Patients with perianal Crohn's fistulas experience delays in accessing anti-TNF therapy due to slow recognition, diagnosis and integration of specialist services: lessons learned from three referral centres.

AIM: Crohn's anal fistula should be managed by a multidisciplinary team. There is no clearly defined 'patient pathway' from presentation to treatment. The aim of this study was to describe the patient route from presentation with symptomatic Crohn's anal fistula to starting anti-tumour necrosis factor (anti-TNF) therapy. METHOD: Case note review was undertaken at three hospitals with established inflammatory bowel disease services. Patients with Crohn's anal fistula presenting between 2010 and 2015 were identified through clinical coding and local databases. Baseline demographics were captured. Patient records were interrogated to identify route of access, and clinical contacts during the patient pathway. RESULTS: Seventy-nine patients were included in the study, of whom 54 (68%) had an established diagnosis of Crohn's disease (CD). Median time from presentation to anti-TNF therapy was 204 days (174 vs 365 days for existing and new diagnosis of CD, respectively; P = 0.019). The mean number of surgical outpatient attendances, operations and MRI scans per patient was 1.03, 1.71 and 1.03, respectively. Patients attended a mean of 1.49 medical clinics. Seton insertion was the most common procedure, accounting for 48.6% of all operations. Where care episodes ('clinical events per 30 days') were infrequent this correlated with prolongation of the pathway (r = -0.87; P < 0.01). CONCLUSION: This study highlights two key challenges in the treatment pathway: (i) delays in diagnosis of underlying CD in patients with anal fistula and (ii) the pathway to anti-TNF therapy is long, suggesting issues with service design and delivery. These should be addressed to improve patient experience and outcome

Rectal cancer management during the COVID-19 pandemic (ReCaP): multicentre prospective observational study.

Concerns over unacceptable high mortality in patients with rectal cancer undergoing surgery or systemic therapy who contract COVID-19 have led to widespread adoption of alternative treatment strategies.The ReCaP study aimed to study these variations and associated outcomes

Severity of Dementia and Survival in Patients Diagnosed with Colorectal Cancer: A National Cohort Study in England and Wales

AIMS: There is little evidence about the survival of patients with colorectal cancer (CRC) also diagnosed with dementia. We quantified dementia severity and estimated how it is associated with 2-year overall survival. MATERIALS AND METHODS: Records of patients aged 65 years or older diagnosed with CRC in England and Wales were identified. A novel proxy for dementia severity combined dementia diagnosis in administrative hospital data with Eastern Cooperative Oncology Group performance status. Cox regression was used to estimate hazard ratios with and without risk adjustment. RESULTS: In total, 4033 of 105 250 CRC patients (3.8%) had dementia recorded. Two-year survival decreased with increasing dementia severity from 65.4% without dementia, 53.5% with mild dementia, 33.0% with moderate dementia to 16.5% with severe dementia (hazard ratio comparing severe with no dementia: 2.97; 95% confidence interval 2.79, 3.16). Risk adjustment for comorbidity and cancer stage reduced this association slightly (hazard ratio 2.52; 95% confidence interval 2.37, 2.68) and additional adjustment for treatment factors reduced it further (hazard ratio 1.60; 95% confidence interval 1.50, 1.70). CONCLUSIONS: Survival of CRC patients varied strongly according to dementia severity, suggesting that a 'one-size-fits-all' policy for the care of CRC patients with dementia is not appropriate. Comprehensive assessment of cancer patients with dementia that considers dementia severity is essential in a shared decision-making process that ensures patients receive the most appropriate treatment for their individual needs and preferences

Malnutrition, nutritional interventions and clinical outcomes of patients with acute small bowel obstruction: results from a national, multicentre, prospective audit.

OBJECTIVE: The aim of this study was to assess the nutritional status of patients presenting with small bowel obstruction (SBO), along with associated nutritional interventions and clinical outcomes. DESIGN: Prospective cohort study. SETTING: 131 UK hospitals with acute surgical services. PARTICIPANTS: 2069 adult patients with a diagnosis of SBO were included in this study. The mean age was 67.0 years and 54.7% were female. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was in-hospital mortality. Secondary outcomes recorded included: major complications (composite of in-hospital mortality, reoperation, unplanned intensive care admission and 30-day readmission), complications arising from surgery (anastomotic leak, wound dehiscence), infection (pneumonia, surgical site infection, intra-abdominal infection, urinary tract infection, venous catheter infection), cardiac complications, venous thromboembolism and delirium. RESULTS: Postoperative adhesions were the most common cause of SBO (49.1%). Early surgery (<24 hours postadmission) took place in 30.0% of patients, 22.0% underwent delayed operation and 47.9% were managed non-operatively. Malnutrition as stratified by Nutritional Risk Index was common, with 35.7% at moderate risk and 5.7% at severe risk of malnutrition. Dietitian review occurred in just 36.4% and 55.9% of the moderate and severe risk groups. In the low risk group, 30.3% received nutritional intervention compared with 40.7% in moderate risk group and 62.7% in severe risk group. In comparison to the low risk group, patients who were at severe or moderate risk of malnutrition had 4.2 and 2.4 times higher unadjusted risk of in-hospital mortality, respectively. Propensity-matched analysis found no difference in outcomes based on use or timing of parenteral nutrition. CONCLUSIONS: Malnutrition on admission is associated with worse outcomes in patients with SBO, and marked variation in management of malnutrition was observed. Future trials should focus on identifying effective and cost-effective nutritional interventions in SBO

Wnt signalling in adenomas of familial adenomatous polyposis patients

BACKGROUND: Epigenetic silencing of Wnt antagonists and expression changes in genes associated with Wnt response pathways occur in early sporadic colorectal tumourigenesis, indicating that tumour cells are more sensitive to Wnt growth factors and respond differently. In this study, we have investigated whether similar changes occur in key markers of the Wnt response pathways in the genetic form of the disease, familial adenomatous polyposis (FAP). METHODS: We investigated epigenetic and expression changes using pyrosequencing and real-time RT-PCR in samples from seven patients without neoplasia, and matched normal and tumour tissues from 22 sporadic adenoma and 14 FAP patients. RESULTS: We found that 17 out of 24 (71%) FAP adenomas were hypermethylated at sFRP1, compared with 20 out of 22 (91%) of sporadic cases. This was reflected at the level of sFRP1 transcription, where 73% of FAP and 100% of sporadic cases were downregulated. Increased expression levels of c-myc and FZD3 were less common in FAP (35 and 46% respectively) than sporadic tumours (78 and 67% respectively). CONCLUSION: Overall, the changes in expression and methylation were comparable, although the degree of change was generally lower in the FAP adenomas. Molecular heterogeneity between multiple adenomas from individual FAP patients may reflect different developmental fates for these premalignant tumours

Novel APC mutations in Czech and Slovak FAP families: clinical and genetic aspects

BACKGROUND: Germline mutations in the adenomatous polyposis gene (APC) result in familial adenomatous polyposis (FAP). FAP is an autosomal dominantly inherited disorder predisposing to colorectal cancer. Typical FAP is characterized by hundreds to thousands of colorectal adenomatous polyps and by several extracolonic manifestations. An attenuated form of polyposis (AFAP) is characterized by less than 100 adenomas and later onset of the disease. METHODS: Here, we analyzed the APC gene for germline mutations in 59 Czech and 15 Slovak FAP patients. In addition, 50 apparently APC mutation negative Czech probands and 3 probands of Slovak origin were screened for large deletions encompassing the APC gene. Mutation screening was performed using denaturing gradient gel electrophoresis and/or protein truncation test. DNA fragments showing an aberrant electrophoretic banding pattern were sequenced. Screening for large deletions was performed by multiplex ligation dependent probe amplification. The extent of deletions was analyzed using following microsatellite markers: D5S299, D5S82, D5S134 and D5S346. RESULTS: In the set of Czech and Slovak patients, we identified 46 germline mutations among 74 unrelated probands. Total mutation capture is 62,2% including large deletions. Thirty seven mutations were detected in 49 patients presenting a classical FAP phenotype (75,5%) and 9 mutations in 25 patients with attenuated FAP (36%). We report 20 novel germline APC mutations and 3 large deletions (6%) encompassing the whole-gene deletions and/or exon 14 deletion. In the patients with novel mutations, correlations of the mutation localization are discussed in context of the classical and/or attenuated phenotype of the disease. CONCLUSION: The results of the molecular genetic testing are used both in the establishment of the predictive diagnosis and in the clinical management of patients. In some cases this study has also shown the difficulty to classify clinically between the classical and the attenuated form of FAP according to the established criteria. Interfamilial and/or intrafamilial phenotype variability was also confirmed in some cases which did not fit well with predicted genotype-phenotype correlation. All these findings have to be taken into consideration both in the genetic counselling and in the patient care

A unified framework for multi-locus association analysis of both common and rare variants

<p>Abstract</p> <p>Background</p> <p>Common, complex diseases are hypothesized to result from a combination of common and rare genetic variants. We developed a unified framework for the joint association testing of both types of variants. Within the framework, we developed a union-intersection test suitable for genome-wide analysis of single nucleotide polymorphisms (SNPs), candidate gene data, as well as medical sequencing data. The union-intersection test is a composite test of association of genotype frequencies and differential correlation among markers.</p> <p>Results</p> <p>We demonstrated by computer simulation that the false positive error rate was controlled at the expected level. We also demonstrated scenarios in which the multi-locus test was more powerful than traditional single marker analysis. To illustrate use of the union-intersection test with real data, we analyzed a publically available data set of 319,813 autosomal SNPs genotyped for 938 cases of Parkinson disease and 863 neurologically normal controls for which no genome-wide significant results were found by traditional single marker analysis. We also analyzed an independent follow-up sample of 183 cases and 248 controls for replication.</p> <p>Conclusions</p> <p>We identified a single risk haplotype with a directionally consistent effect in both samples in the gene <it>GAK</it>, which is involved in clathrin-mediated membrane trafficking. We also found suggestive evidence that directionally inconsistent marginal effects from single marker analysis appeared to result from risk being driven by different haplotypes in the two samples for the genes <it>SYN3 </it>and <it>NGLY1</it>, which are involved in neurotransmitter release and proteasomal degradation, respectively. These results illustrate the utility of our unified framework for genome-wide association analysis of common, complex diseases.</p

Single nucleotide polymorphisms of the APC gene and colorectal cancer risk: a case-control study in Taiwan

BACKGROUND: Colorectal cancer (CRC), which has become especially prevalent in developed countries, is currently the third highest cause of cancer mortality in Taiwan. Mutation of the adenomatous polyposis coli (APC) gene, a tumour suppressor, is thought to be an early event in colorectal tumourigenesis. To date, however, no large-scale screening for APC gene variants in Chinese subjects has been performed. The present study was undertaken to identify APC gene variants that are significantly associated with the occurrence of CRC in Taiwanese subjects. METHODS: In order to compare the genotype distribution of variant sites, the full-length APC genes of 74 healthy individuals and 80 CRC patients were sequenced. RESULTS: Among the 154 Taiwanese subjects examined in this study, three new mutations, but no previously reported mutations, were found. One deletion at codon 460 leading to a frameshift and two missense mutations resulting in p.V1125A and p.S1126R substitutions were identified. Additionally, three high risk genotypes associated with three single nucleotide polymorphisms and one low risk genotype at codon 1822 were identified. CONCLUSION: The findings of this case-control study are consistent with the proposal that Taiwanese subjects differ from other subjects with respect to phenotypic presentation of APC and CRC risk

Differential gene expression profile reveals deregulation of pregnancy specific β1 glycoprotein 9 early during colorectal carcinogenesis

BACKGROUND: APC (Adenomatous polyposis coli) plays an important role in the pathogenesis of both familial and sporadic colorectal cancer. Patients carrying germline APC mutations develop multiple colonic adenomas at younger age and higher frequency than non-carrier cases which indicates that silencing of one APC allele may be sufficient to initiate the transformation process. METHODS: To elucidate the biological dysregulation underlying adenoma formation we examined global gene expression profiles of adenomas and corresponding normal mucosa from an FAP patient. Differential expression of the most significant gene identified in this study was further validated by mRNA in situ hybridization, reverse transcriptase PCR and Northern blotting in different sets of adenomas, tumours and cancer cell lines. RESULTS: Eighty four genes were differentially expressed between all adenomas and corresponding normal mucosa, while only seven genes showed differential expression within the adenomas. The first group included pregnancy specific β-1 glycoprotein 9 (PSG9) (p < 0.006). PSG9 is a member of the carcinoembryonic antigen (CEA)/PSG family and is produced at high levels during pregnancy, mainly by syncytiotrophoblasts. Further analysis of sporadic and familial colorectal cancer confirmed that PSG9 is ectopically upregulated in vivo by cancer cells. In total, deregulation of PSG9 mRNA was detected in 78% (14/18) of FAP adenomas and 75% (45/60) of sporadic colorectal cancer cases tested. CONCLUSION: Detection of PSG9 expression in adenomas, and at higher levels in FAP cases, indicates that germline APC mutations and defects in Wnt signalling modulate PSG9 expression. Since PSG9 is not found in the non-pregnant adult except in association with cancer, and it appears to be an early molecular event associated with colorectal cancer monitoring of its expression may be useful as a biomarker for the early detection of this disease