Blood levels of adiponectin and IL-1Ra distinguish type 3c from type 2 diabetes: Implications for earlier pancreatic cancer detection in new-onset diabetes.

BACKGROUND: Screening for pancreatic ductal adenocarcinoma (PDAC) in populations at high risk is recommended. Individuals with new-onset type 2 diabetes mellitus (NOD) are the largest high-risk group for PDAC. To facilitate screening, we sought biomarkers capable of stratifying NOD subjects into those with type 2 diabetes mellitus (T2DM) and those with the less prevalent PDAC-related diabetes (PDAC-DM), a form of type 3c DM commonly misdiagnosed as T2DM. METHODS: Using mass spectrometry- and immunoassay-based methodologies in a multi-stage analysis of independent sample sets (n=443 samples), blood levels of 264 proteins were considered using Ingenuity Pathway Analysis, literature review and targeted training and validation. FINDINGS: Of 30 candidate biomarkers evaluated in up to four independent patient sets, 12 showed statistically significant differences in levels between PDAC-DM and T2DM. The combination of adiponectin and interleukin-1 receptor antagonist (IL-1Ra) showed strong diagnostic potential, (AUC of 0.91; 95% CI: 0.84-0.99) for the distinction of T3cDM from T2DM. INTERPRETATION: Adiponectin and IL-1Ra warrant further consideration for use in screening for PDAC in individuals newly-diagnosed with T2DM. FUNDING: North West Cancer Research, UK, Cancer Research UK, Pancreatic Cancer Action, UK.

The nutritional status of people with alkaptonuria: An exploratory analysis suggests a protein/energy dilemma.

BACKGROUND: Alkaptonuria (AKU) is a disorder of tyrosine/protein metabolism leading to accumulation of homogentisic acid. Clinical management historically recommended reducing dietary protein intake, especially in childhood, which has since been discredited in the literature. For the first time, analysis of baseline cross-sectional nutritional surveillance data from a large cohort of AKU patients is presented, which has clinical implications in all aspects of treatment planning. METHOD: Seventy-four patients (mean 55 years) admitted to the National Alkaptonuria Centre (NAC), underwent a global nutritional assessment, which included objective anthropometry, bioimpedance measures, habitual nutritional intake using a 7-day food diary and key nutritional biomarkers, including 24 hours urinary nitrogen, serum albumin, total protein and total 25-hydroxy vitamin D. All data was compared with cohort norms or recommended nutrient intakes for health (RNI). The potential beneficial impact of protein and anti-inflammatory nutrients such as vitamin C, selenium, and zinc were statistically interrogated against the AKU severity score index (AKUSSI)-a validated measure of disease progression stratified by age. RESULTS: Fifty percent of AKU patients reported some level of protein restriction at some point in their lives. In comparison with national data sets, AKU patients present with significantly lower than predicted mid-upper arm circumference, grip strength, BMI, total energy and protein intake, and higher than predicted percentage body fat. They therefore meet the ESPEN criteria as "clinically undernourished." Severity fluctuates over the life course. No statistical association is identified between protein intake, expressed as %RNI or g/kg, or anti-inflammatory nutrients, including vitamin C as a high dose supplement on the severity of the disease, when correlated against the validated AKUSSI score. CONCLUSION: AKU patients are at risk of protein depletion associated with a "perfect storm" of risk factors: historical, poorly evidenced recommendations to reduce total protein intake; limited mobility as the condition progresses, compromising muscle integrity; frequent hospital admissions for major surgery associated with multiple joint replacements, creating pinch points of high metabolic demand and the potential impact of the disease itself. As this is the first time this risk has been identified, the authors consider the dietetic implications of nitisinone treatment, which requires dietary protein control to manage the acquired tyrosinaemia. The lack of statistically significant evidence to support dietary manipulation of any kind to impede disease progression in AKU is demonstrated.

Homogentisic acid is not only eliminated by glomerular filtration and tubular secretion but also produced in the kidney in alkaptonuria.

The clinical effects of alkaptonuria (AKU) are delayed and ageing influences disease progression. Morbidity of AKU is secondary to high circulating homogentisic acid (HGA) and ochronosis. It is not known whether HGA is produced by or processed in the kidney in AKU. Data from AKU patients from four studies were merged to form a single AKU group. A control group of non-AKU subjects was generated by merging data from two non-AKU studies. Data were used to derive renal clearance and fractional excretion (FE) ratios for creatinine, HGA, phenylalanine (PHE) and tyrosine (TYR) using standard calculations, for comparison between the AKU and the control groups. There were 225 AKU patients in the AKU group and 52 in the non-AKU control group. Circulating HGA increased with age (P < 0.001), and was significantly associated with decreased HGA clearance (CLHGA ) (P < 0.001) and FEHGA (P < 0.001). CLHGA and FEHGA were increased beyond the theoretical maximum renal plasma flow, confirming renal production and emphasising the greater contribution of net tubular secretion than glomerular filtration to renal elimination of HGA. The kidneys are crucial to elimination of HGA. Elimination of HGA is impaired with age resulting in worsening disease over time. The kidney is an important site for production of HGA. Tubular secretion of HGA contributes more to elimination of HGA in AKU than glomerular filtration.

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment.

BACKGROUND: Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. METHODS: Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. FINDINGS: A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. CONCLUSIONS: In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. TRIAL REGISTRATION NUMBER: EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.

What Is the Best Way to Identify Malignant Transformation Within Pancreatic IPMN: A Systematic Review and Meta-Analyses.

OBJECTIVES: Pancreatic intraductal papillary mucinous neoplasias (IPMNs) represent 25% of all cystic neoplasms and are precursor lesions for pancreatic ductal adenocarcinoma. This study aims to identify the best imaging modality for detecting malignant transformation in IPMN, the sensitivity and specificity of risk features on imaging, and the usefulness of tumor markers in serum and cyst fluid to predict malignancy in IPMN. METHODS: Databases were searched from November 2006 to March 2014. Pooled sensitivity and specificity of diagnostic techniques/imaging features of suspected malignancy in IPMN using a hierarchical summary receiver operator characteristic (HSROC) approach were performed. RESULTS: A total of 467 eligible studies were identified, of which 51 studies met the inclusion criteria and 37 of these were incorporated into meta-analyses. The pooled sensitivity and specificity for risk features predictive of malignancy on computed tomography/magnetic resonance imaging were 0.809 and 0.762 respectively, and on positron emission tomography were 0.968 and 0.911. Mural nodule, cyst size, and main pancreatic duct dilation found on imaging had pooled sensitivity for prediction of malignancy of 0.690, 0.682, and 0.614, respectively, and specificity of 0.798, 0.574, and 0.687. Raised serum carbohydrate antigen 19-9 (CA19-9) levels yielded sensitivity of 0.380 and specificity of 0903. Combining parameters yielded a sensitivity of 0.743 and specificity of 0.906. CONCLUSIONS: PET holds the most promise in identifying malignant transformation within an IPMN. Combining parameters increases sensitivity and specificity; the presence of mural nodule on imaging was the most sensitive whereas raised serum CA19-9 (>37 KU/l) was the most specific feature predictive of malignancy in IPMNs.

Colonoscopy performance is stable during the course of an extended three-session working day.

BACKGROUND: Three-session days were introduced in our endoscopy unit to accommodate the increased demand resulting from the introduction of the National Health Service Bowel Cancer Screening Programme (BCSP). Cecal intubation rate (CIR) and adenoma detection rate (ADR) may decline with time during a standard working day, but data are lacking for an extended three-session day. We assessed colonoscopy performance in an extended three-session day. METHODS: Colonoscopies performed during the year 2011 were retrospectively analyzed. The CIR and ADR were analyzed according to the time of day when procedures were done: morning (AM), afternoon (PM), or evening (EVE). Because of an expected higher incidence of adenomas in the BCSP patients, ADR was analyzed according to indication (BCSP or non-BCSP). RESULTS: Of the 2574 colonoscopies, 1328 (51.7 %) were in male patients and 1239 (48.3 %) in female patients with a median age of 63 years (interquartile range [IQR], 51 - 70). Of the 2574 colonoscopies, 1091 (42.4 %) were performed in AM lists, 994 (38.6 %) in PM lists, and 489 (19 %) in EVE lists. Time of day did not affect the CIRs for the AM, PM, and EVE lists (90.5 %, 90.1 %, and 89.9 %, respectively; χ (2) [2, N = 2540] = 0.15, P = 0.927). The CIR was reduced in female patients and those with poor bowel preparation (P < 0.05). After exclusion of the BCSP patients, the ADR was lower in the EVE lists than in the AM and PM lists on univariate analysis, but on multivariate analysis, this difference was not significant (P > 0.05). The ADR was significantly higher in patients older than 60 years and in men (P < 0.001). Queue position did not independently influence the CIR or ADR. CONCLUSIONS: Colonoscopy quality does not appear to depend on time of day or queue position in an extended three-session day.

Nitisinone Arrests but Does Not Reverse Ochronosis in Alkaptonuric Mice.

Alkaptonuria (AKU) is an ultrarare autosomal recessive disorder resulting from a deficiency of homogentisate 1,2 dioxygenase (HGD), an enzyme involved in the catabolism of phenylalanine and tyrosine. Loss of HGD function prevents metabolism of homogentisic acid (HGA), leading to increased levels of plasma HGA and urinary excretion. Excess HGA becomes deposited in collagenous tissues and subsequently undergoes polymerisation, principally in the cartilages of loaded joints, in a process known as ochronosis. This results in an early-onset, devastating osteoarthropathy for which there is currently no effective treatment. We recently described the natural history of ochronosis in a murine model of AKU, demonstrating that deposition of ochronotic pigment begins very early in life and accumulates with age. Using this model, we were able to show that lifetime treatment with nitisinone, a potential therapy for AKU, was able to completely prevent deposition of ochronotic pigment. However, although nitisinone has been shown to inhibit ochronotic deposition, whether it can also facilitate removal of existing pigment has not yet been examined. We describe here that midlife administration of nitisinone to AKU mice arrests further deposition of ochronotic pigment in the tibiofemoral joint, but does not result in the clearance of existing pigment. We also demonstrate the dose-dependent response of plasma HGA to nitisinone, highlighting its efficacy for personalised medicine, where dosage can be tailored to the individual AKU patient.

Relationship Between Serum Concentrations of Nitisinone and Its Effect on Homogentisic Acid and Tyrosine in Patients with Alkaptonuria.

BACKGROUND: Alkaptonuria (AKU) is a serious genetic disease due to a defect in tyrosine metabolism, leading to increased serum levels of homogentisic acid (HGA). Nitisinone decreases HGA in AKU, but the concentration-response relationship has not been previously reported. OBJECTIVES: To determine the relationship between serum concentrations of nitisinone and the effect on both HGA and tyrosine; secondly to determine steady-state pharmacokinetics of nitisinone in AKU patients. METHOD: Thirty-two patients with AKU received either 1, 2, 4, or 8 mg nitisinone daily. Urine and serum HGA and serum tyrosine and nitisinone were measured during 24 h at baseline (before first dose) and after 4 weeks of treatment. RESULTS: Nitisinone pharmacokinetics (area under the curve [AUC] and maximum concentrations [C max]) were dose proportional. The median oral clearance determined in all patients, irrespective of dose, was 3.18 mL/h·kg (range 1.6-6.7).Nitisinone decreased urinary excretion of HGA in a concentration-dependent manner, with a maximum effect seen at average nitisinone concentrations of 3 µmol/L. The association between nitisinone and tyrosine concentrations was less pronounced. Serum levels of HGA at Week 4 were below the limit of quantitation in 65% of samples, which prevented determination of the relationship with nitisinone concentrations. CONCLUSION: Nitisinone exhibits dose-proportional pharmacokinetics in the studied dosage interval. Urinary excretion of HGA decreases in a concentration-dependent manner, while the increase in tyrosine is less clearly related to nitisinone concentrations.

Enhanced recovery in the resection of colorectal liver metastases.

BACKGROUND: There is limited evidence for the use of enhanced recovery after surgery (ERAS) in patients undergoing hepatectomy, and the impact of the evolution of ERAS over time has not been examined. This study sought to evaluate the effect of an evolving ERAS program in patients undergoing hepatectomy for colorectal liver metastases (CRLM). METHODS: A multimodal ERAS program was introduced in 2/2008. Consecutive patients undergoing hepatectomy for CRLM between 2/2008 and 9/2012 were included in the study. Data were collected prospectively. Retrospective analysis compared an early ERAS cohort (2/2008-4/2010) with a later cohort with a matured ERAS program (5/2010-8/2012). RESULTS: Length of stay reduced as experience of ERAS increased (Log-rank χ(2) = 10.43, P = 0.001). Although median length of stay remained unchanged (6 days), the probability of hospitalization beyond 10 days was 25% in the early cohort compared with 7% in the later cohort. Critical care utilization reduced over time (75.5% vs. 54.7%, P < 0.0001). Complications occurred in 38.2%, with no difference in between cohorts. One postoperative death occurred in the early cohort (<0.3%). CONCLUSIONS: This study suggests that as experience of ERAS evolves, there is a progressive reduction in hospitalization and critical care admission. This is without any increase in morbidity and mortality.