Utility and cost evaluation of multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease.

BACKGROUND: Validated diagnostic tools that are accurate, cost effective and acceptable to patients are required for disease stratification and monitoring in NAFLD. AIMS: To investigate the performance and cost of multiparametric MRI alongside existing biomarkers in the assessment of NAFLD. METHODS: Adult patients undergoing standard of care liver biopsy for NAFLD were prospectively recruited at two UK liver centres and underwent multiparametric MRI, blood sampling and transient elastography withing 2 weeks of liver biopsy. Non-invasive markers were compared to histology as the gold standard. RESULTS: Data were obtained in 50 patients and 6 healthy volunteers. Corrected T1 (cT1) correlated with NAFLD activity score (ρ = 0.514, P < .001). cT1, enhanced liver fibrosis (ELF) test and liver stiffness differentiated patients with simple steatosis and NASH with AUROC (95% CI) of 0.69 (0.50-0.88), 0.87 (0.77-0.79) and 0.82 (0.70-0.94) respectively and healthy volunteers from patients with AUROC (95% CI) of 0.93 (0.86-1.00), 0.81 (0.69-0.92) and 0.89 (0.77-1.00) respectively. For the risk stratification of NAFLD, multiparametric MRI could save £150,218 per 1000 patients compared to biopsy. Multiparametric MRI did not discriminate between individual histological fibrosis stages in this population (P = .068). CONCLUSIONS: Multiparametric MRI accurately identified patients with steatosis, stratifies those with NASH or simple steatosis and reliably excludes clinically significant liver disease with superior negative predictive value (83.3%) to liver stiffness (42.9%) and ELF (57.1%). For the risk stratification of NAFLD, multiparametric MRI was cost effective and, combined with transient elastography, had the lowest cost per correct diagnosis.

Erratum to: 2016 WSES guidelines on acute calculous cholecystitis.

[This corrects the article DOI: 10.1186/s13017-016-0082-5.].

2016 WSES guidelines on acute calculous cholecystitis.

Acute calculus cholecystitis is a very common disease with several area of uncertainty. The World Society of Emergency Surgery developed extensive guidelines in order to cover grey areas. The diagnostic criteria, the antimicrobial therapy, the evaluation of associated common bile duct stones, the identification of "high risk" patients, the surgical timing, the type of surgery, and the alternatives to surgery are discussed. Moreover the algorithm is proposed: as soon as diagnosis is made and after the evaluation of choledocholitiasis risk, laparoscopic cholecystectomy should be offered to all patients exception of those with high risk of morbidity or mortality. These Guidelines must be considered as an adjunctive tool for decision but they are not substitute of the clinical judgement for the individual patient.

Relaxation of the mouse isolated aorta and carotid artery in response to adenosine analogues in genetically-modified mice lacking the adenosine A(2A) receptor.

The aim of this study was to characterise the receptor(s) mediating responses to adenosine and/or adenosine analogues in mouse isolated aorta and carotid artery. In addition, since mice lacking the A(2A) adenosine receptor are reported to be hypertensive, the possibility that this gene deletion or the altered phenotype results in alteration of responses mediated via adenosine analogues was investigated. This was achieved by comparing results obtained in parallel within single experiments using tissues from A(2A) knock-out animals and their wild-type littermates.In aortic rings, adenosine and 5'- N-ethylcarboxamidoadenosine (NECA) caused relaxations above 10 microM and 30 microM, respectively, which were unaffected by either 8-sulphophenyltheophylline (8-SPT, 100 microM) or A(2A) receptor knockout. 2-[ p-(2-Carbonylethyl)phenylethylamino]-5'- N-ethylcarboxamidoadenosine (CGS 21680) was virtually inactive. R- N(6)-Phenylisopropyladenosine (R-PIA) induced relaxations which were not inhibited by 8-SPT (100 microM) or altered by A(2A) receptor knockout. No A(1)-mediated contractile responses were observed in wild-type or knock-out tissues in contrast with results in mice of the same strain obtained commercially rather than from our breeding programme. In carotid artery rings NECA contracted at low concentrations (0.1-1 microM) and relaxed at higher concentrations. Curves to NECA were not different in tissues from wild-type and A(2A) receptor knock-out mice and both the contractile and relaxant phases were right-shifted by 8-SPT (100 microM) in tissues from animals of both genotype. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX, 3 nM) attenuated contractile NECA responses but did not affect relaxant responses. CGS 21680 was inactive in carotid artery rings from both wild-type and A(2A) receptor knock-out mice. In the presence of DPCPX (30 nM) to abolish contractions, R-PIA induced relaxant curves which were not different in tissues from wild-type and A(2A) knock-out mice and were not inhibited by 8-SPT (100 microM). These results confirm the absence of A(2A) or A(2B) receptors in murine aorta and suggest that relaxations to NECA in carotid artery are A(2B) receptor-mediated whilst contractions are A(1) receptor-mediated. They also indicate the presence of an antagonist-resistant site activated by R-PIA in both vascular preparations. There is no evidence for compensatory changes in responses mediated by adenosine and its analogues due to the gene deletion or the reported resulting hypertensive phenotype in either aortic or carotid arterial rings obtained from A(2A) knock-out mice.

The outcome of voiding dysfunction managed with clean intermittent catheterization in neurologically and anatomically normal children.

OBJECTIVE: To describe the tolerability and efficacy of clean intermittent catheterization (CIC) in the management of dysfunctional voiding in patients who are neurologically and anatomically normal. PATIENTS AND METHODS: The medical records were reviewed in 23 patients (16 girls, mean age 9 years, range 6-14.5, and seven males, mean age 8 years, range 5-20.5) with urinary incontinence and/or urinary tract infection (UTI) who were offered CIC because they had a large postvoid residual urine volume (PVR). All had extensive instruction before starting CIC. All patients underwent urodynamic studies, and urinary and fecal elimination habits were recorded. Detrusor hyperactivity, when present, was treated with anticholinergic medication. The follow-up evaluation included tolerance of CIC, continence status and the incidence of UTI. Behavioural modification or biofeedback training was not used in any patient. RESULTS: Of the 23 patients, 13 presented with both UTI and urinary incontinence, five with incontinence only, four with UTI only, one with frequency and no incontinence, and one with haematuria. Associated symptoms included frequency/urgency, constipation or soiling, and straining to void or incomplete emptying (in nine each), and infrequent voiding in six. CIC was performed within 2 days by 15 patients, while four others required up to 2 weeks to master CIC. However, three of the four patients (all older girls) who needed 2 weeks to learn the technique did not tolerate CIC and discontinued it within 3 weeks. Four other adolescents (three girls and one boy) refused to learn CIC. Of the 16 patients remaining on CIC only three had cystitis; no patient had a febrile UTI. Once successfully instituted, all patients became continent while on CIC. Six boys (mean follow-up 4 months) had a marked decrease in their PVR. CIC was discontinued in three girls who voided normally to emptiness within 6 months of starting CIC; they remained dry and infection-free 16 months (two) and 6 years later. CONCLUSION: CIC is a viable therapeutic option for the treatment of dysfunctional voiding, associated with a large PVR, in the absence of any neurological abnormality. CIC is well tolerated in the sensate patient and provides a means for expeditiously achieving continence and improving bladder emptying cost-effectively.

Effects of external beam irradiation on the TRAM flap: an experimental model.

The rat model of the transverse rectus abdominis musculocutaneous (TRAM) flap was used in the present study to determine the effects of external beam radiation on myocutaneous flap histology and pathophysiology. A total of 57 adult Sprague-Dawley rats underwent a TRAM procedure. A pilot study with 17 animals was first performed to determine proper radiation dosages, and the remaining 40 rats were then used in the definitive study. In half of the definitive study group, the flaps were subjected to fractionated doses of external beam radiation, whereas the other half served as controls. Six weeks after the last radiation dose, all animals were killed and the flaps were harvested for mechanical assessment and histopathologic evaluation. All TRAM flaps survived in both groups. The irradiated and nonirradiated flaps were minimally distinguishable in viscoelastic properties, as well as by histopathologic examination. Growth of the flap in the irradiated animals was significantly diminished (48 percent average surface area increase in irradiated flaps, versus 92 percent increase in nonirradiated flaps, p < 0.05). These findings suggest that the myocutaneous flap is relatively resistant to some of the known adverse affects of radiation on living tissues.

Results of resection for hilar cholangiocarcinoma with analysis of prognostic factors.

BACKGROUND/AIMS: Resection for hilar cholangiocarcinoma remains a challenging procedure and recent published results continue to show that few patients are cured of their disease. The objective of this review was to determine the results of radical resection and to identify factors associated with long-term survival. METHODOLOGY: Retrospective review of resection for hilar cholangiocarcinoma in 29 consecutive patients with statistical analysis of prognostic factors, including p53 status. RESULTS: The mortality and morbidity rates were 6.9% and 34%, respectively. The overall 5-year survival was 20% with the median survival being 16 months. Univariate analysis identified the following factors associated with poor survival; involved lymph nodes, vascular invasion, advanced tumor stage, positive tumor margins, and p53 mutation. However, none of these factors was associated with poor survival by multivariate analyses. CONCLUSIONS: Radical resection for hilar cholangiocarcinoma can be performed with acceptable morbidity and mortality, but most patients succumb to their disease. p53 status may be a helpful adjunct to routine pathological staging.

New p53 mutations in hilar cholangiocarcinoma.

BACKGROUND: Inactivation of the tumour suppressor gene, p53, is the commonest genetic abnormality in human cancer. The study of the type of p53 mutation in a given tumour may provide prognostic information, clues to aetiology and become useful for therapeutics. MATERIALS AND METHODS: The molecular characterisation of p53 was performed by restriction analysis, denaturing gradient gel electrophoresis, and gene sequencing for exons 5-9. RESULTS: We report, p53 mutational analysis in exons 5-9 in 29 European patients with hilar cholangiocarcinoma who underwent attempted resection. Four patients (14%) showed somatic single nucleotide substitutions with amino acid changes (146, 163, 175, 158, and 175) with one showing mutations in two different positions involving a loss of two CfoI sites. All the mutations occurred in exon 5. Three patients had a germline polymorphism (10%) with a silent substitution in codon 213 (exon 6). CONCLUSIONS: The systematic screening for p53 mutations in European patients with hilar cholangiocarcinoma has shown that the type of mutation (except 175) is different and its incidence is much lower when compared to the pattern previously reported for intrahepatic cholangiocarcinoma in East Asian patients. A probable explanation is that the presence and type of p53 mutation is dependent on geographic and environmental factors which vary in different populations.

Microsatellite instability and allelic imbalance in primary and secondary colorectal cancer.

BACKGROUND: Several studies of colorectal cancer have shown an association between the number and type of genomic defects and the stage of disease. A subset of colorectal tumours are due to inactivation of DNA mismatch repair genes and these tumours exhibit microsatellite instability. The aim of the present study was to compare and contrast the genomic defects present in both the primary and metastatic stages of the disease using microsatellite probes. METHODS: Modifications of the allelic profiles of 25 microsatellite regions were studied in a total of 85 colorectal tumours using fluorescent polymerase chain reaction (PCR) technology and subsequent direct analysis on an automatic sequencer. This approach was used because it allows the study of microsatellite instability and allelic imbalance. Stepwise logistic regression analysis was used to develop a model to predict whether the tumour was primary or secondary from the percentage of allelic imbalance. Subsequently, a group of 17 patients with primary colorectal tumours was analysed prospectively to test the proposed model. RESULTS: Six of 39 primary tumours showed microsatellite instability compared to 0 of 29 liver metastases (P = 0.03). Primary tumours showed significantly less allelic imbalance than liver metastases (P < 0.001). Three probes (d18s53, d9s158 and d10s191) were selected for use in a model to classify a tumour as primary or secondary on the basis of the degree of allelic imbalance. When tested prospectively this model had a specificity of 82%. CONCLUSIONS: The present study demonstrates the potential importance of using microsatellite probes both as a diagnostic tool and as a research technique to investigate the mechanisms of tumour progression. An important clinical finding is that none of the colorectal liver metastases showed microsatellite instability (0 of 29). This analysis also confirmed other work that has shown a direct relationship between the degree of allelic imbalance and the stage of disease.

p53 Plasmid Preparation and Techniques for Analysis of Gene Transfer and Expression.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide and is especially prevalent in certain areas of Africa and Asia. The most important etiological factor is infection with the hepatitis B or C virus. Treatment is generally unsatisfactory as the majority of patients are not suitable for surgical resection and chemotherapy is not particularly effective.

Clinical Protocol for p53 Gene Therapy for Liver Tumors.

This chapter is intended to help other workers with the preparation of human gene therapy proposals. What follows is an abridged version of a protocol describing the use of gene replacement with p53 for liver tumors. This was submitted to the Gene Therapy Advisory Committee (GTAC) of the Department of Health (United Kingdom). This is the first trial to be approved by GTAC for gene therapy of liver tumors in humans.

Characterization of p53 mutations in colorectal liver metastases and correlation with clinical parameters.

The presence and type of mutations of the p53 tumor suppressor gene were determined in 40 patients undergoing curative hepatic resection for metastatic colorectal carcinoma. This represents the largest series in the literature on the screening of p53 mutations for liver metastases. The analysis was performed in exons 5-9 by denaturing gradient gel electrophoresis followed by direct sequencing. Forty-five percent of tumors showed mutation in p53, and this was observed only in exons 5-8. Mutations at codon positions 167, 196, 204, 213, 245, 281, 282, 286, and 306; deletion of codon 251 and of the first nucleotide of codon 252; and Leu residue (CTC) insertion downstream codon 252 are reported for the first time in colorectal liver metastasis. Mutations at codon positions 163, 248, and 273 have been reported previously. Correlation of p53 status with clinical parameters showed that patients with mutated p53 had a statistically higher number of lesions when compared with patients with wild-type p53 (P<0.050). In particular, of patients with mutated p53, 41% had three or more metastases compared with 14% of patients with wild-type p53. Synchronous metastases were present in 70% of the patients with p53 mutations and in only 29% of patients with wild-type p53 (P<0.025). In addition, patients with p53 mutations are more likely to develop recurrence (73%) compared with patients with wild-type p53 (33%; P<0.001). Other factors considered, including preoperative carcinoembryonic antigen level, bilobar distribution, and size of the lesion(s), did not show significant correlation with p53 status. These results suggest that p53 status might be an important prognostic indicator to predict the pattern and likelihood of treatment failure after hepatic resection.

Randomized trial of preoperative cimetidine in patients with colorectal carcinoma with quantitative assessment of tumor-associated lymphocytes.

BACKGROUND: Previous studies have suggested that cimetidine, a histamine-2 receptor antagonist with immunostimulatory effects, may improve survival in patients with colorectal carcinoma. This effect may be apparent by an increase in the number of peritumoral lymphocytes. A prospective, double blind, randomized, placebo-controlled trial of a short course of preoperative treatment with cimetidine in patients with colorectal carcinoma was performed to assess the effect of cimetidine on survival and on the number of peritumoral lymphocytes. METHODS: One hundred and twenty-five patients who were scheduled to undergo elective colon or rectal excision for carcinoma were randomized to receive either placebo or cimetidine preoperatively for 5 days. In addition to standard histopathology, immunohistochemistry and computer video image analysis were used to assess the number of peritumoral lymphocytes in an objective manner. Interim survival analysis according to the Kaplan-Meier method was performed. RESULTS: A trend toward a survival advantage in the group of patients receiving cimetidine (800 mg twice daily) compared with the placebo group was observed (P = 0.20, log rank test) that was most marked in patients with replication error negative tumors (P = 0.04). Similarly, in these two groups there was a trend toward an increase in the number of patients with a conspicuous lymphocytic infiltration (P = 0.10, chi-square test). However, there was no difference in the number of peritumoral lymphocytes as measured by image analysis. CONCLUSIONS: Based on the results of the current study, a short course of preoperative treatment with cimetidine does appear to have an effect on patient survival; however, the exact mechanism is unknown. The failure of this study to demonstrate a clear increase in the local lymphocyte response does not exclude an immunologic mechanism of action.

Successful treatment of a patient with stage IV rhabdoid tumor of the kidney: case report and review.

The clinical course of a 31-month-old patient with advanced (stage IV) rhabdoid tumor of the kidney (RTK) and an analysis of treatment variables that may impact survival are presented. Treatment included complete resection of abdominal disease, radiation therapy to the abdomen and chest, and chemotherapy on a schedule of dose intensification by reduction of the interval between cycles. Inclusion of doxorubicin in treatment was associated with survival among patients in published series (P = 0.002). The patient was in continuous complete remission 60 months from diagnosis. Stage IV rhabdoid tumor of the kidney can be effectively treated with intensive multimodal therapy. Doxorubicin may be an important component of a successful therapeutic regimen.

Dichotomous effects of beta-chemokines on HIV replication in monocytes and monocyte-derived macrophages.

The role of beta-chemokines in the pathogenesis of HIV disease remains undefined. Given the potent capacities of these proteins to attract mononuclear cells to inflammatory sites, such as lymph nodes of patients with HIV disease, the effects of exposure of monocytes and monocyte-derived macrophages to beta-chemokines before HIV infection were compared with their effects when added either simultaneously with or after HIV infection. In this system, HIV replication was substantially increased in cells that had been exposed to beta-chemokines before HIV infection. These effects were pertussis toxin sensitive. By contrast, HIV replication was inhibited in cells that had been exposed to beta-chemokines either simultaneously with or after HIV infection. These effects were not pertussis toxin sensitive. In view of this potent capacity of beta-chemokines to stimulate HIV replication, treatment approaches for HIV disease based on the apparent inhibitory activity of these proteins on viral replication should be undertaken with caution.

Preirradiation PSA predicts biochemical disease-free survival in patients treated with postprostatectomy external beam irradiation.

PURPOSE: To assess the clinical outcome and prostate-specific antigen (PSA) response and to determine prognostic factors for biochemical disease-free survival in patients treated with external beam radiotherapy following radical prostatectomy without hormonal therapy. METHODS AND MATERIALS: Forty-eight patients were treated after prostatectomy with radiotherapy between March, 1988 and December, 1993. Seven patients had undetectable PSA (<0.2) and the remainder had detectable PSA at the time of irradiation (overall: median 2.7, range 0-24.9). Nine patients had biopsy proven local recurrence, palpable local disease, or positive preirradiation imaging. No patients received hormonal therapy prior to irradiation. Median follow-up was 55 months. A median dose of 60 Gy (range 58-66) was given to the prostate bed. Survival was analyzed using the life-table method. Actuarial biochemical disease-free survival was the primary endpoint studied. RESULTS: In patients with detectable PSA, 51% had levels return to undetectable after irradiation. The actuarial 5-year freedom from biochemical failure for all patients was 24%. A significant difference in biochemical disease-free survival was seen for patients irradiated with preirradiation PSA that was undetectable (p < 0.001), or preirradiation PSA that was < or =2.7 (p = 0.002), vs. preirradiation PSA that was >2.7. Five-year actuarial biochemical disease-free survival values were 71, 48, and 0%, respectively, for the three groups. Biochemical disease-free survival was not affected by preoperative PSA level, clinical stage, Gleason's score, pathologic stage, surgical margins, presence of undetectable PSA after surgery, surgery to radiation interval, total dose, or presence of clinically suspicious local disease. Based on digital rectal exam, there were no local failures. CONCLUSION: Biochemical disease-free survival after postprostatectomy radiation is predicted by the PSA at the time of irradiation. Clinical local control is excellent, but distant failure remains a significant problem in this population. The addition of concomitant systemic therapy should be investigated in patients with PSA >2.7.

Primary intestinal Hodgkin's disease complicating ileal Crohn's disease.

An unusual primary intestinal lymphoma that occurred as a complication of ileal Crohn's disease is presented. Immunohistochemistry confirmed the light microscopic diagnosis of Hodgkin's disease (nodular sclerosing), and characterized a distinct mucosal nodule as a large-cell anaplastic non-Hodgkin's lymphoma. This unusual lymphoma developed while the patient was being treated with immunosuppressant medication. The present report is a reminder to clinicians of the possibility of occult lymphoma in ileal Crohn's disease.

Manaing HIV. Part 5: Treating secondary outcomes. 5.17 HIV, weight loss and wasting syndrome.

Weight loss in HIV infection can be severe and distressing. Management must address the likely combination of causes by excluding opportunistic infection, monitoring drug effects, palliating diarrhoea, supporting a healthy diet and using drug therapy to improve appetite or weight gain.