically aged around 80). In men, change in bowel habit (CIBH) and rectal bleeding were associated with different risk of advanced stage colon and rectal cancers (e.g., for colon, CIBH = 2.7% (95% CI 2.2-3.1) and rectal bleeding = 1.7% (95% CI 1.4-2.0)), but without evidence of risk difference between the two symptoms for non-advanced disease. The opposite pattern was apparent in women, with both symptoms associated with similar risk of advanced disease, but different risk of non-advanced colon and rectal cancers (e.g., for colon, CIBH = 1.0% (95% CI 0.8-1.3) and rectal bleeding = 1.3% (95% CI 1.1-1.6)). DISCUSSION: Change in bowel habit and rectal bleeding have different age-specific associations with advanced stage disease, which vary by sex. A substantial proportion of cases is diagnosed at non-advanced stage, supporting the need for prompt diagnostic assessment of patients who present with those symptoms, taking into account the age-specific nature of risks.

High-sensitivity electronic Stark spectrometer featuring a laser-driven light source.

We report developmental details of a high-sensitivity Stark absorption spectrometer featuring a laser-driven light source. The light source exhibits intensity fluctuations of ∼0.3% over timescales ranging from 1 min to 12 h, minimal drift (≤0.1%/h), and very little 1/f noise at frequencies greater than 200 Hz, which are comparable to or better than an arc-driven light source. Additional features of the spectrometer include balanced detection with multiplex sampling, which yielded lower noise in A, and constant wavelength or wavenumber (energy) spectral bandpass modes. We achieve noise amplitudes of ∼7 × 10-4 and ∼6 × 10-6 in measurements of single A and ΔA spectra (with 92 data points) taking ∼7 and ∼19 min, respectively.

Socio-demographic variation in stage at diagnosis of breast, bladder, colon, endometrial, lung, melanoma, prostate, rectal, renal and ovarian cancer in England and its population impact.

BACKGROUND: Stage at diagnosis strongly predicts cancer survival and understanding related inequalities could guide interventions. METHODS: We analysed incident cases diagnosed with 10 solid tumours included in the UK government target of 75% of patients diagnosed in TNM stage I/II by 2028. We examined socio-demographic differences in diagnosis at stage III/IV vs. I/II. Multiple imputation was used for missing stage at diagnosis (9% of tumours). RESULTS: Of the 202,001 cases, 57% were diagnosed in stage I/II (an absolute 18% 'gap' from the 75% target). The likelihood of diagnosis at stage III/IV increased in older age, though variably by cancer site, being strongest for prostate and endometrial cancer. Increasing level of deprivation was associated with advanced stage at diagnosis for all sites except lung and renal cancer. There were, inconsistent in direction, sex inequalities for four cancers. Eliminating socio-demographic inequalities would translate to 61% of patients with the 10 studied cancers being diagnosed at stage I/II, reducing the gap from target to 14%. CONCLUSIONS: Potential elimination of socio-demographic inequalities in stage at diagnosis would make a substantial, though partial, contribution to achieving stage shift targets. Earlier diagnosis strategies should additionally focus on the whole population and not only the high-risk socio-demographic groups.

Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study).

BACKGROUND: Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation. AIMS: To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol. DESIGN: In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x108 RBCs. The primary endpoint was steroid-free clinical remission at 24 weeks. RESULTS: Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03). CONCLUSIONS: Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity.

Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases.

BACKGROUND: Therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients receiving anti-tumour necrosis factor (TNF) agents can help optimise outcomes. Consensus statements based on current evidence will help the development of treatment guidelines. AIM: To develop evidence-based consensus statements for TDM-guided anti-TNF therapy in IBD. METHODS: A committee of 25 Australian and international experts was assembled. The initial draft statements were produced following a systematic literature search. A modified Delphi technique was used with 3 iterations. Statements were modified according to anonymous voting and feedback at each iteration. Statements with 80% agreement without or with minor reservation were accepted. RESULTS: 22/24 statements met criteria for consensus. For anti-TNF agents, TDM should be performed upon treatment failure, following successful induction, when contemplating a drug holiday and periodically in clinical remission only when results would change management. To achieve clinical remission in luminal IBD, infliximab and adalimumab trough concentrations in the range of 3-8 and 5-12 µg/mL, respectively, were deemed appropriate. The range may differ for different disease phenotypes or treatment endpoints-such as fistulising disease or to achieve mucosal healing. In treatment failure, TDM may identify mechanisms to guide subsequent decision-making. In stable clinical response, TDM-guided dosing may avoid future relapse. Data indicate drug-tolerant anti-drug antibody assays do not offer an advantage over drug-sensitive assays. Further data are required prior to recommending TDM for non-anti-TNF biological agents. CONCLUSION: Consensus statements support the role of TDM in optimising anti-TNF agents to treat IBD, especially in situations of treatment failure.

Reduced sensory stimulation alters the molecular make-up of glutamatergic hair cell synapses in the developing cochlea.

Neural activity during early development is known to alter innervation pathways in the central and peripheral nervous systems. We sought to examine how reduced sound-induced sensory activity in the cochlea affected the consolidation of glutamatergic synapses between inner hair cells (IHC) and the primary auditory neurons as these synapses play a primary role in transmitting sound information to the brain. A unilateral conductive hearing loss was induced prior to the onset of sound-mediated stimulation of the sensory hair cells, by rupturing the tympanic membrane and dislocating the auditory ossicles in the left ear of P11 mice. Auditory brainstem responses at P15 and P21 showed a 40-50-dB increase in thresholds for frequencies 8-32kHz in the dislocated ear relative to the control ear. Immunohistochemistry and confocal microscopy were subsequently used to examine the effect of this attenuation of sound stimulation on the expression of RIBEYE, which comprises the presynaptic ribbons, Shank-1, a postsynaptic scaffolding protein, and the GluA2/3 and 4 subunits of postsynaptic AMPA receptors. Our results show that dislocation did not alter the number of pre- or postsynaptic protein puncta. However, dislocation did increase the size of RIBEYE, GluA4, GluA2/3 and Shank-1 puncta, with postsynaptic changes preceding presynaptic changes. Our data suggest that a reduction in sound stimulation during auditory development induces plasticity in the molecular make-up of IHC glutamatergic synapses, but does not affect the number of these synapses. Up-regulation of synaptic proteins with sound attenuation may facilitate a compensatory increase in synaptic transmission due to the reduced sensory stimulation of the IHC.

Exome sequencing and array-based comparative genomic hybridisation analysis of preferential 6-methylmercaptopurine producers.

Preferential conversion of azathioprine or 6-mercaptopurine into methylated metabolites is a major cause of thiopurine resistance. To seek potentially Mendelian causes of thiopurine hypermethylation, we recruited 12 individuals who exhibited extreme therapeutic resistance while taking azathioprine or 6-mercaptopurine and performed whole-exome sequencing (WES) and copy-number variant analysis by array-based comparative genomic hybridisation (aCGH). Exome-wide variant filtering highlighted four genes potentially associated with thiopurine metabolism (ENOSF1 and NFS1), transport (SLC17A4) or therapeutic action (RCC2). However, variants of each gene were found only in two or three patients, and it is unclear whether these genes could influence thiopurine hypermethylation. Analysis by aCGH did not identify any unusual or pathogenic copy-number variants. This suggests that if causative mutations for the hypermethylation phenotype exist they may be heterogeneous, occurring in several different genes, or they may lie within regulatory regions not captured by WES. Alternatively, hypermethylation may arise from the involvement of multiple genes with small effects. To test this hypothesis would require recruitment of large patient samples and application of genome-wide association studies.

Dosing of dabigatran etexilate in relation to renal function and drug interactions at a tertiary hospital.

BACKGROUND: Plasma concentrations of the anticoagulant dabigatran are correlated with clinical outcomes, and are affected by renal function, intestinal P-glycoprotein (P-gp) activity and stomach acidity. AIMS: To determine the adherence to dabigatran etexilate renal dosing guidelines, the frequency of co-prescription of potentially interacting drugs in patients on dabigatran, and how these related to dabigatran dosing. METHODS: A retrospective chart review of 204 patients discharged from a tertiary hospital on dabigatran etexilate over a 12-month period. Creatinine clearance, using the Cockcroft-Gault equation, was used as the surrogate of renal function in the 86 patients where this was calculable. RESULTS: Prescribed dabigatran etexilate dose rates in relation to creatinine clearance and the manufacturer's guidelines were classified as 'standard', 'low' and 'high' in 47% (40/86), 49% (42/86) and 5% (4/86) of patients respectively. Co-prescribed drugs that potentially interact with dabigatran etexilate were present in 75% (154/204) of patients and included strong P-gp inhibitors (16%, 32/204), proton-pump inhibitors (46%, 94/204) and anti-platelet drugs (47%, 95/204). Co-prescription of strong P-gp inhibitors was associated with the prescription of 'low' dose rates relative to renal function (P = 0.025). CONCLUSIONS: Few patients were dosed excessively in relation to creatinine clearance. Around 50% was prescribed with 'low' dose rates in relation to creatinine clearance, which because of the association with co-prescription of strong P-gp inhibitors may be clinically appropriate. Most patients were co-prescribed with drugs that potentially interact with dabigatran etexilate.

High TPMT enzyme activity does not explain drug resistance due to preferential 6-methylmercaptopurine production in patients on thiopurine treatment.

BACKGROUND: Up to 20% of patients on thiopurine therapy fail to achieve adequate drug response. Many of these patients preferentially produce the toxic 6-methylmercaptopurine metabolites (6-MMP) rather than the active 6-thioguanine nucleotides (6-TGN) resulting in a high 6-MMP/6-TGN ratio (>20) and increased risk of hepatotoxicity. AIM: To determine the prevalence of preferential 6-MMP producers and define the relationships between 6-TGN, 6-MMP and thiopurine methyltransferase (TPMT). METHODS: The database of 6-TGN, 6-MMP and TPMT measurements from patients throughout New Zealand was used to calculate patients' 6-MMP/6-TGN ratios and identify those with high (>20) or normal ratio (≤20).The TPMT enzyme activity was compared amongst the groups. RESULTS: Of 1879 patients with TPMT, 6-TGN and 6-MMP results, 349 (19%) had a 6-MMP/6-TGN ratio >20. The mean TPMT enzyme activity was slightly lower for those with a 6-MMP/6-TGN ratio ≤20 vs. >20, which achieved statistical significance (12.2 vs. 13.2; P < 0.001). However, the distributions of TPMT enzyme activity were similar, with 97% of TPMT results falling between 5.0 and 17.6 IU/mL for both groups. In all, 17% of those with 6-MMP/6-TGN ratio ≤20 were intermediate TPMT metabolisers (TPMT 5.0-9.2 IU/mL) vs. 7% in those with a ratio >20. CONCLUSIONS: In this patient population with measured 6-MMP/6-TGN ratios, 19% of patients were preferential 6-MMP producers. The results show that high TPMT enzyme activity is not the major reason for preferential 6-MMP production in most patients with a high metabolite ratio. This suggests that there are one or more important alternative mechanisms for preferentially producing 6-MMP.

Clinical and genetic risk factors for perianal Crohn's disease in a population-based cohort.

OBJECTIVES: Perianal Crohn's disease (CD) affects around one-quarter of CD patients and represents a distinct disease phenotype. The objective of this study was to investigate a large population-based cohort of inflammatory bowel disease (IBD) patients to identify clinical and genetic risk factors for perianal CD. METHODS: Data were collected in the Canterbury IBD database, estimated to include 91% of all patients with IBD in Canterbury, New Zealand. Genotyping was performed for selected loci previously demonstrated to be associated with CD. Patients with perianal disease were then compared with both CD patients without perianal disease and healthy controls to assess the presence of potential phenotypic, environmental, and genetic risk factors. RESULTS: Of the 715 CD patients in the database, 190 (26.5%) had perianal disease. In all, 507 patients with genotype data available were analyzed. Perianal disease was associated with younger age at diagnosis (P < 0.0001), complicated intestinal disease (P < 0.0001), and ileal disease location (P = 0.002). There was no association with gender, ethnicity, smoking, or breast feeding. Genotype analysis revealed an association with the neutrophil cytosolic factor 4 (NCF4) gene compared with both non-perianal CD patients (odds ratio (OR): 1.47; 95% confidence interval (CI): 1.08-1.99) and healthy controls (OR: 1.47; 95% CI: 1.10-1.95). There was no association identified with other genes, including IBD5 (OR: 0.91; 95% CI: 0.69-1.20), tumor necrosis factor α (OR: 1.04; 95% CI: 0.56-1.85), and IRGM (immunity-related guanosine triphosphatase protein type M) (OR: 1.21; 95% CI: 0.80-1.82). CONCLUSIONS: This study suggests that younger age at diagnosis, complicated disease behavior, and ileal disease location are risk factors for perianal CD. In addition, this paper represents the first report of an association of the NCF4 gene with perianal disease.

Relationship between serum urate and plasma oxypurinol in the management of gout: determination of minimum plasma oxypurinol concentration to achieve a target serum urate level.

The treatment of gout requires a lowering of serum urate (SU) levels, and allopurinol is the drug that is most commonly used for this purpose. The objectives of this study were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other and to determine the minimum plasma oxypurinol concentration that would result in a target level of <6 mg/dl (0.36 mmol/l) of SU. For this purpose, 82 patients who had been receiving allopurinol for at least 1 month were recruited. Patients with SU <6 mg/dl were followed up quarterly for 12 months. In patients with SU ≥6 mg/dl, the dose of allopurinol was increased to bring the level of SU to <6 mg/dl. These patients were followed up once a month until the SU level remained at <6 mg/dl for 3 consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured 6-9 hours after administration of the allopurinol dose. There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P = 0.002), between allopurinol dose and SU (P < 0.0001) and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6 mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100 µmol/l (15.2 mg/l). Increasing the allopurinol dose resulted in increased plasma oxypurinol and reduced SU concentrations. Plasma oxypurinol concentrations >100 µmol/l were required to achieve SU <6 mg/dl.

Ileal disease is associated with surgery for perianal disease in a population-based Crohn's disease cohort.

BACKGROUND: The aim of this study was describe the frequency and characteristics of perianal surgical intervention (PSI) for Crohn's disease in a population-based cohort of patients with inflammatory bowel disease (IBD). METHODS: A total of 1421 patients with IBD were recruited, representing approximately 91 per cent of people with IBD in Canterbury, New Zealand. The clinical notes were screened to confirm the diagnosis and extract clinical data, including details of PSIs. RESULTS: Some 649 patients with Crohn's disease were included in the analysis, of whom 119 (18.3 per cent) had at least one PSI. Of these, 61 (51.3 per cent) required further procedures. Operations for perianal abscess and fistula accounted for 72.4 per cent of interventions. PSI rates did not differ between the sexes (P = 0.218). Age less than 17 years (adjusted odds ratio (OR) 1.89 (95 per cent confidence interval 1.08 to 3.28)) and ileal disease (OR 1.76 (1.06 to 2.92)) were identified as predictors of PSI. As disease duration increased, so did the proportion of patients with complicated intestinal disease among those who had undergone PSI. The median time to first PSI from diagnosis of Crohn's disease was 28 (interquartile range 7-82) months. Sex, age at diagnosis and disease location did not influence the time to first PSI. CONCLUSION: PSIs are frequent in patients with Crohn's disease, particularly those with ileal disease and those diagnosed at a young age.

Evidence that glioma-associated oncogene homolog 1 is not a universal risk gene for inflammatory bowel disease in Caucasians.

The transcription factor glioma-associated oncogene homolog 1 (GLI1) has a central function in gastrointestinal tract development and homeostasis. A non-synonymous single-nucleotide polymorphism (SNP) (rs2228226; Q1100E) in GLI1, which impairs GLI1 function in vitro, has been proposed as a risk factor for inflammatory bowel disease (IBD). In this study, we assessed the cumulative evidence for association of GLI1 with IBD. New genotype data for rs2228226 from New Zealand (907 controls, 990 IBD patients) and Belgian Caucasian case-control data sets (312 controls, 1214 IBD patients) were combined with data from the National Institute of Diabetes and Digestive and Kidney Diseases and three previously studied Caucasian case-control data sets. Meta-analysis of rs2228226 did not detect any association with ulcerative colitis (UC) (P=0.09, odds ratio (OR)=1.07, 95% confidence interval (CI)=0.92-1.24), Crohn's disease (CD) (P=0.29, OR=1.06, 95% CI=0.93-1.21) or overall IBD (P=0.15, OR=1.05, 95% CI=0.92-1.19). Our analyses of rs2228226 suggest that GLI1 is not a significant risk factor for IBD in Caucasians.

Evidence of interaction of CARD8 rs2043211 with NALP3 rs35829419 in Crohn's disease.

The location of CARD8 within an inflammatory bowel disease (IBD) locus and its role in the NALP3 inflammasome and as a nuclear factor (NF)kappaB inhibitor make it an attractive candidate risk gene for IBD. However, studies testing for the association of the CARD8 loss-of-function single-nucleotide polymorphism (SNP) rs2043211 with IBD have yielded mixed results. A recent study provided evidence that this discordance may result from an interaction of rs2043211 with loss-of-function variants in nucleotide-binding oligomerization domain protein 2 (NOD2) and a gain-of-function SNP (rs35829419) in NALP3. To confirm this interaction, we conducted a replication in an independent IBD sample set (n=1009 patients, n=517 controls). We found that the presence of the minor allele of rs2043211 with the major allele of rs35829419 conferred a protective effect against Crohn's disease (and vice versa), which intensified in the absence of NOD2 mutations (P(1,2/1,1)=0.009, odds ratio (OR)=0.66, 95% confidence interval (CI) (0.48-0.90); P(1,1/1,2)=0.015, OR=0.35, 95% CI (0.15-0.82)). We propose that these genotype combinations protect against gut inflammation by preventing the NALP3 inflammasome from producing excessive interleukin-1beta.