Surgical treatment of intestinal stricture in inflammatory bowel disease.

Fibroblast infiltration and collagen deposition result in structural changes in the bowel wall, and lead to strictures in intestinal inflammatory disease. While strictures can also occur in other contexts, such as malignancy, this review focuses on the surgical treatment of stricture secondary to inflammatory bowel disease. Distinguishing between predominantly inflammation vs established fibrosis as the cause of a stricture can be challenging. While inflammatory strictures may be responsive to medication, predominantly fibrotic strictures usually need surgical intervention. Both endoluminal and extraluminal approaches are described in this review. Endoscopic dilatation of strictures is suitable for short-segment isolated small bowel strictures. Other options are to divide the stricture surgically but preserve the length, performing a strictureplasty or resecting the strictured segment. The mesentery is increasingly recognized as playing a role in stricture recurrence. In a relapsing-remitting disease such as Crohn's disease, the preservation of intestinal length is essential and balance is needed between this and a complete resection to reduce the risk of recurrence. Pre- and postoperative involvement of the multidisciplinary team is essential to improve outcomes in this challenging clinical scenario.

The Mesenteric Organ: New Anatomical Concepts and an Imaging-based Review on Its Diseases.

The proposal of reclassifying the mesentery as an organ prompts clinicians and radiologists to reappraise their approach to it and to mesenteric diseases (mesenteropathies). Recent updates in mesenteric anatomy and the better comprehension of its structure constitute a basis to push forward the process of disease management and allow the development of less radical (including endoscopic, radiological, and pharmacotherapeutic) treatments. Radiological evaluation currently plays a pivotal role in the noninvasive characterization of abdominal diseases. Mesenteric-based radiological assessments form an essential component in planning radiological interventions and postoperative surveillance programs. The purpose of this article, therefore, is to provide an update on the new anatomical concepts related to the mesentery, also performing an imaging-based review of mesenteric diseases by categorizing them as primary and secondary.

Expression of protein kinase C gamma promotes cell migration in colon cancer.

Despite extensive efforts, Protein Kinase Cs (PKCs) have proven to be an intractable target in cancer therapies. Traditionally it was accepted that PKCs act as tumour promoters, however new research suggests that PKCs may play an important role in the suppression of cancer. A challenge in targeting PKCs is the limited data available in patient samples. One of the PKC isozymes, PKC gamma, is thought to be present only in the brain and has been largely neglected in the context of cancer. Analysis of gene expression levels of PKC gamma in patient matched normal and colon cancer tissue samples revealed an up-regulation of the gene in the cancer tissue of 54% of the patients examined. Mechanistically we demonstrate that a reduction in the levels of PKC gamma in the colon cancer cells inhibits cell migration and foci formation. Further to this, we observe an increase in cell adhesion and proliferation following the reduction of PKC gamma levels in the cell. Thus, PKC gamma plays a key role in colon cancer; making it an important isozyme that needs to be reconsidered in the context of cancer therapies.

Lymph Node Ratio in Sentinel Lymph Node Biopsy Era: Are We Losing Prognostic Information?

BACKGROUND: The number of involved axillary lymph nodes (LNs) found pathologically is regarded as a significant prognostic factor in early-stage breast cancer (EBC). Recently, there is speculation that LN ratio (LNR) may be a better surrogate at predicting cancer-specific outcome than number of involved LNs. This study investigated prognostic value of LNR, using predetermined cutoff values. METHODS: Data included all women diagnosed with node-positive EBC between January 1, 2001, and December 31, 2010 (N = 553). Retrospective evaluation for clinical, demographic, and pathologic data was performed. Most had axillary node clearance (ANC) (548/553; 99.1%). Cohorts were divided by LNR risk groups (low: ≤ 0.20; intermediate: 0.21-0.65; high: >0.65). Proportional hazard modeling was undertaken to evaluate whether LNR was associated with overall survival (OS). RESULTS: Median follow-up was 59.8 months. LNR distribution was as follows: low, 303/553 (54.8%); intermediate, 160/553 (28.9%); high, 90/553 (16.3%). Kaplan-Meier estimates for OS were stratified by LNR: low-risk group had better outcome for OS (P < .001). Overall 5- and 10-year OS was 63% and 58%, respectively. Number of positive LNs correlated with 10-year OS (66%, 48%, and 48% for patients with N1, N2, and N3 stage, respectively; P < .001). LNR also correlated with 5-year OS (69%, 48%, and 41% for low-, intermediate-, and high-risk groups, respectively; P < .001). Significantly, LNR on multivariate analysis also formed a prognostic model when combined with age, estrogen receptor status, PgR status and, HER2 status (P < .001). CONCLUSION: The Findings support LNR as a predictor for OS in EBC. LNR should be considered an independent prognostic variable to current prognostic instruments already in use.

Extracellular matrix gene expression profiling using microfluidics for colorectal carcinoma stratification.

In cancer, biomarkers have many potential applications including generation of a differential diagnosis, prediction of response to treatment, and monitoring disease progression. Many molecular biomarkers have been put forward for different diseases but most of them do not possess the required specificity and sensitivity. A biomarker with a high sensitivity has a low specificity and vice versa. The inaccuracy of the biomarkers currently in use has led to a compelling need to identify more accurate markers with diagnostic and prognostic significance. The aim of the present study was to use a novel, droplet-based, microfluidic platform to evaluate the prognostic value of a panel of thirty-four genes that regulate the composition of extracellular matrices in colorectal carcinoma. Our method is a novel approach as it uses using continuous-flowing Polymerase Chain Reaction for the sensitive detection and accurate quantitation of gene expression. We identified a panel of relevant extracellular matrix genes whose expression levels were measured by real-time quantitative polymerase chain reaction using Taqman® reagents in twenty-four pairs of matched colorectal cancer tumour and associated normal tissue. Differential expression patterns occurred between the normal and malignant tissue and correlated with histopathological parameters and overall surgical staging. The findings demonstrate that a droplet-based microfluidic quantitative PCR system enables biomarker classification. It was further possible to sub-classify colorectal cancer based on extracellular matrix protein expressing groups which in turn correlated with prognosis.

Protein kinase C beta II suppresses colorectal cancer by regulating IGF-1 mediated cell survival.

Despite extensive efforts, cancer therapies directed at the Protein Kinase C (PKC) family of serine/threonine kinases have failed in clinical trials. These therapies have been directed at inhibiting PKC and have, in some cases, worsened disease outcome. Here we examine colon cancer patients and show not only that PKC Beta II is a tumour suppressor, but patients with low levels of this isozyme have significantly decreased disease free survival. Specifically, analysis of gene expression levels of all PKC genes in matched normal and cancer tissue samples from colon cancer patients revealed a striking down-regulation of the gene coding PKC Beta in the cancer tissue (n = 21). Tissue microarray analysis revealed a dramatic down-regulation of PKC Beta II protein levels in both the epithelial and stromal diseased tissue (n = 166). Of clinical significance, low levels of the protein in the normal tissue of patients is associated with a low (10%) 10 year survival compared with a much higher (60%) survival in patients with relatively high levels of the protein. Consistent with PKC Beta II levels protecting against colon cancer, overexpression of PKC Beta II in colon cancer cell lines reveals that PKC Beta II reverses transformation in cell based assays. Further to this, activation of PKC Beta II results in a dramatic downregulation of IGF-I-induced AKT, indicating a role for PKCs in regulating IGF-1 mediated cell survival. Thus, PKC Beta II is a tumour suppressor in colon cancer and low levels serve as a predictor for poor survival outcome.

The importance of selecting the appropriate reference genes for quantitative real time PCR as illustrated using colon cancer cells and tissue.

Quantitative real-time reverse-transcription polymerase chain reaction (RT-qPCR) remains the most sensitive technique for nucleic acid quantification. Its popularity is reflected in the remarkable number of publications reporting RT-qPCR data. Careful normalisation within RT-qPCR studies is imperative to ensure accurate quantification of mRNA levels. This is commonly achieved through the use of reference genes as an internal control to normalise the mRNA levels between different samples. The selection of appropriate reference genes can be a challenge as transcript levels vary with physiology, pathology and development, making the information within the transcriptome flexible and variable. In this study, we examined the variation in expression of a panel of nine candidate reference genes in HCT116 and HT29 2-dimensional and 3-dimensional cultures, as well as in normal and cancerous colon tissue. Using normfinder we identified the top three most stable genes for all conditions. Further to this we compared the change in expression of a selection of PKC coding genes when the data was normalised to one reference gene and three reference genes. Here we demonstrated that there is a variation in the fold changes obtained dependent on the number of reference genes used. As well as this, we highlight important considerations namely; assay efficiency tests, inhibition tests and RNA assessment which should also be implemented into all RT-qPCR studies. All this data combined demonstrates the need for careful experimental design in RT-qPCR studies to help eliminate false interpretation and reporting of results.

Transcriptional profiles underpin microsatellite status and associated features in colon cancer.

INTRODUCTION: While microsatellite instability is associated with prognosis and distinct clinical phenotypes in colon cancer, the basis for this remains incompletely defined. Novel bioinformatic techniques enable a detailed interrogation of the relationship between gene expression profiles and tumor characteristics. AIM: We aimed to determine if microsatellite instability high (MSI-H) and microsatellite stable (MSS) tumors could be differentiated by gene expression profiles. We investigated the basis of this using a system and network based algorithmic approach. METHODS: Microsatellite status was established using a polymerase chain reaction (PCR) panel and fragment length analysis. Gene expression was determined using Illumina© microarrays comprising 48,701 transcripts, and scaling normalization was conducted using Limma in R. Following filtration for non-significant changes a meta-gene was established and subjected to unsupervised hierarchical clustering using Chipster©. A supervised learning algorithm (PAM) was used to generate a gene-expression based clinical-outcome predictor that was further tested using an independent validation group. A network based linkage analysis was conducted using Ingenuity© focusing on canonical, functional pathways, and associated therapeutic modalities. RESULTS: MSI-H and MSS tumors clustered separately following an unsupervised hierarchical clustering analysis. A transcriptomic classifier (with 19 component genes) was generated that reliably and reproducibly predicted microsatellite status. MSI-H associated canonical pathways were predominantly immune or inflammation related converging on increased IL-1B and thymidylate synthase expression. The network linkage analysis identified canakinumab, IL-trap and MDX-1100 as the strongest therapeutic candidates that remain to be assessed in the colon cancer setting. CONCLUSIONS: Microsatellite status is underpinned by transcriptional events and can be accurately and reliably defined by differential gene expression. A specific transcriptomic profile is pathognomonic and provides insight into the differences in biology between MSS and MSI-H colon cancers.

Correlation between Nottingham Prognostic Index and Adjuvant! Online prognostic tools in patients with early-stage breast cancer in Mid-Western Ireland.

BACKGROUND: Prognostic tools are widely used in the practice of oncology and have been developed to help stratify patients into specific risk-related grouping. We sought to apply tool such tools used for patients with early-stage breast cancer (EBC) and correlate them to actual outcomes. METHODS: A retrospective analysis was designed to include EBC cases seen at the Mid-Western Regional Hospital from January 1, 2002, to December 31, 2002. Information was derived from the patients' records, and indices were derived from prognostic tools. Information was analyzed using descriptive statistics and chi-square or Fisher exact test. RESULTS: A total of 77 patients were found, with a median age of 52.2 years. A median overall survival (OS) of 84 months was observed. The majority presented with moderately differentiated estrogen receptor positive invasive ductal carcinoma and lymph node involvement (60%). Sixty-four percent of patients underwent mastectomy as opposed to breast conservation. Adjuvant cytotoxic chemotherapy uptake was 61%, which was comparable to the proportion of node positive disease. The Nottingham Prognostic Index and Adjuvant! Online (AO) tools were both correlated with actual survival, with the AO showing better correlation. CONCLUSIONS: This report underscores that these predicting tools were both underestimations consistent with the actual OS and highlights the importance of further work in validating these tools within our own population.

Artificial interfaces ("AI") in surgery: historic development, current status and program implementation in the public health sector.

The past two decades have seen considerable advances in the application of artificial interfaces (AI) in surgery. Several have been developed including AESOP (Automated Endoscopic System for Optimal Positioning), Zeus and the Da Vinci Surgical System (DVSS). Whilst each has advantages DVSS is being used increasingly across multiple surgical specialities. These developments generate many challenges in an era where the emphasis is increasingly on safer and cost-effective surgery. Whilst the role of DVSS is firmly established in urologic and gynaecologic surgery, the role of DVSS in gastrointestinal surgery is evolving. Recent data indicate that it is at least as oncologically effective, whilst providing numerous benefits (e.g. reduced conversion and complication rates) over traditional laparoscopic approaches. The increasing adoption of AI/DVSS worldwide places institutes and health sectors under increasing pressure to adopt and develop such programs. This article provides (1) an update on the current status of AI in surgery in general and in colorectal surgery and (2) an appraisal of the cost implications of the establishment and implementation of AI/DVSS-based provisions in the public health sector. The numerous challenges faced generate many opportunities in the implementation of present and future surgical technologies.

Impact of resident participation in surgical operations on postoperative outcomes: National Surgical Quality Improvement Program.

OBJECTIVE: To evaluate whether resident participation in operations influences postoperative outcomes. BACKGROUND: : Identification of potential differences in outcome associated with resident participation in operations may facilitate planning from educational and health resource perspectives. METHODS: From the National Surgical Quality Improvement Program database (2005-2007), postoperative outcomes were compared for patients with and without resident participation (RES vs no-RES). Groups were matched in a 2:1 ratio, based on age, sex, specialty, surgical procedure, morbidity probability, and important comorbidities and risk factors. RESULTS: RES (40,474; 66.7%) and no-RES (20,237; 33.3%) groups were comparable for matched characteristics. Mortality was similar (0.18% vs 0.20%, P = 0.55). Thirty-day complications classified as "mild" (4.4% vs 3.5%, P < 0.001) and "surgical" (7% vs 6.2%, P < 0.001) were higher in RES group. Individual complications were largely similar, except superficial surgical site infection (3.0% vs 2.2%, P < 0.001). Operative time was longer in the RES group [mean (SD) 122 (80) vs 97 (67) minutes, P < 0.001]. Overall complications were lower for postgraduate year 1-2 residents than for other years. These differences persisted on multivariate analysis adjusting for confounders. CONCLUSIONS: Resident involvement in surgical procedures is safe. The small overall increase in mild surgical complications is mostly caused by superficial wound infections. Reasons for this are likely multifactorial but may be related to prolonged operative time.

Clinical Inquiry. How best to diagnose asthma in infants and toddlers?

No reliable way exists to diagnose asthma in infants and toddlers. Recurrent wheezing, especially apart from colds, combined with physician-diagnosed eczema or atopic dermatitis, eosinophilia, and a parental history of asthma, increase the probability of a subsequent asthma diagnosis in the absence of other causes (strength of recommendation: B, 2 good-quality cohort studies).

The perioperative period is an underutilized window of therapeutic opportunity in patients with colorectal cancer.

OBJECTIVE: In this review, we address the underlying mechanisms by which surgery augments metastases outgrowth and how these insights can be used to develop perioperative therapeutic strategies for prevention of tumor recurrence. SUMMARY BACKGROUND DATA: Surgical removal of the primary tumor provides the best chance of long-term disease-free survival for patients with colorectal cancer (CRC). Unfortunately, a significant part of CRC patients will develop metastases, even after successful resection of the primary tumor. Paradoxically, it is now becoming clear that surgery itself contributes to development of both local recurrences and distant metastases. METHODS: Data for this review were identified by searches of PubMed and references from relevant articles using the search terms "surgery," "CRC," and "metastases." RESULTS: Surgical trauma and concomitant wound-healing processes induce local and systemic changes, including impairment of tissue integrity and production of inflammatory mediators and angiogenic factors. This can lead to immune suppression and enhanced growth or adhesion of tumor cells, all of which increase the chance of exfoliated tumor cells developing into secondary malignancies. CONCLUSIONS: Because surgery remains the appropriate and necessary means of treatment for most CRC patients, new adjuvant therapeutic strategies that prevent tumor recurrence after surgery need to be explored since the perioperative therapeutic window of opportunity offers promising means of improving patient outcome but is unfortunately underutilized.