The increasing role of endoscopic ultrasound (EUS) in the management of pancreatic and biliary disease.

Pancreatic and biliary disease continues to have a significant impact on the workload of the National Health Service (NHS), for which there exists a multimodality approach to investigation and diagnosis. Endoscopic ultrasound (EUS) is fast becoming a fundamental tool in this cohort of patients, not only because of its ability to provide superior visualization of a difficult anatomical region, but also because of its valuable role as a problem-solving tool and ever-improving ability in an interventional capacity. We provide a comprehensive review of the benefits of EUS in everyday clinical practice.

PET/CT in anal cancer - is it worth doing?

AIM: To evaluate the role of 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)/ computed tomography (CT) in the current multidisciplinary management of anal cancer, both in initial staging and in follow-up post-treatment. MATERIALS AND METHODS: All patients referred to the region-wide multidisciplinary meeting for anal cancer during the study period received PET/CT imaging in addition to conventional imaging [CT and magnetic resonance imaging (MRI)]. Whether PET/CT altered the stage of the tumour from that suggested by conventional imaging was retrospectively assessed. The effect on management was evaluated. RESULTS: Fifty PET/CT examinations were performed on 44 patients with anal cancer. Thirty were part of initial staging, and 20 were post-chemo/radiotherapy or surgery. Two PET/CTs produced inadequate contemporaneous conventional imaging to allow comparison. Overall PET/CT increased the stage of the anal cancer in 17% of cases (8/48), decreased the stage in 19% (9/48), and did not alter the stage in 65% (31/48). The tumour stage was altered more frequently in initial staging than in follow up imaging. The PET/CT findings altered patient management in 29% (14/48) of cases. The majority (11) of these were cases in which PET/CT was used as part of initial staging. CONCLUSION: PET/CT alters the initial staging sufficiently frequently that it should be used routinely in anal cancer, where it is available. The role of PET/CT in the follow-up of anal cancer is not as clear. Routine follow-up with PET/CT may not be justified, but selected use is of definite benefit in problem solving or if salvage surgery is planned, after multidisciplinary discussion.

Imaging features of ductal plate malformations in adults.

Ductal plate malformations, also known as fibrocystic liver diseases, are a group of congenital disorders resulting from abnormal embryogenesis of the biliary ductal system. The abnormalities include choledochal cyst, Caroli's disease and Caroli's syndrome, adult autosomal dominant polycystic liver disease, and biliary hamartoma. The hepatic lesions can be associated with renal anomalies such as autosomal recessive polycystic kidney disease (ARPKD), medullary sponge kidney, and nephronophthisis. A clear knowledge of the embryology and pathogenesis of the ductal plate is central to the understanding of the characteristic imaging appearances of these complex disorders. Accurate diagnosis of ductal plate malformations is important to direct appropriate clinical management and prevent misdiagnosis.

Loss of fluorescence by anthracycline antibiotics: effects of xanthine oxidase and identification of the nonfluorescent metabolites.

Rat liver cytosol and buttermilk xanthine oxidase both converted 7-deoxypyrromycinone, the 7-deoxyaglycone of marcellomycin, a new anthracycline antibiotic, to a nonfluorescent compound under anaerobic conditions and in the presence of an electron donor. Reduced nicotinamide adenine dinucleotide and reduced nicotinamide adenine dinucleotide phosphate were equally effective electron donors for liver cytosol, and xanthine was the best cofactor for xanthine oxidase. However, xanthine was inactive with liver cytosol. Reactions with xanthine oxidase obeyed Menten-Michaelis kinetics and were inhibited by allopurinol. No xanthine oxidase activity was detected in liver cytosol. Xanthine oxidase also induced a loss of fluorescence when incubated with 7-deoxydaunorubicin aglycone. The nonfluorescent metabolite of 7-deoxypyrromycinone was tentatively identified as the dihydroquinonic derivative of the parent deoxyaglycone on the basis of its spectrophotometric, fluorescent, thin layer chromatographic, and mass spectral characteristics. Our data demonstrate that more than one enzymatic activity, xanthine oxidase, and an unidentified rat liver cytosolic enzyme convert the 7-deoxyaglycones of anthracycline antibiotics to nonfluorescent metabolites.

Comparative anthracycline metabolism in rats: loss of marcellomycin fluorescence.

The in vitro metabolism of marcellomycin by rat tissue fractions showed conversion of marcellomycin to 7-deoxypyrromycinone, bisanhydropyrromycinone, and an as yet unidentified compound by rat liver homogenate, microsomes, cytosol, and mitochondria, and purified hepatic reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase, under anaerobic conditions and in the presence of reduced nicotinamide adenine dinucleotide phosphate. All these fractions except the purified reductase subsequently induced a progressive loss of fluorescence. Mitochondria, however, were much less active than microsomes, cytosol, and homogenate in inducing this latter phenomenon. Marcellomycin was converted to 7-deoxyaglycones only partially by nuclei. No loss of fluorescence was observed with this subcellular fraction. No loss of fluorescence was observed when doxorubicin or daunorubicin were incubated under similar conditions. The appearance of a compound with distinct spectrophotometric properties was demonstrated by absorbance spectrometry. The formation of a compound with different fluorescent characteristics was excluded, as was the binding of the aglycones to subcellular components. The activity inducing the loss of fluorescence was studied in greater detail with cytosol. It predominated in the liver and required both an electron donor and anaerobic conditions. The optimal pH for the reaction was between 7.5 and 8.0. Our results suggest the existence of an enzymatic pathway capable of converting the fluorescent nucleus of marcellomycin to a nonfluorescent metabolite.

Cellular pharmacology in murine and human leukemic cell lines of diaziquone (NSC 182986).

We investigated the in vitro interaction with and antitumor effect on several murine and human leukemic cell lines of diaziquone (AZQ). L1210 cells accumulated AZQ from Roswell Park Memorial Institute Medium 1640 with or without newborn calf serum by a temperature-dependent and sodium azide-resistant process. AZQ inhibited, in a dose-dependent fashion, [3H]thymidine incorporation into L1210 cells, but this inhibition was slow to develop, requiring approximately 6 hr to become apparent. The minimal inhibitory concentration of AZQ for this process was 0.05 to 0.25 nmol/ml. AZQ was a much less effective inhibitor of L1210 cell [3H]uridine and [14C]valine incorporation. In suspension cultures, AZQ inhibited growth of L1210 and HL-60 cells at minimal inhibitory concentrations of 0.5 to 1 nmol/ml. In soft agar cultures, AZQ inhibited HL-60 cell cloning at minimal inhibitory concentrations of 0.1 to 0.3 nmol/ml. AZQ provoked a dose-dependent increase in oxygen consumption when added to intact L1210, HL-60, and K562 cells and was converted to an AZQ anion free radical by these cells. When the aziridine rings of AZQ were opened by acid treatment, the resulting molecule was not accumulated by L1210 cells, did not provoke O2 consumption, did not form free radicals when added to L1210 cells, and was a much less effective inhibitor of [3H]thymidine incorporation by L1210 cells than was AZQ.

Preparation and evaluation of sulfide derivatives of the antibiotic brefeldin a as potential prodrug candidates with enhanced aqueous solubilities.

Several sulfide (+)-brefeldin A (BFA) analogues were prepared through the Michael addition of various thiols. Many of the sulfides were also oxidized to the corresponding sulfoxide with m-CPBA. The sulfides were designed to act as BFA prodrugs via the metabolic oxidation to the sulfoxide and subsequent syn elimination. Kinetic experiments were used to prove that the syn elimination of the sulfoxides prepared did in fact take place. Five selenide BFA prodrugs were also prepared that are envisioned to act in the same manner as the sulfides. As expected, when oxidation of the selenide to selenoxide was attempted, in situ syn elimination was observed. All of the compounds prepared were evaluated for antiproliferative activity against human cancer cell lines in the National Cancer Institute screen. The sulfoxides were much more potent than either the sulfides or selenides. Especially notable were sulfoxide 21, which possessed a cytotoxicity mean graph midpoint value (MGM) value lower than BFA itself, and sulfoxide 22, which possessed an MGM value slightly less potent than that of BFA. The sulfide analogues were shown to possess increased aqueous solubilty with respect to BFA.

Synthesis of new indeno[1,2-c]isoquinolines: cytotoxic non-camptothecin topoisomerase I inhibitors.

In an attempt to design and synthesize potential anticancer agents acting by inhibition of topoisomerase I (top1), a new series of indenoisoquinolines was prepared and tested for cytotoxicity in human cancer cell cultures and for activity against top1. The synthesis relied on the condensation of substituted Schiff bases with homophthalic anhydrides to produce cis-3-aryl-4-carboxyisoquinolones that were cyclized to indenoisoquinolines in the presence of thionyl chloride. Both top1 inhibitory activity and cytotoxicity maximized in a single compound, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-2,3-dimethoxy-8, 9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline hydrochloride (19a), which proved to be a very potent top1 inhibitor having a 110 nM mean graph midpoint (MGM) when tested for cytotoxicity in 55 human cancer cell cultures. A number of structurally related indenoisoquinolines were also obtained that had both potent cytotoxicity as well as top1 inhibitory activity. The key feature of the more potent compounds was the presence of an aminoalkyl side chain on the indenoisoquinoline nitrogen atom. The DNA cleavage patterns induced by top1 in the presence of the indenoisoquinolines were different from those seen with camptothecin. Some of the cleavage sites induced by the indenoisoquinolines were different from those seen with camptothecin, and conversely, camptothecin induced unique cleavage sites not apparent with the indenoisoquinolines. However, both camptothecin and the indenoisoquinolines also induced DNA cleavage sites that were the same in both series but varied in intensity. In addition, some of the DNA cleavages seen with the free base of 19a (compound 18c) in the presence of top1 were inhibited at higher drug concentrations, suggesting either a direct inhibition of the enzyme or an alternative mechanism involving DNA intercalation. Consistent with intercalation, compound 18c did unwind DNA.

Cellular activation of diaziquone [2,5-diaziridinyl-3,6-bis (carboethoxyamino)-1,4-benzoquinone] to its free radical species.

Human leukemic cell lines K562 and HL60, and the murine leukemic cell line L1210, reduce Diaziquone (AZQ) (NCS182986) to its free radical anion. With all cell lines, the free radical was observed immediately in both aerobic and anaerobic cell suspensions. The steady-state concentration of AZQ free radicals was approximately 1% of the total AZQ concentration. L1210 cells treated with azide reduced AZQ, but cells treated with diamide and N-ethylmaleimide did not. NADPH and L-cysteine reduced AZQ. The latter did so under anaerobic conditions; the former did so under both anaerobic and aerobic conditions.

Synergistic inhibition of human leukemia cell growth by deoxyguanosine and 1-beta-D-arabinofuranosylcytosine.

We studied the ability of 2'-deoxyguanosine (dGuo) to influence 1-beta-D-arabinofuranosylcytosine (ara-C) inhibition of soft agar cloning of the cultured human leukemia cell line K562. Ara-C alone inhibited cloning in concentrations of greater than 10 nM, with a steep drop in colony formation observed between 10 and 100 nM. dGuo and ara-C synergistically inhibited cloning; the combination of ineffective concentrations of dGuo (10-50 microM) and ara-C (less than or equal to nM) inhibited cloning by 40-70%. In K562 cells, dGuo is metabolized by both nucleoside kinase and purine nucleoside phosphorylase (PNP), resulting in augmentation of both the GTP pool (to more than 200% of control after a 3 hr incubation with 500 microM dGuo) and the dGTP pool (to more than 2700% of control after 3 hr with 500 microM dGuo). dGuo (50-500 microM) caused a decrease in the dCTP and dTTP pools and an increase in the dATP pool. Synergistic concentrations of dGuo plus 10 nM ara-C augmented the ara-CTP pool up to 800% of control after 3 hr to levels equivalent to those observed after incubation with 500 nM ara-C alone. Incorporation of 10 nM ara-CTP into DNA also increased in the presence of dGuo (up to a maximum of 300% of control), but only to a level that approximated the value observed with nM ara-C alone. The disparity between enlargement of the ara-CTP pool and augmentation of ara-C incorporation into DNA is consistent with the observation of Steinberg et al. [Cancer Res. 39, 4330 (1979)] that high concentrations of dGTP may inhibit DNA polymerase activity. Thus, synergy between dGuo and ara-C is multifactorial, possibly involving inhibition of DNA polymerase by elevated dGTP and ara-CTP pools and augmented incorporation of ara-C into DNA.

Severe hypotension, bronchospasm, and urticaria from intravenous indigo carmine.

Indigo carmine is generally believed to be a safe, biologically inert substance. Adverse reactions to the intravenous administration of this dye have been seen only rarely. We report a life-threatening anaphylactoid reaction to indigo carmine that may have been due to either a drug allergy or to its intrinsic serotonergic properties.

Endoscopic vesicourethropexy. Experience and complications.

Thirty-one patients with stress urinary incontinence were treated with the optical vesicourethropexy. Of these patients, 70.9 per cent had previous pelvic or vaginal operations, of which 59 per cent also had failed stress incontinence procedures. In 90 per cent of the cases, cure or improvement was obtained. However, the procedure is not free of complications (38%). Aside from the problems reported by others, vaginal bleeding or discomfort due to erosion of the mucosa by the Dacron pledget was observed. We also had a case complicated by an obstruction of the small bowel secondary to fixation of a jejunal loop to the retropubic area. We believe that excellent results may be obtained with this technique in patients with previous pelvic surgery or concomitant medical problems. Remarks in the evaluation of these patients and technical aspects of the procedure are presented.

Plasma kinetics of aclacinomycin A and its major metabolites in man.

The plasma pharmacokinetics of the antineoplastic anthracycline antibiotic aclacinomycin A (Acm) and its metabolites were studied in 12 patients treated with 60-120 mg/m2 during a phase I clinical trial. Total plasma drug fluorescence initially declined very rapidly, but from 2 to 24 h after injection, fluorescence rose progressively to intensities greater than those measured 1 min after Acm injection. Plasma total drug fluorescence slowly declined from 24 to 72 hours after Acm administration. These events reflected the rapid disappearance of Acm and the subsequent appearance of two highly fluorescent metabolites. One metabolite co-chromatographed with and had a fluorescence spectrum identical to known metabolite F1 (bisanhydroaklavinone). The other metabolite did not co-chromatograph with any previously described Acm metabolite. This metabolite had a fluorescence spectrum unlike any previously described Acm metabolite and was not altered by treatment for 60 min with 0.2 N HCl at 100 degrees C or by treatment for 24 h at 37 degrees C with bacterial beta-glucuronidase or limpet aryl sulfatase.

Electron spin resonance of electrochemically generated free radicals from diaziquone and its derivatives.

The one-electron electrochemical reduction of diaziquone (AZQ) and 12 analogs is analyzed using ESR spectroscopy and cyclic voltammetry. The hyperfine coupling constants arising from the interaction of the unpaired electron with the aziridine nitrogen nuclei fall within 1.20 and 2.26 G. Smaller couplings are observed arising from the protons and nitrogens in the carboethoxyamino groups. The in vitro activity of AZQ and its analogs is examined. Methyl groups in the aziridine rings increase the activity of some analogs. In the absence of aziridines, a chloroquinone compound with only carboethoxyamino groups was surprisingly active. This compound has a more positive cathodic peak than diaziquone.

Pre-cervical soft tissues: a cautionary note.

Visualization of pre-cervical soft tissue swelling on a lateral radiograph is an important indicator of possible bony injury in the context of cervical spine trauma. We report a case where apparent swelling was in fact an artefact due to an inappropriately placed endotracheal tube. We recommend review of the position of endotracheal tubes when interpreting pre-cervical soft tissue swelling.

The Preoperative Assessment of Hepatic Tumours: Evaluation of UK Regional Multidisciplinary Team Performance.

Introduction. In the UK, patients where liver resection is contemplated are discussed at hepatobiliary multidisciplinary team (MDT) meetings. The aim was to assess MDT performance by identification of patients where radiological and pathological diagnoses differed. Materials and Methods. A retrospective review of a prospectively maintained database of all cases undergoing liver resection from March 2006 to January 2012 was performed. The presumed diagnosis as a result of radiological investigation and MDT discussion is recorded at the time of surgery. Imaging was reviewed by specialist gastrointestinal radiologists, and resultswereagreedonby consensus. Results. Four hundred and thirty-eight patients were studied. There was a significant increase in the use of preoperative imaging modalities (P ≤ 0.01) but no change in the rate of discrepant diagnosis over time. Forty-two individuals were identified whose final histological diagnosis was different to that following MDT discussion (9.6%). These included 30% of patients diagnosed preoperatively with hepatocellular carcinoma and 25% with cholangiocarcinoma of a major duct. Discussion. MDT assessment of patients preoperatively is accurate in terms of diagnosis. The highest rate of discrepancies occurred in patients with focal lesions without chronic liver disease or primary cancer, where hepatocellular carcinoma was overdiagnosed and peripheral cholangiocarcinoma underdiagnosed, where particular care should be taken. Additional care should be taken in these groups and preoperative multimodality imaging considered.

Azygos reflux: a CT sign of cardiac tamponade.

Three patients who were investigated with dynamic contrast medium enhanced computed tomography (CT) of the thorax were noted to have pericardial effusions with reflux of contrast medium back along the azygos vein. The diagnosis of cardiac tamponade was not made clinically, but in each case was suggested from the CT findings. Confirmation of the diagnosis was made in all three cases, two patients with echocardiography and one at post mortem. One patient made a rapid recovery following the insertion of a pericardial drain, another made a temporary recovery after pericardiocentesis but the third died. Thirty CT scans performed with similar protocol were reviewed and none of these demonstrated reflux along the azygos vein. The presence of contrast medium refluxing into the azygos vein implies significant haemodynamic disturbance, and in the presence of a pericardial effusion suggests the diagnosis of cardiac tamponade.