Opioid burden in patients with inoperable pancreatic adenocarcinoma and the development of a multivariable risk prediction model for opioid use: A retrospective cohort study.

INTRODUCTION: Risk prediction models to guide patient selection for early pre-emptive endoscopic ultrasound guided coeliac plexus neurolysis are lacking. This study aimed to determine in patients with inoperable pancreatic cancer: (1) opioid burden, (2) the relationship between opioid use and all-cause mortality, (3) risk factors for opioid use, and (4) develop and internally validate a risk prediction model for opioid use at three months. METHODS: This was a single-centre retrospective cohort study of patients with confirmed pancreatic cancer. Cox proportional hazard regression estimated the association between opioid use at baseline and all-cause mortality. Logistic regression estimated the associations between clinical and radiological variables with opioid use by three months. Two risk prediction models were developed for opioid use (clinical and clinical-radiological). Model discrimination and calibration was assessed. RESULTS: In total, 383 patients with inoperable pancreatic cancer were included. Prevalence of pain ranged between 37% and 47% at three monthly intervals in the first year of diagnosis. Opioid use at baseline was associated with poorer survival. Age, pain at presentation, performance status, tumour distance from the right ganglion, the anterior-posterior and the latero-lateral tumour dimensions were independent risk factors for the opioid use at three months. The Area Under Curve (AUC) for the clinical and clinical-radiological models was 0.81 and 0.84, respectively. Models were well calibrated. CONCLUSIONS: Opioid use is prevalent in patients with pancreatic cancer, associated with poor prognosis, and can be predicted based on clinical and radiological variables. External validation of this predictive model is required.

Clinical and Endoscopic Characteristics Associated With Post-Endoscopy Upper Gastrointestinal Cancers: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Ten percent of patients with an upper gastrointestinal cancer will have received an esophagogastroduodenoscopy (EGD) within 3 years before diagnosis, termed post-endoscopy upper gastrointestinal cancers (PEUGIC). We aimed to determine the characteristics of PEUGIC, and compare these with detected cancers. METHODS: We searched MEDLINE and Embase from inception for studies comparing the characteristics of PEUGIC and detected upper gastrointestinal cancers, and reported findings at the initial "cancer-negative" endoscopy. We synthesized results using random effects meta-analysis. This review is registered on PROSPERO, CRD42019125780. RESULTS: A total of 2696 citations were screened and 25 studies were included, comprising 81,184 UGI cancers, of which 7926 were considered PEUGIC. For PEUGIC assessed within 6 to 36 months of a "cancer-negative" EGD, the mean interval was approximately 17 months. Patients with PEUGIC were less likely to present with dysphagia (odds ratio [OR] 0.37) and weight loss (OR 0.58) and were more likely to present with gastroesophageal reflux (OR 2.64) than detected cancers. PEUGICs were more common in women in Western populations (OR 1.30). PEUGICs were typically smaller at diagnosis and associated with less advanced disease staging compared with detected cancers (OR 2.87 for stage 1 vs 2-4). Most EGDs (>75%) were abnormal preceding diagnosis of PEUGIC. CONCLUSIONS: There is a substantial delay in the diagnosis of PEUGIC. They are less likely to present with alarm symptoms than detected cancers. PEUGICs are overall less advanced at diagnosis. Most patients with PEUGIC have abnormalities reported at the preceding "cancer-negative" EGD. The epidemiology of PEUGIC may inform preventive strategy.

Statins as Potential Chemoprevention or Therapeutic Agents in Cancer: a Model for Evaluating Repurposed Drugs.

PURPOSE OF REVIEW: Repurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here. RECENT FINDINGS: In the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with "target" trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer.

Endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) technique and analgesic efficacy in patients with pancreatic cancer: A systematic review and meta-analysis.

BACKGROUND: Endoscopic Ultrasound-guided Celiac Plexus Neurolysis (EUS-CPN) for the treatment of abdominal pain in pancreatic cancer can be administered in three different ways, depending on the site of needle insertion: central injection (CI), bilateral injection (BI) and celiac ganglia neurolysis (CGN). This meta-analysis aimed to (1) estimate the overall efficacy of the EUS-CPN; (2) compare the efficacy of each of the three techniques; and (3) investigate demographic and disease characteristics as potential predictors of treatment response. METHODS: We searched MEDLINE and EMBASE for studies that reported the proportion of treatment responders to EUS-CPN overall, and according to the technique used. We performed a random effects meta-analysis of proportions, and meta-regression was used to estimate the association between technique and clinical characteristics on treatment response. The safety profile was reviewed through narrative synthesis. RESULTS: Overall response rate to EUS-CPN was 68% (95% CI 61%-74%) at week two and 53% (95% CI 45%-62%) at week four. There was no evidence of a significant difference in the response rates between the three techniques. Demographics and disease characteristics were not associated with treatment response. Serious complications have been reported for BI and CGN but not for CI. Moderate to high risk of bias was observed. DISCUSSION: EUS-CPN is a useful adjunct to opioids in the management of pain. There is no evidence of a difference in the efficacy among the three techniques, however, CI is the only one for which serious complications have not been reported. Future research should focus on the appropriate timing of EUS-CPN (early versus on demand) and randomised comparison to establish the comparative efficacy of each technique.

Iron deficiency: a modern primer to diagnosis and management.

PURPOSE OF REVIEW: Iron deficiency with anemia (IDA) and without anemia remain a diagnostic and management challenge. Iron deficiency has a broad spectrum of causes, including gastrointestinal malignancy. The purpose of this review is to summarize the value and limitations of current methods to diagnose iron deficiency and underline the relevance of contemporaneous evidence to guide the pretest probability of gastrointestinal disease. RECENT FINDINGS: A number of biomarkers for iron deficiency exist, and all have their caveats. Serum ferritin remains the most pragmatic means of diagnosing iron deficiency. Hepcidin holds future promise as a marker of iron status during inflammatory states. Men and postmenopausal women with IDA have the highest overall prevalence of gastrointestinal malignancy (∼11%), while premenopausal women with IDA (<1.5%) and those with iron deficiency without anemia (<0.5%) have a very low risk. Noninvasive investigation with fecal immunochemical test and fecal calprotectin hold promise to guide further investigations in lower risk groups. SUMMARY: Confirmation of iron deficiency remains a challenge. Appropriate risk stratification is the key to guiding judicious gastrointestinal investigation. Use of noninvasive tests may play an important role in lower risk groups. Risk prediction tools applicable to relevant populations are required.

Efficacy and safety profile of statins in patients with cancer: a systematic review of randomised controlled trials.

PURPOSE: A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review of randomised controlled trials (RCTs) in patients with solid tumours aimed to determine the efficacy of statin therapy on mortality outcomes, their safety profile and the risk of bias of included studies. METHODS: Full-text articles comparing statin therapy versus control in solid tumours and reporting mortality outcomes were identified from Medline and Embase from conception to February 2020. A systematic review with qualitative (primarily) and quantitative synthesis was conducted. This systematic review was prospectively registered (Prospero registration CRD42018116364). RESULTS: Eleven trials of 2165 patients were included. Primary tumour sites investigated included lung, colorectal, gastro-oesophageal, pancreatic and liver. Most trials recruited patients with advanced malignancy and used sub-maximal statin doses for relatively short durations. Aside from one trial which demonstrated benefit with allocation to pravastatin 40 mg in hepatocellular carcinoma, the remaining ten trials did not demonstrate efficacy with statins. The pooled hazard ratio for all-cause mortality with allocation to pravastatin in patients with hepatocellular carcinoma in two trials was 0.69 (95% confidence interval CI 0.30-1.61). Study estimates were imprecise. There were no clinically important differences in statin-related adverse events between groups. Overall, included trials were deemed low risk of bias. CONCLUSION: The trial evidence is not sufficiently robust to confirm or refute the efficacy and safety of statins in patients with solid malignant tumours. Study and patient characteristics may explain this uncertainty. The potential role of high-dose statins in adjuvant settings deserves further research.

Prevalence of gastrointestinal malignancy in iron deficiency without anaemia: A systematic review and meta-analysis.

BACKGROUND: Iron deficiency anaemia is associated with gastrointestinal (GI) malignancy and is an indication for GI investigations. However, the relevance of iron deficiency without anaemia (IDWA) and the underlying risks of GI malignancy are uncertain. Therefore, the aim of this study was to estimate the prevalence of GI malignancy in patients with IDWA overall and in clinically relevant subgroups. METHODS: We searched MEDLINE and EMBASE for studies that reported on the prevalence or risk of GI malignancy in patients with confirmed IDWA. We performed a random effects meta-analysis of proportions and assessed statistical heterogeneity using the I2 statistic. RESULTS: A total of 1923 citations were screened and 5 studies (4 retrospective cohorts, 1 prospective cohort) comprising 3329 participants with IDWA were included in the meta-analysis. Overall pooled random-effects estimates for prevalence of GI malignancy in those with IDWA were low (0.38%, 95% CI 0.00%-1.84%, I2 = 87.7%). Older patients (2.58%, 95% CI 0.00%-8.77%); non-screening populations (2.45%, 95% CI 0.16%-6.39%) and men and post-menopausal women (0.90%, 95% CI 0.11%-3.23%) with IDWA were at increased risk of GI malignancy compared to younger patients (0.00%, 95% CI 0.00%-0.21%); screened populations (0.24%, 95% CI 0.00%-1.10%) and pre-menopausal women (0.00%, 95% CI 0.00%-1.05%). CONCLUSION: Overall, IDWA is associated with a low risk of GI malignancy. Older patients and non-screening populations are at elevated risk and require GI investigations. Those not in these subgroups have a lower risk of GI malignancy and may wish to be monitored following discussion of the risk and potential benefits of GI investigations.

Single Nucleotide Polymorphisms and Post-operative Complications Following Major Gastrointestinal Surgery: a Systematic Review and Meta-analysis.

BACKGROUND: The human genome is an under-researched area of pre-operative risk stratification. Studies of genetic polymorphisms and their associations with acute post-operative complications in gastrointestinal surgery have reported statistically significant results, but have varied in methodology, genetic variations studied, and conclusions reached. To provide clarity, we conducted a systematic review and meta-analysis of single nucleotide polymorphisms and their association with post-operative complications after major gastrointestinal surgery. METHODS: We performed a literature search using Ovid MEDLINE and Web of Science databases. Studies were included if they investigated genetic polymorphisms and their associations with post-operative complications after major gastrointestinal surgery. We extracted clinical and genetic data from each paper and assessed for quality against the STrengthening the REporting of Genetic Association Studies (STREGA) guidelines. Odds ratios were presented, with 95% confidence intervals, to assess strengths of association. We conducted a meta-analysis on TNF-α-308, which had been assessed in three papers. RESULTS: Our search returned 68 papers, of which 5 were included after screening and full-text review. Twenty-two different single nucleotide polymorphisms (SNPs) were investigated in these studies. We found that all papers were genetic association studies, and had selected SNPs related to inflammation. The outcome investigated was most commonly post-operative infection, but also anastomotic leak and other non-infectious complications. Statistically significant associations were found for TNF-α-308, IL-10-819, PTGS2-765 and IFN-γ-874. There was significant variability in study quality and methodology. We conducted a meta-analysis on associations between the TNF-α-308 polymorphism and post-operative infection and report an OR of 1.18 (CI 0.27-5.21). CONCLUSIONS: We found biologically plausible associations between SNPs involved in inflammation and post-operative infection, but the available data were too limited and of insufficient quality to reach definitive conclusions. Further work is needed, including genome-wide association studies (GWAS).

The association between preoperative cardiopulmonary exercise-test variables and short-term morbidity after esophagectomy: A hospital-based cohort study.

BACKGROUND: Postoperative complications after esophagectomy are thought to be associated with reduced fitness. This observational study explored the associations between aerobic fitness, as determined objectively by preoperative cardiopulmonary exercise testing (CPEX), and 30-day morbidity after esophagectomy. METHODS: We retrospectively identified 254 consecutive patients who underwent esophagectomy at a single academic teaching hospital between September 2011 and March 2017. Postoperative complication data were measured using the Esophageal Complications Consensus Group definitions and graded using the Clavien-Dindo classification system of severity (blinded to cardiopulmonary exercise testing values). Associations between preoperative cardiopulmonary exercise testing variables and postoperative outcomes were estimated using logistic regression. RESULTS: A total of 206 patients (77% male) were included in the analyses, with a mean age of 67 years (SD 9). The mean values for the maximal oxygen consumed at the peak of exercise (VO2peak) and the anaerobic threshold were 21.1 mL/kg/min (SD 4.5) and 12.4 mL/kg/min (SD 2.8), respectively. The vast majority of patients (98.5%) had malignant disease-predominantly adenocarcinoma (84.5%), for which most received neoadjuvant chemotherapy (79%) and underwent minimally invasive Ivor Lewis esophagectomy (53%). Complications at postoperative day 30 occurred in 111 patients (54%), the majority of which were cardiopulmonary (72%). No associations were found between preoperative cardiopulmonary exercise testing variables and morbidity for either VO2peak (OR 1.00, 95% CI 0.94-1.07) or anaerobic threshold (OR 0.98, 95% CI 0.89-1.09). CONCLUSION: Preoperative cardiopulmonary exercise testing variables were not associated with 30-day complications after esophagectomy. The findings do not support the use of cardiopulmonary exercise testing as an isolated preoperative screening tool to predict short-term morbidity after esophagectomy. This modestly sized observational work highlights the need for larger studies examining associations between preoperative cardiopulmonary exercise testing and outcomes after esophagectomy to look for consistency in our findings.

Dietary antioxidant intake and the risk of developing Barrett's oesophagus and oesophageal adenocarcinoma.

BACKGROUND: We investigated in a cohort study, for the first time using 7-day food diaries (7-DFDs), for age-dependent inverse associations with antioxidants, which have anti-carcinogenic properties, and development of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). METHODS: A total of 24,068 well individuals completed 7-DFDs and donated blood. Vitamins C and E, carotenes, zinc and selenium intakes, and plasma vitamin C were measured. Participants were monitored for 15 years for BO and OAC. Hazard ratios (HRs) were estimated for: quintiles of intake and in participants younger and >=65 years at recruitment, the midpoint of BO peak prevalence. RESULTS: A total of 197 participants developed BO and 74 OAC. There were no significant associations between antioxidants and BO or OAC in the whole cohort or if >65 years at recruitment. In participants <65 years, for BO, there was an inverse trend across plasma vitamin C quintiles (trend HR = 0.82; 95% CI = 0.71-0.96, P = 0.01), OAC for plasma vitamin C (trend HR = 0.58; 95% CI = 0.37-0.92, P = 0.02) and for dietary vitamins C and E (trend HR = 0.71 95% CI = 0.51-0.99, P = 0.04 and trend HR = 0.70; 95% CI = 0.51-0.96; P = 0.03). CONCLUSIONS: Data supports a role for dietary antioxidants prevent BO and OAC, perhaps at the earlier stages of carcinogenesis.

Adjuvant Statin Therapy for Esophageal Adenocarcinoma: A Cost-Utility Analysis.

BACKGROUND: Emerging preclinical evidence indicates statins, medications commonly used in the prevention of cardiovascular disease (CVD), inhibit proliferation, promote apoptosis and limit invasiveness of esophageal adenocarcinoma (EAC). Population-based observational data demonstrate statin treatment after diagnosis of EAC is associated with significant reductions in all-cause and cancer-specific mortality. A feasibility study of adjuvant statin therapy following potentially curative resection for EAC has been completed, with planned progression to a full phase III, randomized controlled trial. OBJECTIVE: The aim was to estimate the cost-utility of statin therapy following surgical resection for EAC from a UK National Health Service (NHS) perspective. METHODS: A Markov model was developed to estimate the costs and outcomes [quality-adjusted life years (QALYs)] for hypothetical cohorts of patients with EAC exposed or not exposed to statins following potentially curative surgical resection. Model parameters were based on estimates from published observational and trial data. Costs, utilities and transition probabilities were modeled to reflect clinical practice from a payer's perspective. Probabilistic and one-way sensitivity analyses were performed to account for uncertainty in key parameters. RESULTS: Overall, a cost saving of £6781 per patient was realized with statin treatment compared to no statins. In probabilistic sensitivity analysis, 99% of all iterations were cost saving and 99% of all iterations were less than £20,000 per QALY gained. These results were robust to changes in the price and effectiveness of statins. CONCLUSIONS: The cohort exposed to statins had lower costs and better QALY outcomes than the no statin cohort. Assuming a causal improvement in disease outcomes following resection for EAC, statin therapy is very likely to be a cost-saving treatment.

The association between physical activity and the risk of symptomatic Barrett's oesophagus: a UK prospective cohort study.

BACKGROUND: Physical activity affects the functioning of the gastrointestinal system through both local and systemic effects and may play an important role in the aetiology of gastroesophageal reflux disease, Barrett's oesophagus and oesophageal adenocarcinoma. We investigated, for the first time in a large prospective cohort study, associations between recreational and occupational levels of physical activity and the incidence of Barrett's oesophagus. PARTICIPANTS AND METHODS: The European Prospective Investigation of Cancer-Norfolk recruited 30 445 men and women between 1993 and 1997. Occupational and recreational levels of physical activity were measured using a baseline questionnaire. The cohort was followed up until 2015 to identify symptomatic cases of Barrett's oesophagus. Cox proportional hazard regression estimated hazard ratios (HR) for physical activity and the development of disease. RESULTS: Two hundred and three participants developed Barrett's oesophagus (mean age: 70.6 years) the majority of whom were men (70.9%). There was an inverse association between standing occupations and disease risk [HR: 0.50, 95% confidence interval (CI): 0.31-0.82, P=0.006] when compared with sedentary jobs. Heavy manual occupations were positively associated with disease risk (HR: 1.66, 95% CI: 0.91-3.00), but conventional statistical significance was not reached (P=0.09). No associations were found between recreational activity and the risk of Barrett's oesophagus (HR: 1.34, 95% CI: 0.72-2.50, P=0.35, highest vs. lowest levels of activity). CONCLUSION: Our study suggests that occupational levels of physical activity may be associated with the risk Barrett's oesophagus. However, further work is required to confirm and describe specific occupations that may be protective.

Association Between Statin Use After Diagnosis of Esophageal Cancer and Survival: A Population-Based Cohort Study.

BACKGROUND & AIMS: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), commonly prescribed in the primary and secondary prevention of cardiovascular disease, promote apoptosis and limit proliferation of esophageal cancer cell lines. We investigated whether statin use after a diagnosis of esophageal cancer is associated with reduced esophageal cancer-specific and all-cause mortality. METHODS: We identified a cohort of 4445 men and women in the United Kingdom diagnosed with esophageal cancer from January 2000 through November 2009 using the General Practice Research Database. The National Cancer Registry and Office of National Statistics datasets established the histologic subtype and cancer-specific mortality, respectively. Cox proportional hazard regression analysis with time-dependent exposures estimated the association between statin use after diagnosis and esophageal cancer-specific and all-cause mortality. RESULTS: The median survival time of the entire cohort was 9.2 months (interquartile range [IQR], 3.7-23.2 mo). Among subjects who used statins after a diagnosis of esophageal cancer, the median survival time was 14.9 months (IQR, 7.1-52.3 mo) compared with 8.1 months for nonusers (IQR, 3.3-20 mo). In the entire cohort, statin use after diagnosis was associated with a decreased risk of esophageal cancer-specific mortality (adjusted hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.44-0.86) and all-cause mortality (HR, 0.67; 95% CI, 0.58-0.77). In patients with esophageal adenocarcinoma, statin use after diagnosis was associated with a decreased risk of esophageal cancer-specific mortality (HR, 0.61; 95% CI 0.38-0.96) and all-cause mortality (HR, 0.63; 95% 0.43-0.92). This effect was not observed in patients with esophageal squamous cell carcinoma. There was no evidence for effect modification of these associations with statin use before the cancer diagnosis. CONCLUSIONS: In a large population-based cohort, statin use after a diagnosis of esophageal adenocarcinoma, but not esophageal squamous cell carcinoma, was associated with reduced esophageal cancer-specific and all-cause mortality.

BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett's Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia.

OBJECTIVES: Barrett's esophagus (BE) is a common premalignant lesion for which surveillance is recommended. This strategy is limited by considerable variations in clinical practice. We conducted an international, multidisciplinary, systematic search and evidence-based review of BE and provided consensus recommendations for clinical use in patients with nondysplastic, indefinite, and low-grade dysplasia (LGD). METHODS: We defined the scope, proposed statements, and searched electronic databases, yielding 20,558 publications that were screened, selected online, and formed the evidence base. We used a Delphi consensus process, with an 80% agreement threshold, using GRADE (Grading of Recommendations Assessment, Development and Evaluation) to categorize the quality of evidence and strength of recommendations. RESULTS: In total, 80% of respondents agreed with 55 of 127 statements in the final voting rounds. Population endoscopic screening is not recommended and screening should target only very high-risk cases of males aged over 60 years with chronic uncontrolled reflux. A new international definition of BE was agreed upon. For any degree of dysplasia, at least two specialist gastrointestinal (GI) pathologists are required. Risk factors for cancer include male gender, length of BE, and central obesity. Endoscopic resection should be used for visible, nodular areas. Surveillance is not recommended for <5 years of life expectancy. Management strategies for indefinite dysplasia (IND) and LGD were identified, including a de-escalation strategy for lower-risk patients and escalation to intervention with follow-up for higher-risk patients. CONCLUSIONS: In this uniquely large consensus process in gastroenterology, we made key clinical recommendations for the escalation/de-escalation of BE in clinical practice. We made strong recommendations for the prioritization of future research.

Pathophysiological mechanisms linking obesity and esophageal adenocarcinoma.

In recent decades there has been a dramatic rise in the incidence of esophageal adenocarcinoma (EAC) in the developed world. Over approximately the same period there has also been an increase in the prevalence of obesity. Obesity, especially visceral obesity, is an important independent risk factor for the development of gastro-esophageal reflux disease, Barrett's esophagus and EAC. Although the simplest explanation is that this mediated by the mechanical effects of abdominal obesity promoting gastro-esophageal reflux, the epidemiological data suggest that the EAC-promoting effects are independent of reflux. Several, not mutually exclusive, mechanisms have been implicated, which may have different effects at various points along the reflux-Barrett's-cancer pathway. These mechanisms include a reduction in the prevalence of Helicobacter pylori infection enhancing gastric acidity and possibly appetite by increasing gastric ghrelin secretion, induction of both low-grade systemic inflammation by factors secreted by adipose tissue and the metabolic syndrome with insulin-resistance. Obesity is associated with enhanced secretion of leptin and decreased secretion of adiponectin from adipose tissue and both increased leptin and decreased adiponectin have been shown to be independent risk factors for progression to EAC. Leptin and adiponectin have a set of mutually antagonistic actions on Barrett's cells which appear to influence the progression of malignant behaviour. At present no drugs are of proven benefit to prevent obesity associated EAC. Roux-en-Y reconstruction is the preferred bariatric surgical option for weight loss in patients with reflux. Statins and aspirin may have chemopreventative effects and are indicated for their circulatory benefits.

Strategy for prevention of cancers of the esophagus.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the animal reflux-inflammation models for Barrett's esophagus and esophageal adenocarcinoma; genomic/epigenomic analyses; eflornithine-based combinations; the molecular derangements that promote neoplastic transformation; the role of COX-2 inhibitors, proton pump inhibitors, and phase II trials in Barrett's adenocarcinoma; statins in chemoprevention and treatment of esophageal cancer; and biomarkers as potential targets in Barrett's adenocarcinoma.

Statin use is associated with reduced risk of histologic subtypes of esophageal cancer: a nested case-control analysis.

BACKGROUND & AIMS: Most patients with esophageal adenocarcinoma (EAC) or squamous cell cancer (ESCC) present with advanced, incurable disease. Statins have reported anti-carcinogenic effects and may be chemoprotective. We investigated the association between regular use of statins and the main histologic subtypes of esophageal malignancy (EAC, esophagogastric junctional adenocarcinoma, and ESCC) in the UK general population. METHODS: We identified all individuals in the UK General Practice Research Database diagnosed with esophageal cancer from 2000 through 2009. Patients were linked to the National Cancer Registry to confirm histologic subtypes. Each patient was matched with up to 4 controls for age, sex, and practice. We performed a nested case-control analysis using conditional logistic regression to estimate the risk of each subtype with regular statin use, adjusted for body mass index, smoking, alcohol intake, and concomitant use of medications. RESULTS: In total, 581 participants with EAC, 213 with esophagogastric junctional adenocarcinoma, and 332 with ESCC were matched to 2167, 783, and 1242 controls, respectively. Regular statin use was inversely associated with development of EAC (odds ratio = 0.58; 95% confidence interval: 0.39-0.87) (with significant dose and duration responses) and esophagogastric junctional adenocarcinoma (odds ratio = 0.29; 95% confidence interval: 0.09-0.92) (with high-dose use only). Statin use for 1-4 years was inversely associated with ESCC (odds ratio = 0.51; 95% confidence interval: 0.27-0.98). CONCLUSIONS: In a nested case-control analysis of a UK population-based cohort, statin use was inversely associated with histologic subtypes of esophageal cancer. Randomized controlled trials are warranted to determine whether statins have chemopreventive effects in high-risk groups.

Clenbuterol and formoterol decrease force production in isolated intact mouse skeletal muscle fiber bundles through a beta2-adrenoceptor-independent mechanism.

Although the acute actions of short-acting ß(2)-adrenoceptor agonists on force production in isolated mammalian skeletal muscle fibers have been the subject of a number of previous studies, those of long-acting ß(2)-adrenoceptor agonists have never been investigated. Also, little is known about the cellular signal transduction events mediating their actions. Therefore, the primary aim of this study was to investigate the acute effects of treatment of mouse fast- and slow-twitch muscle fiber bundles with clenbuterol, formoterol, and salbutamol. Both clenbuterol and salbutamol increased the levels of cAMP in both fiber types, and this effect was reversed by ICI-118551. On the other hand, clenbuterol and formoterol decreased force production in both fiber types. They also increased the phosphorylation of phospholamban and ß(2)-adrenoceptors in slow-twitch fiber bundles, and their effects were insensitive to propranolol, ICI-118551, and 14-22 amide. In contrast, salbutamol increased force production in both fiber types. It also increased the phosphorylation of ß(2)-adrenoceptors in slow-twitch fibers only, but it had no effect on the phosphorylation of phospholamban in either fiber type. These effects were reversed by propranolol and ICI-118551 but not by 14-22 amide. Instead, 14-22 amide further potentiated the effects of salbutamol on force. In summary, long- and short-acting ß(2)-adrenoceptor agonists have opposite effects on force production in isolated intact mouse skeletal muscle fiber bundles. From these results, we suggest that the acute actions of short-acting ß(2)-adrenoceptor agonists on force production in mammalian skeletal muscles are mediated through the ß(2)-adrenoceptor, whereas those of long-acting ß(2)-adrenoceptor agonists are not.

Dejeto líquido de suínos: I - perdas de nitrogênio e fósforo na solução escoada na superfície do solo, sob plantio direto / Pig slurry: I - nitrogen and phosphorus losses by surface run off in a soil cropped under no tillage

A aplicação de dejeto líquido de suínos em áreas de lavoura e/ou pastagem representa a adição de nutrientes às plantas e também uma alternativa de reciclagem. Contudo, as perdas de nitrogênio e fósforo por escoamento superficial no plantio direto podem diminuir sua eficiência à nutrição de plantas e representar um poluente potencial, comprometendo a qualidade da água no ambiente. Esse trabalho teve por objetivo avaliar a importância do escoamento superficial às perdas de nitrogênio e fósforo aplicados via dejeto líquido de suínos. O trabalho foi conduzido na Universidade Federal de Santa Maria, RS, no período de maio de 2000 a maio de 2002 em Argissolo Vermelho Arênico distrófico. Numa rotação aveia preta/milho/nabo forrageiro, foram estudadas as doses de 0, 20, 40 e 80 m³ ha-1 de dejetos líquidos de suínos, distribuídas a lanço sobre a superfície antes da semeadura de cada espécie da rotação. As concentrações de fósforo disponível e nitrogênio mineral na solução escoada na superfície do solo foram diretamente relacionados com as doses de dejeto aplicadas. As concentrações de nitrogênio e fósforo na solução escoada na superfície do solo, bem como a predominância de amônio ou nitrato, estão diretamente relacionadas ao intervalo entre a aplicação do dejeto e o primeiro escoamento superficial. As perdas de nitrogênio e fósforo por escoamento superficial, expressas em kg ha-1, são pequenas, porém as maiores concentrações observadas nos picos de perdas preocupam com relação à possibilidade de eutroficação de mananciais de água.