The role of minimally invasive surgery in the treatment of cholangiocarcinoma.

Cholangiocarcinoma (CC) is the second most common type of primary liver cancer after hepatocellular carcinoma. Surgical resection is considered the only curative treatment for CC. In general, laparoscopic liver surgery (LLS) is associated with improved short-term outcomes without compromising the long-term oncological outcome. However, the role of LLS in the treatment of CC is not yet well established. In addition, CC may arise in any tract of the biliary tree, thus requiring different types of treatment, including pancreatectomies and extrahepatic bile duct resections. This review presents and discusses the state of the art in the laparoscopic and robotic surgical treatment of all types of CC. An electronic search was performed to identify all studies dealing with laparoscopic or robotic surgery and cholangiocarcinoma. Laparoscopic resection in patients with intrahepatic CC (ICC) is feasible and safe. Regarding oncologic adequacy, as R0 resections, depth of margins, and long-term overall and disease-free survival, laparoscopy is comparable to open procedures for ICC. An adequate patient selection is required to obtain optimal results. Use of laparoscopy in perihilar CC (PHC) has not gained popularity. Further studies are still needed to confirm the benefit of this approach over conventional surgery for PHC. Laparoscopic pancreaticoduodenectomy for distal CC (DCC) represents one of the most advanced abdominal operations owing to the necessity of a complex dissection and reconstruction and has also had small widespread so far. Minimally invasive surgery seems feasible and safe especially for ICC. Laparoscopy for PHC is technically challenging notably for the caudate lobectomy. Not least as for the LLR, the robotic approach for DCC appears technically achievable in selected patients.

Liver Transplantation and Abuse of Drugs and Alcohol: A Correlation Between Scales of the MMPI-2.

BACKGROUND: Clinical practice requires an accurate psychological assessment of subjects with clinical history of alcohol abuse and/or substance abuse (abuse history [AH]) for therapeutic choice. This study aims to identify significant correlations between the Minnesota Multiphasic Personality Inventory (MMPI)-2 scales in patients awaiting liver transplantation. METHODS: We evaluated a personality questionnaire containing MMPI-2 scales in the sample of 308 patients (81.8% males and 18.2% females) awaiting liver transplantation. The AH group composed 44.49% of patients and in the abuse free (AF) group, 55.51%. Scales were compared using Shapiro-Wilk test and Mann-Whitney U test. Interrelationships were examined using Spearman's correlation. RESULTS: This analysis found 27 scales of the MMPI-2 that were statistically different between 2 groups (AF and AH). In the AH group, we found a significant correlation between the following pairs of scales: Schizophrenia Scale (Sc) with the Addictions Potential Scale, Social Introversion scale (Si) with the Psychopathic Deviate scale (Pd), and Social Discomfort scale with Pd; the ES scale was negatively correlated with the Sc and Si scales. This interim study showed that the understanding of these indicators is crucial both for the assessment accuracy and for a prediction of the degree of therapy compliance after the transplantation. CONCLUSIONS: The scales of the MMPI-2 indicated a marked tendency to emotional rigidity, a lack of self-esteem and susceptibility judgment. Social introversion and social discomfort trends lead to impulsive behavior and deviant actions that combine poorly with good compliance with treatment.

Hanging of the hepatic veins septa: a safe control prior and during outflow anastomosis in liver transplantation.

Inferior vena cava (IVC) preservation during orthotopic liver transplantation (OLT) is known as the "piggyback" technique. The end-to-side anastomosis is constructed between the graft's IVC and recipient's hepatic veins using a Satinsky side clamp applied in a transverse position. To stabilize the large Satinsky clamp and preserve a sufficient vascular stump after hepatectomy and before graft implantation, we propose a technical innovation consisting of hanging the septa between the left and middle hepatic vein and between the middle and right hepatic vein using 2 tapes. This technique showed some advantages when performing the caval outflow anastomosis, representing a further technical refinement of the piggyback end-to-side technique for the implantation on the 3 hepatic veins. From November 2001 to September 2012, we performed 272 consecutive OLT at our institution with the piggyback technique using the hanging of the hepatic veins septa in all cases. In conclusion, the hanging of the 3 hepatic veins septa presented in this study represents a simple, safe and reproducible technique for the outflow anastomosis using the piggyback technique.

T-level downstaging and complete pathologic response after preoperative long-term radiochemotherapy for locally advanced rectal cancer.

Advantages of neoadjuvant chemoradiotherapy for locally advanced carcinoma of the middle and the lower third of the rectum are downstaging and downsizing of the tumor. Results of pathologic results are affected by post-treatment tissue changes and may influence the choice of surgical procedure. Forty-three consecutive patients (27 male, 16 female; mean age 64 years) were operated after receiving a long-term chemoradiotherapy during a period of 16 months. The data of initial staging procedure (high resolution magnetic resonance imaging) and results of pathological examination of the surgical specimens were analyzed. Regression of tumor was assessed by the absence of vital tumor cells and the post-treatment fibrotic tissue alterations. Regression of tumor size was seen in 42/43 patients leading to an improved T-stage in 27 patients. R0-resection was possible in all cases, although there was a perirectal tumor infiltration to less than 2 mm to circumference of the surgical specimen in 2 cases and unexpected small liver metastasis in 5 cases. Complete remission rate was 23.3% (10 cases). Detecting small amounts of vital tumor cells in altered tissue after chemoradiotherapy is a major problem of pathological examination procedure and should be taken into consideration by the surgeons. The choice of operation (resection vs. abdominoperineal extirpation vs. local excision) should be committed to the initial imaging procedure and not to any restaging procedure after neoadjuvant chemoradiotherapy.

An unusual case of synovial cyst of the hip joint presenting as femoral vein compression and severe lower limb edema.

INTRODUCTION: Synovial cyst of the hip joint causing the compression of the femoral vein is a rare occurrence. We carefully reviewed the international literature collecting 26 additional cases. REPORT: A case of a patient affected with synovial cyst of the hip joint causing the compression of the femoral vein and severe lower limb edema is presented. DISCUSSION: The treatment of choice of synovial cyst compressing the femoral vein is surgical removal.

Inhibitory effect of NO-releasing ciprofloxacin (NCX 976) on Mycobacterium tuberculosis survival.

Here, we report the antimycobacterial activity of NCX 976, a new molecule obtained adding a NO moiety to the fluoroquinolone ciprofloxacin, on Mycobacterium tuberculosis H37Rv strain, both in a cell-free model and in infected human macrophages. Unlike unaltered ciprofloxacin, NCX976 displayed a marked activity also at low-nanomolar concentrations.

NO donors inhibit Leishmania infantum cysteine proteinase activity.

Nitric oxide (NO) releasing drugs (e.g., glyceryl trinitrate) were successfully used in the treatment of cutaneous leishmaniasis in man. In the present study, the effect of NO donors on the catalytic activity of the cysteine proteinase from promastigotes of Leishmania infantum, an agent of Old World visceral and cutaneous leishmaniases, is reported. In particular, one equivalent of NO, released by the NO donors S-nitrosoglutathione, glyceryl trinitrate, (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide, 3-morpholinosydnonimine, S-nitrosoacetylpenicillamine and sodium nitroprusside, inhibited one equivalent of the parasite cysteine proteinase. As expected, NO-deprived compounds did not affect the catalytic activity of the parasite cysteine proteinase. Furthermore, the absorption spectrum of the (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide-treated inactive L. infantum enzyme displayed a maximum in the 330-350 nm wavelength range. The reducing agents dithiothreitol and L-ascorbic acid completely prevented parasite cysteine proteinase inhibition by NO, fully restored the catalytic activity, and reversed the NO-induced absorption spectrum of the inactive enzyme. Moreover, S-nitrosoacetylpenicillamine displayed a leishmanicidal effect, inhibiting the cysteine proteinase activity in vivo. As expected, the NO-deprived compound N-acetylpenicillamine did not affect significantly the parasite viability and the enzyme activity in vivo. These data suggest that the L. infantum cysteine proteinase undergoes NO-mediated S-nitrosylation, thereby representing a possible mechanism of antiparasitic host defence.

Inhibition of cysteine protease activity by NO-donors.

Cysteine proteases represent a broad class of proteolytic enzymes widely distributed among living organisms. Although well known as typical lysosomal enzymes, cysteine proteases are actually recognized as multi-function enzymes, being involved in antigen processing and presentation, in membrane-bound protein cleavage, as well as in degradation of the cellular matrix and in processes of tissue remodeling. Very recently, it has been shown that the NO(-donor)-mediated chemical modification of the Cys catalytic residue of cysteine proteases, including Coxsackievirus and Rhinovirus cysteine proteases, cruzain, Leishmania infantum cysteine protease, falcipain, papain, as well as mammalian caspases, cathepsins and calpain, blocks the enzyme activity in vitro and in vivo. Here, inhibition of representative cysteine proteases by NO(-donors) is reviewed.

Re-evaluation of amino acid sequence and structural consensus rules for cysteine-nitric oxide reactivity.

Nitric oxide (NO), produced in different cell types through the conversion of L-arginine into L-citrulline by the enzyme NO synthase, has been proposed to exert its action in several physiological and pathological events. The great propensity for nitrosothiol formation and breakdown represents a mechanism which modulates the action of macromolecules containing NO-reactive Cys residues at their active centre and/or allosteric sites. Based on the human haemoglobin (Hb) structure and accounting for the known acid-base catalysed Cys beta93-nitrosylation and Cys beta393NO-denitrosylation processes, the putative amino acid sequence (Lys/Arg/His/Asp/Glu)Cys(Asp/Glu) (sites -1, 0, and + 1, respectively) has been proposed as the minimum consensus motif for Cys-NO reactivity. Although not found in human Hb, the presence of a polar amino acid residue (Gly/Ser/Thr/Cys/Tyr/Asn/Gln) at the -2 position has been observed in some NO-reactive protein sequences (e.g., NMDA receptors). However, the most important component of the tri- or tetra-peptide consensus motif has been recognised as the Cys(Asp/Glu) pair [Stamler et al., Neuron (1997) 18, 691-696]. Here, we analyse the three-dimensional structure of several proteins containing NO-reactive Cys residues, and show that their nitrosylation and denitrosylation processes may depend on the Cys-Sy atomic structural microenvironment rather than on the tri- or tetra-peptide sequence consensus motif.

The dual personality of NO.

In the body, nitric oxide (NO) is an important physiological regulator of functions such as vasodilatation and neurotransmission. Under pathological conditions, high concentrations of NO can be either beneficial(e.g. anti-bacterial, anti-parasitic and anti-viral) or detrimental; NO can therefore be considered a double-edged sword. When manipulating NO levels clinically, attention should be paid to minimize the negative effects and maximize the beneficial effects of NO. This article highlights recent evidence that supports the complexity of the regulatory mechanisms that lead to sophisticated endogenous NO production.

Modulation of the nitric oxide pathway by copper in glial cells.

The action of copper on the nitric oxide (NO) pathway was investigated in rat C6 glioma cells expressing both inducible and constitutive NO synthase (NOS) isoforms. The inducible NOS-II-mediated NO synthesis (i.e., nitrite production induced by LPS plus IFNgamma) was found to be increased upon copper uptake by cells, this effect being attributable to NOS-II mRNA transcriptional over-expression. On the other hand, the constitutive neuronal isoform (NOS-I) was inhibited after copper uptake, as revealed by the decrease of basal intracellular cGMP levels in C6 cells. Consistently, in vitro experiments showed that copper selectively blocked the catalytic activity of NOS-I, but not of NOS-II. The observed modulation of NOS isoforms by copper in C6 cells is in line with the previous hypothesis that selective inhibition of NOS-I leads to enhanced NO production through transcriptional activation of NOS-II.

Selective inhibition of nitric oxide synthase type I by clonidine, an anti-hypertensive drug.

Clonidine, clinically used in the treatment of hypertension, is a central alpha(2)-adrenergic agonist that reduces blood pressure and slows heart rate by reducing sympathetic stimulation. Considering the structural similarity between clonidine and hydrophobic heterocyclic nitric oxide synthase (NOS) inhibitors, the effect of clonidine on the nitric oxide (NO) pathway was investigated. This was verified by determination of NOS activity in vitro and by analysis of inducible Ca(2+)-independent NOS (NOS-II) mRNA expression and measurement of nitrite levels in rat C6 glioma cells, taken as a cellular model. Clonidine inactivated neuronal Ca(2+)-dependent NOS (NOS-I) competitively without affecting NOS-II and endothelial Ca(2+)-dependent NOS (NOS-III) activity. However, the value of K(i) for clonidine binding to NOS-I depended on tetrahydrobiopterin (BH(4)) concentration, as reported for NOS inhibition by other nitrogen heterocyclic compounds. In particular, the value of K(i) for clonidine binding to NOS-I increased (from [7. 9 +/- 0.4] x 10(-5) M to [8.0 +/- 0.4] x 10(-3) M) as BH(4) concentration was increased (between 3.0 x 10(-7) M and 1.0 x 10(-3) M), at pH 7.5 and 37.0 degrees. In addition, clonidine (1.0 x 10(-4) M) enhanced NOS-II mRNA expression in rat C6 glioma cells, as induced by Escherichia coli lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma). Finally, clonidine (1.0 x 10(-4) M to 1.0 x 10(-3) M) dose dependently increased the levels of LPS/IFN-gamma-induced nitrites, the breakdown product of NO, in supernatants of rat C6 glioma cells. As reported for other NOS inhibitors, clonidine was also able to regulate NOS-I and NOS-II inversely.

Nitric oxide: an inhibitor of NF-kappaB/Rel system in glial cells.

Nitric oxide (NO) has been reported to regulate NF-kappaB, one of the best-characterized transcription factors playing important roles in many cellular responses to a large variety of stimuli. NO has been suggested to induce or inhibit the activation of NF-kappaB, its effect depending, among others, on the cell type considered. In this review, the inhibitory effect of NO on NF-kappaB (and subsequent suppression of NF-kappaB-dependent gene expression) in glial cells is reported. In particular, exogenous and endogenous NO has been observed to keep NF-kappaB suppressed, thus preventing the expression of NF-kappaB-induced genes, such as inducible NO synthase itself or HIV-1 long terminal repeat. Furthermore, the possible molecular mechanisms of NO-mediated NF-kappaB inhibition are discussed. More specifically, NO has been reported to suppress NF-kappaB activation inducing and stabilizing the NF-kappaB inhibitor, IkappaB-alpha. On the other hand, NO may inhibit NF-kappaB DNA binding through S-nitrosylation of cysteine residue (i. e., Cys62) of the p50 subunit. As a whole, a novel concept that the balance of intracellular NO levels may control the induction of NF-kappaB in glial cells has been hypothesized.

Nitric oxide inhibits falcipain, the Plasmodium falciparum trophozoite cysteine protease.

Nitric oxide (NO) is a pluripotent regulatory molecule possessing, among others, an antiparasitic activity. In the present study, the inhibitory effect of NO on the catalytic activity of falcipain, the papain-like cysteine protease involved in Plasmodium falciparum trophozoite hemoglobin degradation, is reported. In particular, NO donors S-nitrosoglutathione (GSNO), (+/-)-(E)-p6ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenami de (NOR-3), 3-morpholinosydnonimine (SIN-1), and sodium nitroprusside (SNP) inhibit dose-dependently the falcipain activity present in the P. falciparum trophozoite extract, this effect likely attributable to S-nitrosylation of the Cys25 catalytic residue. The results represent a new insight into the modulation mechanism of falcipain activity, thereby being relevant in developing new strategies for inhibition of the P. falciparum life cycle.

Nitric oxide inhibits cruzipain, the major papain-like cysteine proteinase from Trypanosoma cruzi.

Nitric oxide (NO) is a pluripotent regulatory molecule showing, among others, an antiparasitic activity. Moreover, NO inhibits cysteine proteinase action by nitrosylating the Cys catalytic residue. In the present study, the inhibitory effect of the substrate N-alpha-benzyloxycarbonyl-L-phenylalanyl-L-arginine-(7-amino-4-methyl coumarin) and of NO on the catalytic activity of cruzipain, the major papain-like cysteine proteinase from Trypanosoma cruzi (the hemoflagellate protozoan parasite which causes the American trypanosomiasis), is reported. In particular, NO-donors S-nitroso-glutathione (GSNO), (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR-3), 3-morpholinosydnonimine (SIN-1), S-nitroso-acetyl-penicillamine (SNAP), and sodium nitroprusside (SNP) dose-dependently inhibited cruzipain, this effect being likely attributable to the S-nitrosylation of the Cys25 catalytic residue. These results were analyzed in parallel with those concerning the inhibitory effect of the substrate and of NO on the catalytic activity of falcipain, the cruzipain-homologous cysteine proteinase from Plasmodium falciparum. The modulation of the cruzipain and falcipain activity by NO may be relevant in developing new strategies against T. cruzi and P. falciparum in human host. As a whole, the NO-mediated S-nitrosylation of pathogenic viral, bacterial, fungal, and parasitic cysteine proteinases may represent a general mechanism of antimicrobial and antiparasitic host defences.