Factors associated with advanced colorectal cancer differ between young and older adults in England: a population-based cohort study.

AIM: Advanced stage presentation of colorectal cancer is associated with poorer survival outcomes, particularly among young adults. This study aimed to determine whether demographic risk factors for advanced stage presentation differed between young and older adults. METHOD: Individual-level data on all incident colorectal cancers in people aged 20 years and above were extracted from the National Cancer Registration and Analysis Service database for the years 2012 to 2015. Patients were divided into two cohorts: young-onset colorectal cancer (YOCC) if aged 20-49 years and older-onset colorectal cancer (OOCC) if aged 50 years and above. Logistic regression was used to identify risk factors for advanced stage presentation, defined as TNM Stage III or IV, in each cohort. RESULTS: There were 7075 (5.2%) patients in the YOCC cohort and 128 345 (94.8%) patients in the OOCC cohort. Tumours in the YOCC cohort were more likely to be at an advanced stage (67.2% vs 55.3%, P < 0.001) and located distally (63.7% vs 55.4%, P < 0.001). No demographic factor was consistently associated with advanced stage presentation in the YOCC cohort. Among the OOCC cohort, increased social deprivation [OR (Index of Multiple Deprivation quintile 5 vs 1) = 1.11 (95% CI 1.07-1.16), P < 0.001], Black/Black British ethnicity [OR (baseline White) = 1.25 (95% CI 1.11-1.40), P < 0.001] and residence in the East Midlands [OR (baseline London) = 1.11 (95% CI 1.04-1.17), P = 0.001] were associated with advanced stage presentation. CONCLUSION: Demographic factors associated with advanced disease were influenced by age. The effects of social deprivation and ethnicity were only observed in older adults and mirror trends in screening uptake. Targeted interventions for high-risk groups are warranted.

Demographic trends in the incidence of young-onset colorectal cancer: a population-based study.

BACKGROUND: Evidence is emerging that the incidence of colorectal cancer is increasing in young adults, but the descriptive epidemiology required to better understand these trends is currently lacking. METHODS: A population-based cohort study was carried out including all adults aged 20-49 years diagnosed with colorectal cancer in England between 1974 and 2015. Data were extracted from the National Cancer Registration and Analysis Service database using ICD-9/10 codes for colorectal cancer. Temporal trends in age-specific incidence rates according to sex, anatomical subsite, index of multiple deprivation quintile and geographical region were analysed using Joinpoint regression. RESULTS: A total of 56 134 new diagnoses of colorectal cancer were analysed. The most sustained increase in incidence rate was in the group aged 20-29 years, which was mainly driven by a rise in distal tumours. The magnitude of incident rate increases was similar in both sexes and across Index of Multiple Deprivation quintiles, although the most pronounced increases in incidence occurred in the southern regions of England. CONCLUSION: Colorectal cancer should no longer be considered a disease of older people. Changes in incidence rates should be used to inform future screening policy, preventative strategies and research agendas, as well as increasing public understanding that younger people need to be aware of the symptoms of colorectal cancer.

ANTECEDENTES: Están apareciendo evidencias de que la incidencia del cáncer colorrectal (colorectal cancer, CRC) está aumentando en adultos jóvenes, pero se carece de la epidemiología descriptiva necesaria para comprender mejor estas tendencias. MÉTODOS: Se realizó un estudio de cohortes de base poblacional de todos los adultos de 20 a 49 años diagnosticados de CRC en Inglaterra entre 1974 y 2015. Los datos se extrajeron de la base de datos NCRAS utilizando los códigos ICD9/10 para el CRC. Las tendencias temporales en las tasas de incidencia específicas por edad (incidence rates, IR) según el sexo, la localización anatómica, el quintil del índice de privación múltiple (index of multiple deprivation, IMD) y la región geográfica se analizaron mediante un modelo de regresión joinpoint. RESULTADOS: Se analizaron un total de 56.134 nuevos diagnósticos de CRC. El aumento más sostenido en la IR se produjo en el grupo de edad de 20 a 29 años, principalmente a expensas de un incremento de los tumores distales. La magnitud de los aumentos de IR fue similar en ambos sexos y en los quintiles del IMD, aunque los aumentos más pronunciados en la incidencia se registraron en las regiones del sur de Inglaterra. CONCLUSIÓN: El CRC ya no debe ser considerado una enfermedad de las personas mayores: los cambios en las tasas de incidencia deberán tenerse en cuenta en las futuras políticas de cribado, en las estrategias preventivas y en los proyectos de investigación, así como para aumentar la toma de conciencia de la población de que las personas más jóvenes deben estar al corriente de los síntomas del CRC.

Optimized delivery of siRNA into 3D tumor spheroid cultures in situ.

3D tissue culture provides a physiologically relevant and genetically tractable system for studying normal and malignant human tissues. Despite this, gene-silencing studies using siRNA has proved difficult. In this study, we have identified a cause for why traditional siRNA transfection techniques are ineffective in eliciting gene silencing in situ within 3D cultures and proposed a simple method for significantly enhancing siRNA entry into spheroids/organoids. In 2D cell culture, the efficiency of gene silencing is significantly reduced when siRNA complexes are prepared in the presence of serum. Surprisingly, in both 3D tumour spheroids and primary murine organoids, the presence of serum during siRNA preparation rapidly promotes entry and internalization of Cy3-labelled siRNA in under 2 hours. Conversely, siRNA prepared in traditional low-serum transfection media fails to gain matrigel or spheroid/organoid entry. Direct measurement of CTNNB1 mRNA (encoding ß-catenin) from transfected tumour spheroids confirmed a transient but significant knockdown of ß-catenin when siRNA:liposome complexes were formed with serum, but not when prepared in the presence of reduced-serum media (Opti-MEM). Our studies suggest a simple modification to standard lipid-based transfection protocols facilitates rapid siRNA entry and transient gene repression, providing a platform for researchers to improve siRNA efficiency in established 3D cultures.

Potentiating the effects of radiotherapy in rectal cancer: the role of aspirin, statins and metformin as adjuncts to therapy.

BACKGROUND: Complete tumour response (pCR) to neo-adjuvant chemo-radiotherapy for rectal cancer is associated with a reduction in local recurrence and improved disease-free and overall survival, but is achieved in only 20-30% of patients. Drug repurposing for anti-cancer treatments is gaining momentum, but the potential of such drugs as adjuncts, to increase tumour response to chemo-radiotherapy in rectal cancer, is only just beginning to be recognised. METHODS: A systematic literature search was conducted and all studies investigating the use of drugs to enhance response to neo-adjuvant radiation in rectal cancer were included. 2137 studies were identified and following review 12 studies were extracted for full text review, 9 studies were included in the final analysis. RESULTS: The use of statins or aspirin during neo-adjuvant therapy was associated with a significantly higher rate of tumour downstaging. Statins were identified as a significant predictor of pCR and aspirin users had a greater 5-year progression-free survival and overall survival. Metformin use was associated with a significantly higher overall and disease-free survival, in a subset of diabetic patients. CONCLUSIONS: Aspirin, metformin and statins are associated with increased downstaging of rectal tumours and thus may have a role as adjuncts to neoadjuvant treatment, highlighting a clear need for prospective randomised controlled trials to determine their true impact on tumour response and overall survival.

Predictive value of abnormally raised serum bilirubin in acute appendicitis: a cohort study.

UNLABELLED: Appendicitis is a common clinical diagnosis aided by biochemical, haematological and radiological investigations. The role of some investigations, such as bilirubin, is controversial but could indicate complicated appendicitis. Accurate diagnosis enables prioritisation of patients on operating lists and a possible reduction in unnecessary investigations. METHODS: This is a retrospective cohort study of 1347 patients who underwent appendicectomy. Statistical analysis of serum bilirubin levels was performed according to histological classification of appendicitis. RESULTS: Mean serum bilirubin levels; perforated/gangrenous appendicitis 20.5 mg/L (SD 12.6), inflamed appendicitis mean 17.5 mg/L (SD CI 11.1), normal appendix mean 12.6 mg/L (7.0). Kruskal-Wallis indicated bilirubin levels were significantly different (H=128.87, df=4, p<.001) between histological groups, and a post hoc analysis with Bonferroni adjustment showed perforated/gangrenous to be significantly higher than all other groups (p<.001). Binary logistic regression combining White Cell Count (WCC) level, C-Reactive Protein (CRP) and Bilirubin levels gave a sensitivity and specificity of .69 with AUROC=.766 (std error .015) for gangrenous/perforated. Assessment according to clinical relevance showed only 30.4% of patients with an abnormally raised bilirubin had gangrenous/perforated appendicitis. CONCLUSIONS: Serum bilirubin does not independently predict perforation/gangrenous appendicitis. Statistical analysis showed differences in mean bilirubin between histological groups however this did not relate to clinical significance as bilirubin levels were still within normal clinical limits. Diagnosis of complicated appendicitis should be made on clinical grounds, with utilization of biochemical/haematological investigations, but there should not be independent reliance on investigations such as bilirubin.

Delayed presentation of vernix caseosa peritonitis.

INTRODUCTION: Vernix caseosa peritonitis (VCP) is a rare and poorly recognised condition resulting from a sustained foreign body reaction to the vernix caseosa of the baby. This case-based review aims to highlight its importance for any medical team managing patients with peritonitis who have undergone a recent Caesarean section. CASE REPORT: A 31-year-old woman presented 5 weeks after a Caesarean section with symptoms and signs of peritonitis. CONCLUSIONS: Laparotomy and peritoneal lavage is the mainstay of treatment for VCP. Knowledge of the condition may stop inadvertent resection of normal intra-abdominal organs. Greater awareness of VCP is required to ensure earlier recognition as patients can recover well following timely operative intervention.

Role of oxygen in wound healing: a review of evidence.

OBJECTIVE: To review the evidence regarding the influence of oxygen as an intrinsic factor on cutaneous wound healing. METHOD: A literature search was performed using Ovid and the Cochrane Database with the search terms: 'Wound healing', 'Oxygen', 'Collagen', 'Angiogenesis', 'Inflammation' and 'Surgical Site Infection'. Human and animal studies were included if relevant and examined for methodological quality. RESULTS: There are no meta-analyses of the use of oxygen in wound healing and only two randomised controlled trials (RCTs). Studies vary in methodological quality. The majority of the data comes from animal models. In total 1568 studies on wound healing and oxygen were found. CONCLUSION: Oxygen is vital throughout wound healing, especially in the inflammatory and proliferative phases. Research suggests that patient supplementation with oxygen could enhance bacterial killing and angiogenesis, reduce surgical site infection rates and increase wound tensile strength, facilitating improved healing. CONFLICT OF INTEREST: None.

Effects of probenecid on brain-cerebrospinal fluid-blood distribution kinetics of E-Delta 2-valproic acid in rabbits.

E-Delta 2-valproic acid (E-Delta 2-VPA), a major active metabolite of VPA, has been proposed as an alternative to VPA because it is less hepatotoxic and is nonteratogenic. In rodents, VPA and E-Delta 2-VPA have a brain tissue/free plasma concentration ratio less than unity, which suggests rapid removal of the alkanoate anticonvulsants from the central nervous system. This study in rabbits employed a simultaneous iv infusion-ventriculocisternal (VC) perfusion technique to investigate the steady-state kinetics of E-Delta 2-VPA transport at the blood-brain barrier, the blood-cerebrospinal fluid (CSF) barrier, and the neural cell membrane. Probenecid (PBD) was coadministered to probe the mediation of transport by organic anion transporter(s). Rabbits in the control group (N = 6) received an iv infusion of E-Delta 2-VPA to achieve a steady-state plasma concentration of 50 to 60 microg/ml. Blood and cisternal outflow of mock CSF perfusate were continuously sampled. Midway through the experiment, the VC perfusate was switched to one containing [3H]E-Delta 2-VPA. At 225 min, the rabbits were sacrificed, and each brain was removed and dissected into ten regions. Rabbits in the PBD group (N = 9) received an iv infusion and VC perfusion as in the control group as well as concomitant iv infusion of the inhibitor. The mean steady-state VC extraction ratio for [3H]E-Delta 2-VPA did not differ between the control and PBD groups (63.7 +/- 8.3% vs. 60. 6 +/- 9.6%), indicating the lack of a significant PBD-sensitive transport at the choroidal epithelium. Coadministration of PBD elevated brain concentration of cold E-Delta 2-VPA in the absence of a significant change in total or free steady-state plasma concentration. Mean E-Delta 2-VPA brain tissue/free plasma concentration ratios in the various brain regions were 3.5- to 5.2-fold higher in PBD-treated animals than in the controls. Significant increases (3.0- to 4.5-fold) in the mean brain tissue/cisternal perfusate concentration ratios were also observed. Compartmental modeling of the steady-state distribution data suggested that clearance of E-Delta 2-VPA from the brain parenchyma is governed jointly by efflux transporters at the neural cell membrane and brain capillary endothelium. Moreover, PBD-induced elevation of E-Delta 2-VPA tissue concentrations is attributed primarily to inhibition of E-Delta 2-VPA efflux transport at the neural cell membrane, resulting in both intracellular trapping and greater tissue retention of E-Delta 2-VPA.