Eftychia E Psarelli

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.

Enhanced recovery in the resection of colorectal liver metastases.

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).

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.

Immunohistochemical hENT1 expression as a prognostic biomarker in patients with resected pancreatic ductal adenocarcinoma undergoing adjuvant gemcitabine-based chemotherapy.

Human equilibrative nucleoside transporters (hENTs) are transmembranous proteins that facilitate the uptake of nucleosides and nucleoside analogues, such as gemcitabine, into the cell. The abundance of hENT1 transporters in resected pancreatic ductal adenocarcinoma (PDAC) might make hENT1 a potential biomarker of response to adjuvant chemotherapy. The aim of this study was to see whether hENT1 expression, as determined by immunohistochemistry, was a suitable predictive marker for subsequent treatment with gemcitabine‐based adjuvant chemotherapy.

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.

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.

The 5‐year outcome of patients having incomplete colonoscopy

Incomplete colonoscopy indicated for the detection of neoplasia occurs in 2−23% of patients, but there is little information on the long‐term outcome of such patients.

Beyond ESPAC-4: better surgery and systemic therapy

www.thelancet.com Vol 389 April 15, 2017 1517 distress syndrome should be the subject of an adequately powered multicentre randomised controlled trial with long-term follow-up. Data from ongoing randomised controlled trials (NCT01731795, NCT01757899, and NCT02819453) will help to determine the role of steroids in acute respiratory distress syndrome. As such data become available, we will update the recommendation in our Seminar. For now, the recommendation that steroids should be avoided is appropriate. Steroids might or might not be beneficial in acute respiratory distress syndrome, but the data are insufficient to support their use, regardless of how much one might wish for it to be so.

Nitisinone arrests ochronosis and decreases rate of progression of Alkaptonuria: Evaluation of the effect of nitisinone in the United Kingdom National Alkaptonuria Centre

QUESTION Does Nitisinone prevent the clinical progression of the Alkaptonuria? FINDINGS In this observational study on 39 patients, 2 mg of daily nitisinone inhibited ochronosis and significantly slowed the progression of AKU over a three-year period. MEANING Nitisinone is a beneficial therapy in Alkaptonuria. BACKGROUND Nitisinone decreases homogentisic acid (HGA), but has not been shown to modify progression of Alkaptonuria (AKU). METHODS Thirty-nine AKU patients attended the National AKU Centre (NAC) in Liverpool for assessments and treatment. Nitisinone was commenced at V1 or baseline. Thirty nine, 34 and 22 AKU patients completed 1, 2 and 3 years of monitoring respectively (V2, V3 and V4) in the VAR group. Seventeen patients also attended a pre-baseline visit (V0) in the VAR group. Within the 39 patients, a subgroup of the same ten patients attended V0, V1, V2, V3 and V4 visits constituting the SAME Group. Severity of AKU was assessed by calculation of the AKU Severity Score Index (AKUSSI) allowing comparison between the pre-nitisinone and the nitisinone treatment phases. RESULTS The ALL (sum of clinical, joint and spine AKUSSI features) AKUSSI rate of change of scores/patient/month, in the SAME group, was significantly lower at two (0.32 ± 0.19) and three (0.15 ± 0.13) years post-nitisinone when compared to pre-nitisinone (0.65 ± 0.15) (p < .01 for both comparisons). Similarly, the ALL AKUSSI rate of change of scores/patient/month, in the VAR group, was significantly lower at one (0.16 ± 0.08) and three (0.19 ± 0.06) years post-nitisinone when compared to pre-nitisinone (0.59 ± 0.13) (p < .01 for both comparisons). Combined ear and ocular ochronosis rate of change of scores/patient/month was significantly lower at one, two and three years post-nitisinone in both VAR and SAME groups compared with pre-nitisinone (p < .05). CONCLUSION This is the first indication that a 2 mg dose of nitisinone slows down the clinical progression of AKU. Combined ocular and ear ochronosis progression was arrested by nitisinone.

Diagnostic tools and strategies for assessing disease progression in Alkaptonuria

Introduction: Alkaptonuria (OMIM 203500) is an iconic autosomal recessive disease present at birth. The clinical effects are due to high circulating homogentisic acid (HGA) and high urine HGA. Oxidative conversion of circulating HGA to pigment is termed ochronosis, a process that alters tissues, resulting in the classical clinical consequences of the disease. There are very few symptoms in early life and very little is known about disease progression in childhood. Areas covered: These include commonly used diagnostic tools that can be employed to document often unrecognised manifestations including structured interview, questionnaires, physical examination and investigation. Analysis of data from systematic use of diagnostic tools can allow estimation of burden of disease as well as the evolution of disease. Expert opinion: In a condition still considered to be mainly irreversible, earlier recognition and management is desirable. This requires an urgent understanding of evolution of disease especially in the young.