132 research outputs found
Fibroblast growth factor-2, chemo-resistance and colorectal cancer
No full textIntroduction:
The role of fibroblast growth factor-2 (FGF-2) on colorectal cancer (CRC) cells
exposed to chemotherapy has not been studied extensively. This thesis investigated
whether FGF-2 mediates chemoresistance in primary (SW480) and metastatic
(SW620) colon adenocarcinoma cell lines.
Methods:
Proliferation assays were used to assess the response of SW480 and SW620 colon
cancer cell lines to varying concentrations of FGF-2 and to optimise the dose of 5-
FU at which 50% cell death was observed. Cell survival assays were performed
following 96 hours exposure to 5-FU ± FGF-2. Levels of chemotherapy induced
apoptosis were determined using Caspase-3/7 assay. Expression of anti-apoptotic
proteins (Bcl-2 and Bcl-XL) and FGFRs at both protein and gene level were
determined to see if these contributed to the difference in chemoprotection observed. Results:
At 0.25 ng/ml, FGF-2 did not affect proliferation in either cell lines. 25μM of 5-FU
resulted in 50% kill in both cell lines. Significant cell survival was observed when
FGF-2 (0.25 ng/ml) pre-treated SW620 cells were exposed to 5-FU (25 μM)
compared to cells exposed to 5-FU alone (81% vs 60%, p=0.015). This
chemoresistance was associated with attenuation of cellular apoptosis (p=0.04) with
no significant change in expression of Bcl-2 and Bcl-XL at gene or protein level. This
survival advantage was not seen in SW480 cells (59% vs 55%, p=0.35). There were
no observed differences in the expression of FGFR1-4 in either cell lines.
Conclusion:
FGF-2 offers chemoresistance to SW620 and not to SW480 cells exposed to 5-FU.
Both cell lines expressed fgf2 and fgfr1-4 genes, suggesting that fgfr expression does
not account for the difference in chemoresistance. FGF-2 offered protection by
causing significant reduction in chemotherapy induced apoptosis in SW620 colon
cancer cell line; however this was not due to increased expression of anti-apoptotic
proteins. The molecular mechanisms for this selective chemoprotection need to be
investigated further
Outcomes of the metabolically healthy obese
No full textIntroduction: Obesity is a worldwide epidemic, Metabolic Healthy Obesity (MHO) is a vital subcohort of obesity that needs to be further investigated and epidemiologically defined. This has not received the clinical and public health attention it deserves and would help in targeting lifestyle and interventions (surgery) to those best suited.
Methods: This thesis utilised long term primary care follow up using the Clinical Practice Research Datalink (CPRD) to quantify prevalence, investigate transition, investigate all-cause mortality in the sub-cohort and study intervention outcomes in the United Kingdom.
Results: Total number of 414,522 patients were extracted, of which 231,399 (55.8%) had a body mass index (BMI) recorded. This thesis utilised 180,560 patients after exclusions. The prevalence of MHO in the UK population was 128,191/180,560 (71.0%), of which 71,485/128,191 (55.8%) remained healthy (p=<0.01) with a mean follow-up of 68.2 months. There was a 3.7% mortality rate in the MHO vs the metabolically unhealthy cohort 7.1% with an increased risk of mortality associated with a high BMI, late age at diagnosis and male gender. Frequency of bariatric surgery was generally was performed more in the metabolically healthy than unhealthy, 2.2% vs 1.9%. On Cox regression analysis, bariatric surgery remained a nonsignificant independent factor of survival within both the metabolically healthy and unhealthy obese.
Conclusion: The implication of this study is that a diagnosis of obesity as an independent factor for immediate determination of impending complications. It is imperative that the body mass index of an obese patient is laid side by side with their metabolic rate indices. On the grounds of conclusions from this thesis, further studies into the pathophysiology of metabolically unhealthy obesity are necessary, with a close reference to the presence or absence of comorbidity.Open Acces
Risk of GERD-related disorders in obese patients on PPI therapy: a population analysis
No full textBackground
Increasing prevalence of obesity has shown an associated increase in gastroesophageal reflux disease (GERD)-related diseases. Proton pump inhibitor (PPI) therapy has been demonstrated to reduce the incidence of such diseases. The study’s aim was to analyze the Clinical Practice Research Datalink (CPRD) to determine factors that increase the propensity of obese patients on PPIs to develop Barrett’s esophagus (BE) and esophageal carcinoma.
Method
A case-control population study was carried out, including patients from the CPRD. Clinicopathological factors were extracted for each patient alongside clinical endpoints of GERD, BE, and esophageal carcinoma. Multivariate analysis was utilized to identify factors that increase the propensity to develop BE and esophageal carcinoma. Statistical significance was p < 0.050.
Results
One hundred sixty five thousand nine hundred twenty nine obese patients on PPI treatment were identified up until July 2017. Median follow-up time was 119.0 months (range 11.3–1397.9 months). In patients with GERD, the following were associated with increased BE risk: age ≥ 60 years (OR = 1.197; p = 0.039), male (OR = 2.209; p < 0.001), H2 antagonists (OR = 1.377; p < 0.001), D2 antagonists (OR = 1.241; p = 0.008), and hiatus hernias (OR = 6.772; p = 0.017). The following were associated with increased risk of esophageal carcinoma: age (OR = 2.831; p = 0.031), male sex (OR = 3.954; p = 0.003), and hiatus hernias (OR = 12.170; p < 0.001). Only D2 antagonists (OR = 2.588; p = 0.002) were associated with increased risk of developing esophageal carcinoma in BE patients.
Conclusions
In obese patients on PPI therapy for reflux, higher BMIs were not associated with increased risk of BE or esophageal carcinoma. Males, older patients, and those with hiatus hernias are at increased risk of developing BE and carcinoma. Failure of PPI monotherapy is predictive of future metaplasia and dysplasia
Fibroblast growth factor-2, chemoresistance and colorectal cancer
No full textIntroduction: The role of fibroblast growth factor-2 (FGF-2) on colorectal cancer (CRC) cells exposed to chemotherapy has not been studied extensively. This thesis investigated whether FGF-2 mediates chemoresistance in primary (SW480) and metastatic (SW620) colon adenocarcinoma cell lines. Methods: Proliferation assays were used to assess the response of SW480 and SW620 colon cancer cell lines to varying concentrations of FGF-2 and to optimise the dose of 5- FU at which 50% cell death was observed. Cell survival assays were performed following 96 hours exposure to 5-FU ± FGF-2. Levels of chemotherapy induced apoptosis were determined using Caspase-3/7 assay. Expression of anti-apoptotic proteins (Bcl-2 and Bcl-XL) and FGFRs at both protein and gene level were determined to see if these contributed to the difference in chemoprotection observed. Results: At 0.25 ng/ml, FGF-2 did not affect proliferation in either cell lines. 25μM of 5-FU resulted in 50% kill in both cell lines. Significant cell survival was observed when FGF-2 (0.25 ng/ml) pre-treated SW620 cells were exposed to 5-FU (25 μM) compared to cells exposed to 5-FU alone (81% vs 60%, p=0.015). This chemoresistance was associated with attenuation of cellular apoptosis (p=0.04) with no significant change in expression of Bcl-2 and Bcl-XL at gene or protein level. This survival advantage was not seen in SW480 cells (59% vs 55%, p=0.35). There were no observed differences in the expression of FGFR1-4 in either cell lines. Conclusion: FGF-2 offers chemoresistance to SW620 and not to SW480 cells exposed to 5-FU. Both cell lines expressed fgf2 and fgfr1-4 genes, suggesting that fgfr expression does not account for the difference in chemoresistance. FGF-2 offered protection by causing significant reduction in chemotherapy induced apoptosis in SW620 colon cancer cell line; however this was not due to increased expression of anti-apoptotic proteins. The molecular mechanisms for this selective chemoprotection need to be investigated further.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Complications after discharge and delays in adjuvant chemotherapy following colonic resection: a cohort study of linked primary and secondary care data
No full textAIM: By understanding the reasons for delays in adjuvant chemotherapy (AC) after colonic resection, there is the potential to improve patient outcome. The aim of this study is to determine the extent and impact of complications after hospital discharge on delays to AC. METHOD: The study cohort included patients from Hospital Episode Statistics (HES) who had a colorectal cancer resection; linkage to primary care data was provided by the Clinical Practice Research Datalink (CPRD). Complications during the index hospital stay (from HES) and after discharge (from CPRD) were compared. The risk of late AC treatment (8 weeks or later) following a complication, stoma at the index procedure or emergency admission was described after accounting for age and Charlson score. A Cox hazards model determined the association of these factors with overall survival (OS). RESULTS: A total of 1266 patients underwent AC following colon cancer resection, of whom 598 (47.2%) received treatment within 8 weeks. Patients receiving late AC had a significantly higher proportion of re-operations (7.0% vs 3.3% P < 0.005) and wound infections (5.5% vs 3.7% P = 0.042), with 96% of the latter only being noted in CPRD. In multivariate analysis, the risk of AC delay significantly increased following a complication (OR 1.53, 95% CI 1.16-2.03, P = 0.003) or a stoma at the index operation. AC delay was associated with worse OS [hazard ratio (HR) 1.44, 95% CI 1.16-1.79, P = 0.001], as was an emergency admission (HR 1.59, 95% CI 1.21-1.98, P < 0.0005). However, the presence of a complication did not independently reduce OS (HR 1.15, 95%CI 0.89-1.48, P = 0.295). CONCLUSION: The true extent and impact of complications following colonic resection is underestimated when only secondary care data are used
Induction of Proteases in Peritoneal Carcinomatosis, the Role of ICAM-1/CD43 Interaction
No full textIntroduction: The development of peritoneal metastases is a significant clinical issue in the treatment of abdominal cancers and is associated with poor prognosis. We have previously shown that ICAM-1-CD43 interaction plays a significant role in tumor adhesion. However, an invasive phenotype is critical to establish tumor progression via cell associated and secreted proteases including matrix metalloproteinases. High metalloproteinases level significantly enhanced metastasis phenotype on tumors, a detrimental effect on surgical outcome. We investigated the role of direct and indirect signaling between the mesothelium and the tumor cells in enhancing tumor invasion and possible therapeutic intervention.Methods: Mesothelial cells were enzymatically derived from human omental tissue and implanted in 24 wells plates. Colorectal cancer cells were then introduced and allowed a direct and an indirect contact with the mesothelial layer. Anti-ICAM antibodies, anti-CD43 antibodies, and heparin were used to block MMP production. Gelatin zymography was performed on the supernatant to detect MMPs activity.Results: MMP production was observed in mesothelial and tumor cells. Direct contact between cell types enhanced MMP9 and 2 (p < 0.05). Indirect contact also stimulate MMPs but at a lower degree. ICAM-1 blocking antibodies attenuated MMP production in direct contact to that observed in the indirect. Heparin introduction achieved a similar outcome. Conclusions: ICAM-1-CD43 interaction plays a vital role in tumor cells-peritoneum adhesion and invasion, which is manifested by the increased production of MMPs leading to tumor invasion and peritoneal loco-regional. Blocking this interaction with heparin can provide a new therapeutic option
The STAR score: a method for auditing clinical records
No full textINTRODUCTION
Adequate medical note keeping is critical in delivering high quality healthcare. However, there are few robust tools available for the auditing of notes. The aim of this paper was to describe the design, validation and implementation of a novel scoring tool to objectively assess surgical notes.
METHODS
An initial ‘path finding’ study was performed to evaluate the quality of note keeping using the CRABEL scoring tool. The findings prompted the development of the Surgical Tool for Auditing Records (STAR) as an alternative. STAR was validated using inter-rater reliability analysis. An audit cycle of surgical notes using STAR was performed. The results were analysed and a structured form for the completion of surgical notes was introduced to see if the quality improved in the next audit cycle using STAR. An education exercise was conducted and all participants said the exercise would change their practice, with 25% implementing major changes.
RESULTS
Statistical analysis of STAR showed that it is reliable (Cronbach’s a = 0.959). On completing the audit cycle, there was an overall increase in the STAR score from 83.344% to 97.675% (p<0.001) with significant improvements in the documentation of the initial clerking from 59.0% to 96.5% (p<0.001) and subsequent entries from 78.4% to 96.1% (p<0.001).
CONCLUSIONS
The authors believe in the value of STAR as an effective, reliable and reproducible tool. Coupled with the application of structured forms to note keeping, it can significantly improve the quality of surgical documentation and can be implemented universally
Randomized controlled multicenter international clinical trial of self-gripping Parietex (TM) ProGrip (TM) polyester mesh versus lightweight polypropylene mesh in open inguinal hernia repair : interim results at 3 months
No full textPurpose: To compare clinical outcomes following sutureless Parietex (TM) ProGrip (TM) mesh repair to traditional Lichtenstein repair with lightweight polypropylene mesh secured with sutures. Methods: This is a 3-month interim report of a 1-year multicenter international study. Three hundred and two patients were randomized; 153 were treated with Lichtenstein repair (L group) and 149 with Parietex (TM) ProGrip (TM) precut mesh (P group) with or without fixation. The primary outcome measure was postoperative pain using the visual analog scale (VAS, 0-150 mm); other outcomes were assessed prior to surgery and up to 3 months postoperatively. Results: Compared to baseline, pain score was lower in the P group at discharge (-10%) and at 7 days (-13%), while pain increased in the L group at discharge (+39%) and at 7 days (+21%). The difference between groups was significant at both time points (P = 0.007 and P = 0.039, respectively). In the P group, patients without fixation suffered less pain compared to those with single-suture fixation (1 month: -20.9 vs. -6.15%, P = 0.02; 3 months: -24.3 vs. -7.7%, P = 0.01). The infection rate was significantly lower in the P group during the 3-month follow-up (2.0 vs. 7.2%, P = 0.032). Surgery duration was significantly shorter in the P group (32.4 vs. 39.1 min; P < 0.001). No recurrence was observed at 3 months in both groups. Conclusion: Surgery duration, early postoperative, pain and infection rates were significantly reduced with self-gripping polyester mesh compared to Lichtenstein repair with polypropylene mesh. The use of fixation increased postoperative pain in the P group. The absence of early recurrence highlights the gripping efficiency effect.</p
Fate of the metabolically healthy obese-is this term a misnomer? A study from the Clinical Practice Research Datalink
No full textINTRODUCTION: The metabolically healthy obese (MHO) phenotype may express typical characteristics on long-term follow-up. Little is known about the initiation of this phenotypes and its future stability. AIM: The Clinical Practice Research Datalink (CPRD) is a large-scale primary care database. The aim of this study was to assess the stability of, and evaluate the factors associated with a transition into an unhealthy outcome in, a MHO population in the UK. METHODS: The CPRD was interrogated for a diagnosis of 'obesity' and cross-referenced with a body mass index (BMI) ≥35 kg/m2; participants were further classified as MH using a clinical diagnostic code or a relative therapeutic code. A hazard cox regression univariate and multivariate analysis evaluated the time to transition for independent variables. RESULTS: There were 231,399 patients with a recorded BMI of 35 kg/m2 or greater. Incomplete records were eliminated and follow-up limited to 300 months, the cohort was reduced to 180,560 patients. The prevalence of MHO within the obese population from the CPRD was 128,191/180,560 (71%). MHO individuals, who were of male gender (hazard ratio (HR) 1.23 (1.21-1.25), p = < 0.01), older age group (HR 3.93 (3.82-4.04), p = < 0.01), BMI of 50-60 kg/m2 at baseline (HR 1.32(1.26-1.38), p = 0.01), smokers (HR 1.07(1.05-1.09), p = < 0.01) and regionally from North West England (HR 1.15(1.09-1.21), p = < 0.01) were more prone to an unhealthy transition (to develop comorbidities). Overall, of those MH at baseline, 71,485/128,191(55.8%) remained healthy on follow-up, with a mean follow-up of 113.5 (standard deviations (SD) 78.6) months or 9.4 (SD 6.6) years. CONCLUSIONS: From this unique large data set, there is a greater prevalence of MHO individuals in the UK population than in published literature elsewhere. Female gender, younger age group, and lower initial weight and BMI were found to be significant predictors of sustained metabolic health in this cohort. However, there remains a steady progressive transition from a healthy baseline over the years
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