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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The location of CARD8 within an inflammatory bowel disease (IBD) locus and its role in the NALP3 inflammasome and as a nuclear factor (NF)κB 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 (P1,2/1,1=0.009, odds ratio (OR)=0.66, 95% confidence interval (CI) (0.48–0.90); P1,1/1,2=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-1β. [ABSTRACT FROM AUTHOR]

Genome-wide association studies have identified PHOX2B, FAM92B, IRGM and NCF4 as candidate susceptibility factors for ileal Crohn's disease (CD). Here we sought to determine whether these genes were also associated with ileal CD in New Zealand Caucasians, as well as with ileocolonic CD, colonic CD and ulcerative colitis (UC). A total of 507 CD patients, 475 UC patients and 576 controls were genotyped for the single nucleotide polymorphisms rs16853571 (PHOX2B), rs4821544 (NCF4), rs13361189 and rs4958847 (IRGM), and rs8050910 (FAM92B). NCF4 and IRGM were significantly associated with ileal CD (P-valuers4821544=0.0090, odds ratio (OR)=1.425, 95% confidence interval (CI): 1.092–1.859; P-valuers13361189=0.0017, OR=1.942, 95% CI: 1.274–2.959; P-valuers4958847=0.0022, OR=1.767, 95% CI: 1.224–2.558), but not with other forms of inflammatory bowel disease (IBD). No association of PHOX2B or FAM92B with IBD was detected. Our study has demonstrated that IRGM and NCF4 are ileal-specific CD susceptibility factors in New Zealand Caucasians.Genes and Immunity (2008) 9, 561–565; doi:10.1038/gene.2008.49; published online 26 June 2008 [ABSTRACT FROM AUTHOR]

Around 9% of inflammatory bowel disease (IBD) patients are resistant to azathioprine. We hypothesized that these patients may carry mutations within inosine-5′-monophosphate dehydrogenase (IMPDH). To test this hypothesis, we screened 20 azathioprine-resistant patients for variations in the two IMPDH genes (IMPDH1 and IMPDH2) using dHPLC and DNA sequencing. A 9 bp insertion within the IMPDH1 P3 promoter was found in a patient exhibiting severe azathioprine resistance. The insertion is predicted to abolish a cAMP-response element (CRE) and was found to significantly reduce IMPDH1 P3 promoter activity in a luciferase reporter gene assay (P-value <0.001). This in vitro assay suggests the variant promoter has altered function in vivo and consequently may have contributed to the thiopurine resistance observed in this patient. The absence of functional variants within the other patients indicates that if IMPDH genetic variability contributes to azathioprine resistance it does so infrequently.The Pharmacogenomics Journal (2007) 7, 312–317; doi:10.1038/sj.tpj.6500421; published online 17 October 2006 [ABSTRACT FROM AUTHOR]

OBJECTIVES: In patients who have had major surgery or trauma, early enteral feeding is safer and more effective than parenteral or nasogastric feeding but is frequently associated with diarrhea. Limited recordings have shown that the patterning of duodenal interdigestive motor activity is frequently abnormal after surgery or in patients who are critically ill. The aims of this study were to evaluate the effects of major abdominal surgery on small intestinal motility, and to elucidate the motor patterns that occur postoperatively in critically ill patients in response to enteral feeding. METHODS: The effects of elective aortic aneurysm repair on small intestinal motility were studied in II patients aged 63-77 yr. A 3.5-mm diameter multilumen extrusion was used to monitor pressures at 12 points, distributed between the antrum and KK) cm distal to the pylorus. An additional lumen allowed enteral feeding into the duodenum. Recordings commenced immediately postoperatively and continued for up to 4 days. Data are given as means and SEMs. RESULTS: Bursts (frequency > 10/min) of small intestinal pressure waves that resembled phase III interdigestive motor activity occurred in all patients immediately after surgery. During mechanical ventilation, the timing of bursts along the segment evaluated was frequently abnormal for true interdigestive phase III activity, with simultaneous on-set in multiple channels (46%), multiple or distal origins (8%). or retrograde migration (20%). When patients were not being ventilated, the migration pattern of the bursts was more typical of interdigestive phase III activity. The interval between bursts was unusually short for interdigestive motor activity, although it increased from 30 ± 12 min on day 1 to 41 ± 18 min on day 3 (p < 0.05). A phase 11 pattern of pressure waves was virtually absent in all patients on all study days. In six patients who received postoperative enteral nutrition, the bursts of pressure waves were not abolished by feeding, contrary to normal phase III activity. CONCLUSIONS: Small intestinal pressure wave bursts are seen immediately after elective aortic aneurysm repair, but the migration of these bursts is frequently abnormal for phase III interdigestive activity. Duodenal nutrient delivery did not interrupt the occurrence of these bursts. Persistence of pressure wave bursts in this setting may be important in the delivery of enteral nutrition. [ABSTRACT FROM AUTHOR]