Characterisation of the Expression of Neurotensin and Its Receptors in Human Colorectal Cancer and Its Clinical Implications.

Introduction: Colorectal Cancer (CRC) accounts for 9% of cancer deaths globally. Hormonal pathways play important roles in some cancers. This study investigated the association of CRC expression of neurotensin (NTS), NTS receptors 1 and 3 (NTSR1 and NTSR3) and clinical outcomes. Methods: A prospective cohort study which quantifies the protein expression of NTS, NTSR1 and NTSR3 in human CRCs using immunohistochemistry. Expression levels were then compared with clinico-pathological outcome including histological grade, overall survival (OS) and disease-free survival (DFS). Results: Sixty-four patients were enrolled with median follow-up of 44.0 months. There was significantly higher expression of NTS in cancer tissue in CRC with higher T stages (p < 0.01), N stages (p = 0.03), and AJCC clinical stages (p = 0.04). There was significantly higher expression of NTS, NTSR1 and NTSR3 in cancer tissue compared to surrounding normal epithelium (median H-score 163.5 vs 97.3, p < 0.01). There was significantly shorter DFS in individuals with CRC with high levels of NTS compared to lower levels of NTS (35.8 months 95% CI 28.7-42.8 months vs 46.4 months 95% CI 42.2-50.5 months, respectively, p = 0.02). Above median NTS expression in cancer tissue was a significant risk factor for disease recurrence (HR 4.10, 95% CI 1.14-14.7, p = 0.03). Discussion: The expression of NTS and its receptors has the potential to be utilised as a predictive and prognostic marker in colorectal cancer for postoperative selection for adjuvant therapy and identify individuals for novel therapies targeting the neurotensinergic pathways. Conclusions: High NTS expression appears to be associated with more advanced CRC and worse DFS.

Klotho and the Treatment of Human Malignancies.

Klotho was first discovered as an anti-ageing protein linked to a number of age-related disease processes, including cardiovascular, renal, musculoskeletal, and neurodegenerative conditions. Emerging research has also demonstrated a potential therapeutic role for Klotho in cancer biology, which is perhaps unsurprising given that cancer and ageing share similar molecular hallmarks. In addition to functioning as a tumour suppressor in numerous solid tumours and haematological malignancies, Klotho represents a candidate therapeutic target for patients with these diseases, the majority of whom have limited treatment options. Here, we examine contemporary evidence evaluating the anti-neoplastic effects of Klotho and describe the modulation of downstream oncogenic signalling pathways, including Wnt/ß-catenin, FGF, IGF1, PIK3K/AKT, TGFß, and the Unfolded Protein Response. We also discuss possible approaches to developing therapeutic Klotho and consider technological advances that may facilitate the delivery of Klotho through gene therapy.

The role of Neurotensin and its receptors in non-gastrointestinal cancers: a review.

BACKGROUND: Neurotensin, originally isolated in 1973 has both endocrine and neuromodulator activity and acts through its three main receptors. Their role in promoting tumour cell proliferation, migration, DNA synthesis has been studied in a wide range of cancers. Expression of Neurotensin and its receptors has also been correlated to prognosis and prediction to treatment. MAIN BODY: The effects of NT are mediated through mitogen-activated protein kinases, epidermal growth factor receptors and phosphatidylinositol-3 kinases amongst others. This review is a comprehensive summary of the molecular pathways by which Neurotensin and its receptors act in cancer cells. CONCLUSION: Identifying the role of Neurotensin in the underlying molecular mechanisms in various cancers can give way to developing new agnostic drugs and personalizing treatment according to the genomic structure of various cancers. Video abstract.

Exploratory Analysis of Plasma Neurotensin as a Novel Biomarker for Early Detection of Colorectal Polyp and Cancer.

Earlier detection of colorectal cancer (CRC) results in improved survival. Existing non-invasive biomarkers have suboptimal accuracy. Neurotensin (NTS) is involved in CRC carcinogenesis. This study evaluated the diagnostic potential of plasma NTS for colorectal polyps and cancers. Participants were selected based on national CRC referral guidelines. All subjects underwent colonoscopy. Average plasma concentrations were compared across different diagnostic groups. Predictors for detecting colorectal neoplasia were identified. Receiver operator characteristic (ROC) curve analysis assessed the diagnostic accuracy of NTS. An independent biobank was used as validation group. Of 165 participants, 46 had polyps or CRC. Significantly higher plasma NTS was found in the colonic neoplasia group (603.6 pg/ml vs. 407.2 pg/ml, p < 0.01). Risk factors for colonic polyps or cancers included Loge (plasma NTS concentration) (OR, 2.73; 95% CI, 1.33-5.59, p < 0.01), loge (Age) (OR, 15.49; 95% CI, 2.67-89.66, p < 0.01) and cigarette smoking (OR, 3.49; 95% CI, 1.31-9.26, p = 0.01). Plasma NTS had an optimal sensitivity of 60.4% and specificity of 71.6% for the diagnosis of colorectal polyps and cancers. Similar diagnostic accuracy was obtained in the validation group. Plasma NTS has the potential to be a non-invasive biomarker for colorectal neoplasia. It appears to be more accurate than existing blood markers and is unique in being able to detect precancerous polyps.

A systematic review and network meta-analysis comparing treatments for faecal incontinence.

BACKGROUND: Although numerous treatments exist for fecal incontinence (FI), no consensus exists on the best treatment strategy. The aim was to review the literature and to compare the clinical outcomes and effectiveness of treatments available for FI. MATERIALS AND METHOD: A systematic literature review was performed, from inception to May 2018, of the following databases: MEDLINE, EMBASE, Science Citation Index Expanded, Cochrane Library. The search terms used were "faecal incontinence" and "treatment". Only randomized controlled trials (RCTs) comparing treatments for FI were considered. A Bayesian network meta-analysis was performed using the Markov chain Monte Carlo method. RESULT: Forty-seven RCTs were included comparing 37 treatments and reporting on 3748 participants. No treatment ranked best or worst with high probability for any outcome of interest. No significant difference was identified between treatments for frequency of FI per week, or in changing the resting pressure, maximum resting pressure, squeeze pressure, and maximum squeeze pressure. Radiofrequency resulted in more adverse events compared to placebo. Sacral nerve stimulation (SNS) and zinc-aluminium improved the fecal incontinence quality of life questionnaire (FIQL) lifestyle, coping, and embarrassment domains compared to placebo. Transcutaneous posterior tibial nerve stimulation (TPTNS) improved the FIQL embarrassment domain compared to placebo. Autologous myoblasts and zinc-aluminium improved the FIQL depression domain compared to placebo. SNS, artificial bowel sphincter (ABS), and zinc-aluminium significantly improved incontinence scores compared to placebo. Injection of non-animal stabilized hyaluronic acid/dextranomer (NASHA/Dx) resulted in more patients with ≥50% reduction in FI episodes compared to placebo. CONCLUSION: SNS, ABS, TPTNS, NASHA/Dx, zinc-aluminium, and autologous myoblasts resulted in isolated improvements in specific outcomes of interest. No difference was identified in incontinence episodes, no treatment ranked best persistently or persistently improved outcomes, and many included treatments did not significantly benefit patients compared to placebo. Large multicentre RCTs with long-term follow-up and standardized inclusion criteria and outcome measures are needed.

The prognostic and therapeutic role of hormones in colorectal cancer: a review.

Colorectal cancer (CRC) is one of the commonest cancers in Western society with a poor prognosis in patients with advanced disease. Targeted therapy is of increasing interest and already, targeted hormone treatment for breast and prostate cancer has improved survival. The aim of this literature review is to summarise the role of hormones in CRC prognosis and treatment. A literature review of all human and animal in vivo and in vitro studies in the last 20 years, which assessed the role of hormones in CRC treatment or prognosis, was carried out. The hormones described in this review have been subdivided according to their secretion origin. Most of the studies are based on in vitro or animal models. The main findings point to adipokines, insulin and the insulin growth factor axis as key players in the link between obesity, type 2 diabetes mellitus and a subset of CRC. Gut-derived hormones, especially uroguanylin and guanylin are being increasingly investigated as therapeutic targets, with promising results. Using hormones as prognostic and therapeutic markers in CRC is still in the preliminary stages for only a fraction of the hormones affecting the GIT. In light of the increasing interest in tailoring treatment strategies, hormones are an important area of focus in the future of CRC management.

Noninvasive Biomarkers of Colorectal Cancer: Role in Diagnosis and Personalised Treatment Perspectives.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide. It has been estimated that more than one-third of patients are diagnosed when CRC has already spread to the lymph nodes. One out of five patients is diagnosed with metastatic CRC. The stage of diagnosis influences treatment outcome and survival. Notwithstanding the recent advances in multidisciplinary management and treatment of CRC, patients are still reluctant to undergo screening tests because of the associated invasiveness and discomfort (e.g., colonoscopy with biopsies). Moreover, the serological markers currently used for diagnosis are not reliable and, even if they were useful to detect disease recurrence after treatment, they are not always detected in patients with CRC (e.g., CEA). Recently, translational research in CRC has produced a wide spectrum of potential biomarkers that could be useful for diagnosis, treatment, and follow-up of these patients. The aim of this review is to provide an overview of the newer noninvasive or minimally invasive biomarkers of CRC. Here, we discuss imaging and biomolecular diagnostics ranging from their potential usefulness to obtain early and less-invasive diagnosis to their potential implementation in the development of a bespoke treatment of CRC.

Systematic review of blood diagnostic markers in colorectal cancer.

The purpose of this systematic review was to compare the diagnostic ability of blood markers for colorectal cancer (CRC). A systematic review of the literature for diagnostic blood markers for primary human colorectal cancer over the last 5 years was performed. The primary outcome was to assess the diagnostic ability of these markers in diagnosing colorectal cancer. The secondary outcome was to see whether the marker was compared to other markers. The tertiary outcome was to assess diagnostic ability in early versus late CRC, including stage IV disease. We identified 51 studies (29 prospective, 14 retrospective, and 8 meta-analyses). The markers were divided in broadly four groups: nucleic acids (RNA/DNA/messenger RNA/microRNAs), cytokines, antibodies, and proteins. The most promising circulating markers identified among the nucleid acids were NEAT_v2 non-coding RNA, SDC2 methylated DNA, and SEPT9 methylated DNA. The most promising cytokine to detect CRC was interleukin 8, and the most promising circulating proteins were CA11-19 glycoprotein and DC-SIGN/DC-SIGNR. Sensitivities of these markers for detecting primary colorectal carcinoma ranged from 70 to 98% and specificities from 84 to 98.7%. The best studied blood marker was SEPT9 methylated DNA, which showed great variability with sensitivities ranging from 48.2 to 95.6% and specificities from 80 to 98.9%, making its clinical applicability challenging. If combined with fecal immunochemical test (FIT), the sensitivity improved from 78 to 94% in detecting CRC. Methylated SEPT9, methylated SDC2, and -SIGN/DC-SIGNR protein had better sensitivity and specificity than CEA or CA 19-9. With the exception of SEPT9 which is currently being implemented as a screening test for CRC all other markers lacked reproducibility and standardization and were studied in relatively small population samples.

Discrepancies between NCCN and ESMO guidelines in the management of anal cancer: a qualitative review.

There is an ever-growing need, with the ongoing developments in research and the progress towards patient centered care, to delineate standardized protocols of management of anal cancer. However, guidelines from different societies show some degree of disagreement. This is a systematic review of the literature to identify similarities and discrepancies between the guidelines for the management of anal cancer drafted by the European Society for Medical Oncology (ESMO) and by the National Comprehensive Cancer Network (NCCN). We found essentially similar management for investigation, diagnosis, chemotherapy regimens, and radiotherapy doses in both ESMO and NCCN recommendations in the management of anal cancer. There were few differences, which included the levels of evidence and grades of recommendations, the delineation of radiotherapy fields, and the treatment of the elderly and personalized medicine based on genetics. The follow-up regime is also marginally different in the first 2 years. Even if the observed differences may be justified by a different implementation of evidence-based medicine among different countries for particular management modalities of anal cancer, we identified the grey areas which need further study. In addition, these facets should be assessed more carefully when planning future guidelines.

Colorectal cancer diagnosed during pregnancy: systematic review and treatment pathways.

The aim of this study was to identify the mode of presentation and incidence of colorectal cancer in pregnancy (CRC-p), assess the outcomes of the mother and foetus according to gestational age, treatment delivered and cancer features and location. A systematic review of the literature was carried out to identify studies reporting on CRC-p and pooled analysis of the reported data. Seventy-nine papers reporting on 119 patients with unequivocal CRC-p were included. The calculated pooled risk is 0.002% and age at diagnosis has decreased over time. The median age at diagnosis was 32 (range, 17-46) years. Twelve per cent, 41 and 47% of CRC-p were diagnosed during the first, second and third trimester. The CRC-p site was the colon in 53.4% of cases, the rectum in 44% and multiple sites in 2.6%. Bleeding occurred in 47% of patients, abdominal pain in 37.6%, constipation in 14.1%, obstruction in 9.4% and perforation in 2.4%. Out of 82 patients whose treatment was described, 9.8% received chemotherapy during pregnancy. None of their newborns developed permanent disability, one developed hypothyroidism and 72% of newborns were alive. Vaginal delivery was possible in 60% of cases. Anterior resection was performed in 30% of patients and abdominoperineal excision of the rectum in 14.9%. Five patients had either synchronous (60%) or metachronous liver resection (40%). The median survival in these patients was 42 (0-120) months. Fifty-five per cent of patients were alive at the last available follow-up. The median survival of the mother was 36 (0-360) months. Patients with rectal cancer had longer survival compared with patients with colon cancer (P=0.0072). CRC-p is rare, leading to symptoms being overlooked, and diagnosis made at advanced stages. Cases described in the literature include patients who had cancer before pregnancy or developed it after delivery. Survival has not increased over time and the management of these patients requires collaboration between specialties and active interaction with the patients.