32 research outputs found
Aetiological and clinical aspects of symptomatic gallstone disease and pancreatic cancer.
Introduction
This work investigated in a UK prospective cohort study, firstly, the aetiology of gallstone disease, and secondly, that of pancreatic cancer, with a focus on physical activity and diet. The epidemiological studies benefitted from the accuracy of measurement tools, namely a validated physical activity questionnaire and a sevenday food diary (7-DFD). These novel methods aided the improved definition of risk factors thus highlighting biological mechanisms leading to disease and
methods of prevention. The third investigation was a clinical survey evaluating benefits for patients of a Pancreatic Support Service (PASS), which screened and treated nutritional and depressive symptoms in patients with pancreatic cancer.
Methods
The European Prospective Investigation into Cancer-Norfolk enrolled 25 639 men and women, aged 45-74 years, between 1993-1997, measuring anthropometrics, lifestyle factors, diet with 7-DFDs, physical activity and collecting serum samples at baseline. The cohort was followed up until 2010, with multi-variate hazard ratios calculated for incident symptomatic gallstones and pancreatic cancer according to risk factors. The clinical survey, compared survival, doses of chemotherapy and clinical parameters in a retrospective group of 16 patients and then in a prospective group of 19 patients who were also reviewed by PASS.
Results
For gallstone disease, positive associations were found for obesity, serum triglycerides, dietary calcium and trans fatty acids, with inverse associations for serum HDL, physical activity, alcohol, caffeinated coffee and dietary niacin, cholesterol and iron intake. Pancreatic cancer had inverse associations detected for physical activity, dietary docosahexaenoic acid, dietary vitamin E and selenium, and serum vitamin C. The survey found those reviewed by PASS had fewer and shorter hospital admissions with no effects on survival or doses of chemotherapy.
Conclusion
This work found associations between various dietary factors and physical activity for both symptomatic gallstones and pancreatic cancer. These findings have implications in understanding biological mechanisms and could lead to preventative public health measures for both diseases. The survey reported the introduction of PASS was associated with a reduced number and duration of hospital admissions and the reasons for this should be explored in future work.
*Submitted with two peer-reviewed articles which have not been uploaded to the repository. Articles available as part of thesis deposited at UEA Library
Dietary Fiber and the Risk of Pancreatic Cancer
Objectives: High dietary fiber may protect against pancreatic ductal adenocarcinoma (PDAC). We investigated associations between fiber intake and the risk of PDAC using for the first time 7-day food diaries. Methods: Participants in the European Prospective Investigation Into CancerâNorfolk completed the 7-day food diaries at recruitment. The cohort was followed up for 17 years to identify those who developed PDAC. Participants were divided into quintiles of fiber intake, and hazard ratios (HR) were estimated with their 95% confidence intervals (CIs). Fiber was tested for effect modification of high red and processed meat intake and smoking and the risk of PDAC. Results: No significant associations for any quintiles of intake (HR Q5 vs Q1, 1.08; 95% CI, 0.56â2.08) were detected with no trend across quintiles. A high-fiber diet modified positive associations between red and processed meats with the development of PDAC (HR trends, 0.89 [95% CI, 0.47â1.69] and 1.02 [95% CI, 0.55â1.88], respectively) but not those with lower fiber intake. Fiber intake did not modify the risk of PDAC in past and current smokers. Conclusion: The findings do not suggest that fiber protects against PDAC, although it may decrease potential deleterious effects of meats
Pain in patients with pancreatic cancer: prevalence, mechanisms, management and future developments
Pain affects approximately 80% of patients with pancreatic cancer, with half requiring strong opioid analgesia, namely: morphine-based drugs on step three of the WHO analgesic ladder (as opposed to the weak opioids: codeine and tramadol). The presence of pain is associated with reduced survival. This article reviews the literature regarding pain: prevalence, mechanisms, pharmacological, and endoscopic treatments and identifies areas for research to develop individualized patient pain management pathways. The online literature review was conducted through: PubMed, Clinical Key, Uptodate, and NICE Evidence. There are two principal mechanisms for pain: pancreatic duct obstruction and pancreatic neuropathy which, respectively, activate mechanical and chemical nociceptors. In pancreatic neuropathy, several histological, molecular, and immunological changes occur which correlate with pain including: transient receptor potential cation channel activation and mast cell infiltration. Current pain management is empirical rather etiology-based and is informed by the WHO analgesic ladder for first-line therapies, and then endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with resistant pain. For EUS-CPN, there is only one clinical trial reporting a benefit, which has limited generalizability. Case series report pancreatic duct stenting gives effective analgesia, but there are no clinical trials. Progress in understanding the mechanisms for pain and when this occurs in the natural history, together with assessing new therapies both pharmacological and endoscopic, will enable individualized care and may improve patientsâ quality of life and survival
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Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohnâs disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource
Objective: Thiopurines are widely used as maintenance therapy in inflammatory bowel disease (IBD) but the evidence base for their use is sparse and their role increasingly questioned. Using the largest series reported to date, we assessed the long-term effectiveness of thiopurines in ulcerative colitis (UC) and Crohnâs disease (CD), including their impact on need for surgery. Design: Outcomes were assessed in 11 928 patients (4968 UC, 6960 CD) in the UK IBD BioResource initiated on thiopurine monotherapy with the intention of maintaining medically induced remission. Effectiveness was assessed retrospectively using patient-level data and a definition that required avoidance of escalation to biological therapy or surgery while on thiopurines. Analyses included overall effectiveness, time-to-event analysis for treatment escalation and comparison of surgery rates in patients tolerant or intolerant of thiopurines. Results: Using 68 132 patient-years of exposure, thiopurine monotherapy appeared effective for the duration of treatment in 2617/4968 (52.7%) patients with UC compared with 2378/6960 (34.2%) patients with CD (p<0.0001). This difference was corroborated in a multivariable analysis: after adjusting for variables including treatment era, thiopurine monotherapy was less effective in CD than UC (OR 0.47, 95% CI 0.43 to 0.51, p<0.0001). Thiopurine intolerance was associated with increased risk of surgery in UC (HR 2.44, p<0.0001); with a more modest impact on need for surgery in CD (HR=1.23, p=0.0015). Conclusion: Thiopurine monotherapy is an effective long-term treatment for UC but significantly less effective in CD
HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn's Disease
Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.This article is freely available via Open Access. Click on Publisher URL to access the full-text
Mechanisms and management of loss of response to anti-TNF therapy for patients with Crohn's disease: 3-year data from the prospective, multicentre PANTS cohort study
This is the final version. Available from Elsevier via the DOI in this record.âŻBackground We sought to report the effectiveness of infliximab and adalimumab over the first 3 years of treatment
and to define the factors that predict anti-TNF treatment failure and the strategies that prevent or mitigate loss of
response.
Methods Personalised Anti-TNF therapy in Crohnâs disease (PANTS) is a UK-wide, multicentre, prospective
observational cohort study reporting the rates of effectiveness of infliximab and adalimumab in anti-TNF-naive patients
with active luminal Crohnâs disease aged 6 years and older. At the end of the first year, sites were invited to enrol
participants still receiving study drug into the 2-year PANTS-extension study. We estimated rates of remission across
the whole cohort at the end of years 1, 2, and 3 of the study using a modified survival technique with permutation
testing. Multivariable regression and survival analyses were used to identify factors associated with loss of response
in patients who had initially responded to anti-TNF therapy and with immunogenicity. Loss of response was defined
in patients who initially responded to anti-TNF therapy at the end of induction and who subsequently developed
symptomatic activity that warranted an escalation of steroid, immunomodulatory, or anti-TNF therapy, resectional
surgery, or exit from study due to treatment failure. This study was registered with ClinicalTrials.gov, NCT03088449,
and is now complete.
Findings Between March 19, 2014, and Sept 21, 2017, 389 (41%) of 955 patients treated with infliximab and
209 (32%) of 655 treated with adalimumab in the PANTS study entered the PANTS-extension study (median age
32·5 years [IQR 22·1â46·8], 307 [51%] of 598 were female, and 291 [49%] were male). The estimated proportion of
patients in remission at the end of years 1, 2, and 3 were, for infliximab 40·2% (95% CI 36·7â43·7),
34·4% (29·9â39·0), and 34·7% (29·8â39·5), and for adalimumab 35·9% (95% CI 31·2â40·5), 32·9% (26·8â39·2),
and 28·9% (21·9â36·3), respectively. Optimal drug concentrations at week 14 to predict remission at any later
timepoints were 6·1â10·0 mg/L for infliximab and 10·1â12·0 mg/L for adalimumab. After excluding patients who
had primary non-response, the estimated proportions of patients who had loss of response by years 1, 2, and 3
were, for infliximab 34·4% (95% CI 30·4â38·2), 54·5% (49·4â59·0), and 60·0% (54·1â65·2), and for adalimumab
32·1% (26·7â37·1), 47·2% (40·2â53·4), and 68·4% (50·9â79·7), respectively. In multivariable analysis, loss of
response at year 2 and 3 for patients treated with infliximab and adalimumab was predicted by low anti-TNF drug
concentrations at week 14 (infliximab: hazard ratio [HR] for each ten-fold increase in drug concentration 0·45
[95% CI 0·30â0·67], adalimumab: 0·39 [0·22â0·70]). For patients treated with infliximab, loss of response was
also associated with female sex (vs male sex; HR 1·47 [95% CI 1·11â1·95]), obesity (vs not obese 1·62 [1·08â2·42]),
baseline white cell count (1·06 [1·02â1·11) per 1 Ă 10âč increase in cells per L), and thiopurine dose quartile. Among
patients treated with adalimumab, carriage of the HLA-DQA1*05 risk variant was associated with loss of response
(HR 1·95 [95% CI 1·17â3·25]). By the end of year 3, the estimated proportion of patients who developed anti-drug
antibodies associated with undetectable drug concentrations was 44·0% (95% CI 38·1â49·4) among patients
treated with infliximab and 20·3% (13·8â26·2) among those treated with adalimumab. The development of antidrug antibodies associated with undetectable drug concentrations was significantly associated with treatment
without concomitant immunomodulator use for both groups (HR for immunomodulator use: infliximab 0·40
[95% CI 0·31â0·52], adalimumab 0·42 [95% CI 0·24â0·75]), and with carriage of HLA-DQA1*05 risk variant for
infliximab (HR for carriage of risk variant: infliximab 1·46 [1·13â1·88]) but not for adalimumab (HR 1·60
[0·92â2·77]). Concomitant use of an immunomodulator before or on the day of starting infliximab was associated
with increased time without the development of anti-drug antibodies associated with undetectable drug
concentrations compared with use of infliximab alone (HR 2·87 [95% CI 2·20â3·74]) or introduction of an
immunomodulator after anti-TNF initiation (1·70 [1·11â2·59]). In years 2 and 3, 16 (4%) of 389 patients treated
with infliximab and 11 (5%) of 209 treated with adalimumab had adverse events leading to treatment withdrawal.
Nine (2%) patients treated with infliximab and two (1%) of those treated with adalimumab had serious infections
in years 2 and 3.
Interpretation Only around a third of patients with active luminal Crohnâs disease treated with an anti-TNF drug were
in remission at the end of 3 years of treatment. Low drug concentrations at the end of the induction period predict
loss of response by year 3 of treatment, suggesting higher drug concentrations during the first year of treatment,
particularly during induction, might lead to better long-term outcomes. Anti-drug antibodies associated with
undetectable drug concentrations of infliximab, but not adalimumab, can be predicted by carriage of HLA-DQA1*05
and mitigated by concomitant immunomodulator use for both drugs.Guts UKCrohnâs and Colitis UKCure Crohnâs ColitisAbbVieMerck Sharp and DohmeNapp PharmaceuticalsPfizerCelltrion Healthcar