Assessing the quality of primary care referrals to surgery of patients with diabetes in the East of England: A multi-centre cross-sectional cohort study.

AIM: Peri-operative hyperglycaemia is associated with an increased incidence of adverse outcomes. Communication between primary and secondary care is paramount to minimise these harms. National guidance in the UK recommends that the glycated haemoglobin (HbA1c) should be measured within 3 months prior to surgery and that the concentration should be less that 69 mmol/mol (8.5%). In addition, national guidance outlines the minimum dataset that should be included in any letter at the time of referral to the surgeons. Currently, it is unclear how well this process is being carried out. This study investigated the quality of information being handed over during the referral from primary care to surgical outpatients within the East of England. METHODS: Primary care referrals to nine different NHS hospital Trusts were gathered over a 1-week period. All age groups were included from 11 different surgical specialties. Referral letters were analysed using a standardised data collection tool based on the national guidelines. RESULTS: A total of 1919 referrals were received, of whom 169 (8.8%) had previously diagnosed diabetes mellitus (DM). However, of these, 38 made no mention of DM in the referral letter but were on glucose-lowering agents. Only 13 (7.7%) referrals for patients with DM contained a recent HbA1c, and 20 (11.8%) contained no documentation of glucose-lowering medication. CONCLUSION: This study has shown that the quality of referral letters to surgical specialties for patients with DM in the East of England remain inadequate. There is a clear need for improving the quality of clinical data contained within referral letters from primary care. In addition, we have shown that the rate of referral for surgery for people with diabetes is almost 50% higher than the background population with diabetes.

Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer.

Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles.

Is there a role for enhanced recovery after laparoscopic bariatric surgery? Preliminary results from a specialist obesity treatment center.

BACKGROUND: There has been a relative lack of research on the effect of enhanced recovery in the context of morbid obesity surgery. OBJECTIVES: To determine if the application of enhanced recovery after surgery (ERAS) principles can contribute to reduce postoperative hospital length of stay after bariatric surgery, controlling for other factors that may influence safe discharge on the first postoperative day. SETTING: University teaching hospital, United Kingdom. METHODS: Between February 2011 and December 2014, prospectively collected data on all patients undergoing laparoscopic bariatric surgery under the care of a single surgeon were reviewed. From January 2012, all patients were enrolled in an ERAS protocol and were assessed for fitness for early discharge (within 24 hr from the operation). Baseline patient characteristics and additional concomitant procedures data were compared for patients treated before and after implementation of the ERAS protocol; 30-day readmission data were analyzed for patients discharged on the first postoperative day and those discharged later. The effect of the implementation of the ERAS protocol on discharge on the first postoperative day was analyzed using multivariate analysis, while taking into account the effects of potential confounders (e.g., age, gender, American Society of Anesthesiologists [ASA] grade, concomitant surgical procedures, etc.). RESULTS: Two-hundred and eighty-eight consecutive patients underwent bariatric surgery. Of these, 278 (96.5%) were potentially suitable for early discharge, while 10 (3.5%) patients developed an acute postoperative complication that delayed discharge irrespective of the effect of ERAS. All these patients required a reoperation within 48 hours and therefore were not considered suitable for early discharge and were not included in the statistical analysis. During the entire study period, 100 of 278 (36%) patients were discharged on the first postoperative day, 28.5% after laparoscopic Roux-en-Y gastric bypass (LRYGB) and 60.9% after laparoscopic sleeve gastrectomy (LSG); 178 of 278 (64%) patients were discharged after ≥ 2 days (mean: 2.58, range: 2-5). After implementation of the ERAS protocol in January 2012, the rate of patients discharged on the first postoperative day increased significantly from 1.6% to 39.7% after LRYGB (P<.01). Early discharge increased from 50% to 67.5% after LSG; although this change did not reach statistical significance (P = .294), it nevertheless represents a clinically relevant result. Four (4%) patients were readmitted after having been discharged on the first postoperative day, 10 (5.3%) patients after having been discharged ≥ 2 postoperative days. This difference was not statistically significant (P = .620). CONCLUSIONS: The implementation of an enhanced recovery program after bariatric surgery is feasible, well tolerated, and can significantly reduce the length of hospital stay without increasing readmission rates. Controlling for several possible confounders, implementation of the ERAS protocol remained the strongest predictor of discharge on the first postoperative day after laparoscopic bariatric surgery.

Incidental oesophageal leiomyoma during laparoscopic Roux-en-Y gastric bypass: finding the unexpected does not affect outcomes.

Most bariatric procedures are now performed laparoscopically. Here, we describe a case of incidental oesophageal leiomyoma found during laparoscopic Roux-en-Y gastric bypass (LRYGB). To our knowledge, this is the first such case reported. Our patient was admitted for an elective LRYGB. She had no upper gastrointestinal symptoms, and therefore did not undergo preoperative oesophagogastroduodenoscopy (OGD). During surgery, a hiatus hernia and an incidental oesophageal leiomyoma were found and treated with hernia repair and enucleation. The end outcome was unaffected. We were able to concomitantly treat the unexpected finding of an oesophageal leiomyoma and a hiatus hernia during the LRYGB. The routine use of OGD prior to bariatric surgery is still controversial. While surgeons should be prepared for unexpected pathologies, when performing laparoscopic bariatric surgery, a routine OGD prior to LRYGB is probably not necessary in asymptomatic patients. Laparoscopic enucleation of oesophageal leiomyoma during LRYGB is feasible and safe.

Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion.

BACKGROUND: Prevalence of colorectal cancer (CRC) in the British Bangladeshi population (BAN) is low compared to British Caucasians (CAU). Genetic background may influence mutations and disease features. METHODS: We characterized the clinicopathological features of BAN CRCs and interrogated their genomes using mutation profiling and high-density single nucleotide polymorphism (SNP) arrays and compared findings to CAU CRCs. RESULTS: Age of onset of BAN CRC was significantly lower than for CAU patients (p=3.0 x 10-5) and this difference was not due to Lynch syndrome or the polyposis syndromes. KRAS mutations in BAN microsatellite stable (MSS) CRCs were comparatively rare (5.4%) compared to CAU MSS CRCs (25%; p=0.04), which correlates with the high percentage of mucinous histotype observed (31%) in the BAN samples. No BRAF mutations was seen in our BAN MSS CRCs (CAU CRCs, 12%; p=0.08). Array data revealed similar patterns of gains (chromosome 7 and 8q), losses (8p, 17p and 18q) and LOH (4q, 17p and 18q) in BAN and CAU CRCs. A small deletion on chromosome 16p13.2 involving the alternative splicing factor RBFOX1 only was found in significantly more BAN (50%) than CAU CRCs (15%) cases (p=0.04). Focal deletions targeting the 5' end of the gene were also identified. Novel RBFOX1 mutations were found in CRC cell lines and tumours; mRNA and protein expression was reduced in tumours. CONCLUSIONS: KRAS mutations were rare in BAN MSS CRC and a mucinous histotype common. Loss of RBFOX1 may explain the anomalous splicing activity associated with CRC.

HSP27 expression in primary colorectal cancers is dependent on mutation of KRAS and PI3K/AKT activation status and is independent of TP53.

Colorectal adenomas display features of senescence, but these are often lost upon progression to carcinoma, indicating that oncogene induced senescence (OIS) could be a roadblock in colorectal cancer (CRC) development. Heat shock proteins (HSPs) have been implicated in the prognosis of CRC and HSP based therapy is a current interest for drug development. Recent cell culture studies have suggested that in the absence of a TP53 mutation, OIS mediated by PI3K/AKT activation can be circumvented by high expression of HSPs. Furthermore, while PI3K/AKT activation and KRAS mutations are independent inducers of OIS, PI3K/AKT activation can suppress KRAS-induced OIS when both are present in cultured cells. As KRAS mutations, PI3K/AKT activation and TP53 mutations are all common features of CRC, it is possible that the requirement for HSP to inhibit OIS in CRC is dependent on the mutation spectrum of a tumour. However, work on HSP that utilised mutation profiled human tumour tissues has been limited. Here, we characterised the expression of two major HSP proteins (HSP27 and 72) by immunohistochemistry (IHC), the mutation status of TP53, KRAS and PIK3CA genes by direct sequencing and the activation status of AKT by IHC in a cohort of unselected primary CRC (n=74). We compare our data with findings generated from cell-based studies. Expression of HSP27 and HSP72 was correlated to clinicopathological and survival data but no significant association was found. We also established the mutation status of TP53, KRAS and PIK3CA genes and the activation status of AKT in our CRC panel. We did not detect any associations between HSP27 or HSP72 expression with TP53 mutation status. However, HSP27 expression in CRCs was strongly associated with the co-presence of wildtype KRAS and activated PI3K/AKT (p=0.004), indicating a possible role of HSP27 in overcoming PI3K/AKT induced OIS in tumours. Our studies suggest a role for using archival tissues in validating hypotheses generated from cell culture based investigations.

A distinct DNA methylation profile associated with microsatellite and chromosomal stable sporadic colorectal cancers.

Aberrant DNA methylation, microsatellite instability (MSI) and chromosomal instability (CIN) are well-characterised molecular features of sporadic colorectal cancers (CRCs). In addition to CpG island methylator phenotype (CIMP) associated with MSI, an intermediate methylation subgroup is also a feature of non-MSI cancers. A large proportion of CRCs have no evidence of either MSI or CIN, here called Microsatellite and Chromosomal Stable (MACS), and require their methylation profile to be established. The clinical and molecular features of 170 sporadic CRC patients were investigated and stratified into MSI, CIN and MACS groups. MACS were most often found in the left colon and had a significantly lower BRAF mutation frequency (p < 0.001) compared with MSI. MACS had better survival [hazard ratio (HR) = 0.244, p = 0.017] compared with CIN, but were similar to MSI. The methylation status of 1,505 CpG loci from cancer-related genes was analysed in a subset of CRCs (n = 44 normal-tumour pairs) and compared with CIN, MSI and MACS status. Using two-way hierarchical clustering, three subgroups were identified, which associated with CIN, MSI and MACS status. Using significance analysis of microarray, 16 CpG loci demonstrating methylation changes associated with MACS were identified. A combination of six loci identified MACS with 81% sensitivity and 93% specificity. This result now requires independent validation. Hypomethylation of a CpG locus within the sonic hedgehog (SHH) promoter correlated with increased gene expression and was associated significantly with MACS cancers. In conclusion, we propose that MACS have distinct clinicopathological features and can be distinguished from other CRCs by a specific set of methylation loci.

Cancer immunoediting and "spontaneous" tumor regression.

The combination of host protective and tumor-promoting actions of the immune system throughout tumor development is termed cancer immunoediting. This review briefly summarizes the currently vast evidence supporting the immune system's role in not only protecting against developing cancer, but also sculpting tumor immunogenicity and immune escape. We also briefly summarize the history of immunotherapy and discuss the immunoediting process in the context of spontaneous tumor regression and whether this observation can be utilized in future treatment regimens.

Targeting gut T cell Ca2+ release-activated Ca2+ channels inhibits T cell cytokine production and T-box transcription factor T-bet in inflammatory bowel disease.

Prolonged Ca(2+) entry through Ca(2+) release-activated Ca(2+) (CRAC) channels is crucial in activating the Ca(2+)-sensitive transcription factor NFAT, which is responsible for directing T cell proliferation and cytokine gene expression. To establish whether targeting CRAC might counteract intestinal inflammation, we evaluated the in vitro effect of a selective CRAC inhibitor on T cell cytokine production and T-bet expression by lamina propria mononuclear cells (LPMC) and biopsy specimens from inflammatory bowel disease (IBD) patients. The inhibitory activity of the CRAC blocker was investigated through patch-clamp experiments on rat basophilic leukemia cells and fluorometric imaging plate reader intracellular Ca(2+) assays using thapsigargin-stimulated Jurkat T cells and its detailed selectivity profile defined using a range of in vitro radioligand binding and functional assays. Anti-CD3/CD28-stimulated LPMC and biopsy specimens from 51 patients with IBD were cultured with a range of CRAC inhibitor concentrations (0.01-10 microM). IFN-gamma, IL-2, IL-8, and IL-17 were analyzed by ELISA. T-bet was determined by immunoblotting. We found that the CRAC blocker concentration-dependently inhibited CRAC current in rat basophilic leukemia cells and thapsigargin-induced Ca(2+) influx in Jurkat T cells. A concentration-dependent reduction in T-bet expression and production of IFN-gamma, IL-2, IL-17, but not IL-8, was observed in IBD LPMC and biopsy specimens treated with the CRAC inhibitor. In conclusion, we provide evidence that the suppression of CRAC channel function may dampen the increased T cell response in the inflamed gut, thus suggesting a promising role for CRAC inhibitor drugs in the therapeutic management of patients with IBD.

Management of colorectal cancer: a role for genetics in prevention and treatment?

Colorectal cancer remains one of the most common cancers in the Western world and amongst the top three causes of cancer morbidity and death. Cancer is caused by genetic mutations, but currently there is little use of genetic information in the clinic with the exception of establishing germline mutations for the uncommon predisposing syndromes. Rapid advances in technologies allowing high throughput analysis of germline and somatic mutations raises the possibility that genetics will find a major role in the clinic distinguishing individuals at low to high risk of cancer, allowing early intervention and stratification of cancers based on mutational pathways for therapeutic interventions. In the future, this will lead to treatment regimes tailored to the individuals and their tumor. Here, we summarize the genetics underlying colorectal cancer and the future role of genetics in prevention, diagnosis, classification and treatment.

Twenty months' routine use of a new percutaneous tracheostomy set using controlled rotating dilation.

After a favorable trial period, we introduced the new percutaneous tracheostomy set, PercuTwist, in February of 2002 for our routine procedures. Over the next 20 mo, 90 procedures were performed with minimal complications. To prospectively evaluate this experience, we collected information on reasons for unit admission, operators' previous experience, the duration of prior tracheal intubation, the time needed for the procedure, the grading of the difficulty, the amount of bleeding, and the complications of the procedure. Twenty-two of 90 (24.4%) procedures were performed by senior consultants with experience; 68 of 90 (75.6%) were safely performed by intensive care residents under close bedside supervision. The mean time needed for the procedure was 13 min 7 s. In only one procedure during the entire study was any difficulty observed during the insertion process. This occurred because the initial skin incision was too small. However, no major bleeding or complications were encountered.