Neoadjuvant therapy in the treatment of hilar cholangiocarcinoma:Review of the literature

Cholangiocarcinoma(CCA) is a malignant tumor of the biliary system and includes, according to the anatomical classification, intra hepatic CCA(iCCA),hilar CCA(hCCA) and distal CCA(dCCA). Hilar CCA is the most challenging type in terms of diagnosis, treatment and prognosis. Surgery is the only treatment possibly providing long-term survival, but only few patients are considered resectable at the time of diagnosis. In fact, tumor's extension to segmentary or subsegmentary biliary ducts, along with large lymph node involvement or intrahepatic metastases, precludes the surgical approach. To achieve R0 margins is mandatory for the disease-free survival and overall survival. In case of unresectable locally advanced hCCA, radiochemotherapy(RCT) as neoadjuvant treatment demonstrated to be a therapeutic option before either hepatic resection or liver transplantation. Before liver surgery, RCT is believed to enhance the R0 margins rate. For patients meeting the Mayo Clinic criteria, RCT prior to orthotopic liver transplant(OLT) has proved to produce acceptable 5-years survivals. In this review, we analyze the current role of neoadjuvant RCT before resection as well as before OLT.     

Transplacental IgG Subclass Concentrations in Pregnancies at Risk of Haemolytic Disease of the Newborn

The relationship of haemolytic disease of the newborn (HDN) to the transplacental passage of the four IgG subclasses was assessed at varous gestational ages by comparing the maternal and fetal IgG subclass concentrations in 34 pregnancies at risk of HDN with those in 30 pregnancies not at risk. Higher maternal and fetal IgG1 levels were attained in pregnancies at risk of HDN than in pregnancies not at risk. In contrast, a slight decrease in maternal IgG2 and IgG4 levels occurred in pregnancies at risk of HDN, as compared with a slight rise in maternal IgG2 and IgG4 levels in pregnancies not at risk of HDN. Changes in fetal IgG2 and 4 concentrations in either type of pregnancy were very similar, showing only slight increases between the 19th and 34th week of gestation. A slight decrease in maternal IgG3 occurred in both types of pregnancy. In contrast, higher and fairly steady levels of fetal IgG3 were observed in fetuses not at risk of HDN throughout gestation, when compared with those in 'at risk' pregnancies. However, the statistical reliability of these results is not clear since only small numbers of samples were tested and because wide variations in IgG concentrations were observed. The IgG subclass concentrations in 50 paired maternal and cord blood samples were also measured and revealed that IgG1 levels were substantially higher in cord rather than maternal blood; cord and maternal IgG2, 3 and 4 levels, on the other hand, were fairly similar.     

Midpregnancy plasma zinc in normal and growth retarded fetuses--a preliminary study.

OBJECTIVE: To determine plasma zinc concentrations in normally and abnormally growing fetuses. DESIGN: Prospective observational study. SETTING: Fetal Medicine Unit, Queen Charlotte's Maternity Hospital. SUBJECTS: 53 pregnant women attending for fetal blood sampling at between 18 and 40 weeks gestation. 27 fetuses were normal (central group), 11 fetuses were growth retarded and 15 were malformed. MAIN OUTCOME MEASURES: Plasma zinc concentrations in maternal and fetal blood at time of fetal blood sampling. RESULTS: In normally growing fetuses, between 18 and 40 weeks gestation, there was no fall in maternal plasma zinc concentration; the fetal level fell by 36%. In 10 fetuses with symmetrical growth retardation, plasma zinc concentration tended to be low, but was not significantly different from that in the normal control fetuses. CONCLUSION: The results suggest that (i) placental transfer of zinc is an uphill secretory process and that it is a rate-limiting step in the accumulation of zinc by the fetus and (ii) in fetuses with symmetrical intrauterine growth retardation, a low plasma zinc is probably a parallel phenomenon and not necessarily an aetiological factor.     

Normal amniotic pressure throughout gestation.

OBJECTIVE: To characterize amniotic pressure (AP) in pregnancies with normal amniotic fluid volume. DESIGN: Observational study, mainly cross-sectional. SETTING: Fetal medicine unit within a tertiary referral hospital. SUBJECTS: Patients undergoing transamniotic invasive procedures in whom amniotic fluid volume was subjectively assessed as normal on ultrasound. Those beyond 16 weeks with a deepest vertical pool on ultrasound less than 3.0 or greater than 8.0 cm were excluded. Overall 194 pregnancies were studied on 232 occasions between 7 and 38 weeks gestation. INTERVENTIONS: Manometry readings referenced to the top of the maternal abdomen were obtained via a fluid-filled line from the needle hub and either connected to a pressure transducer (n = 190) or held vertically against a ruler (n = 42). MAIN OUTCOME MEASURES: AP in mm Hg, AP corrected for gestational age (z scores), semi-quantitative ultrasonic indices of amniotic fluid volume, clinical variables. RESULTS: AP in singleton pregnancies increased with advancing gestation (P less than 0.001), and the sigmoid-shaped regression curve plateaued in the mid-trimester. AP z scores were not influenced by volume-related phenomena such as twin gestation, the deepest vertical pool, or amniotic fluid index, nor by maternal age, parity, gravidity, fetal sex, or subsequent spontaneous preterm delivery. CONCLUSIONS: These findings suggest that AP is not principally determined by intrauterine volume. We speculate that AP, which reflects change in uterine tension as a function of radius, may instead be determined by gestation-specific anatomical and hormonal influences on gravid uterine musculature. A reference range for AP has been constructed for use in amnioinfusion and amnioreduction procedures.     

Myocardial protection in adult cardiac surgery: current options and future challenges

Current techniques of myocardial protection are evolving with the use of less conventional modalities of cardioplegia and have reduced the morbidity and mortality of cardiac operations. Blood cardioplegic solutions appear superior to cold cardioplegia in terms of myocardial protection and adjuncts as glutamate/aspartate enhancement, antioxidant supplementation, nitric oxide donors and maintenance of calcium homeostasis seem effective. In the near future, further experimental and clinical investigations about pharmacological preconditioning, sodium–hydrogen exchangers inhibition and gene therapy need to be addressed to well define their potential role in the improvement of current techniques of myocardial protection that are suboptimal in high-risk clinical settings.     

The physical state of intranuclear water and ions: changes during cell proliferation and chemically induced carcinogenesis

The complex dielectric constant of small quantities of liver nuclei in various functional states was measured in the frequency range of 50-2,000 MHz using an Automatic Network Analyzer. From these measurements, through an electric model of macromolecules in solution, several quantities such as ion content, bound water, and free water have been estimated. Unique changes in the physical state of intranuclear water and ions were then apparent in the resting liver nuclei immediately following induced cell proliferation, as compared to nuclei either from early carcinogen-altered hepatocytes or from late selected carcinogen-initiated hepatocytes. Possible implications of these findings are discussed in terms of the molecular events controlling chemically-induced neoplastic transformation.     

Identification of a novel gp100/pMel17 peptide presented by HLA-A*6801 and recognized on human melanoma by cytolytic T cell clones

Melanoma-associated peptides recognized by cytolytic T lymphocytes (CTL) in the context of several histocompatibility leukocyte antigens (HLA) are required for the development of specific immunotherapies. Using a transient transfection assay into COS-7 cells, we identified the gp100/pMel17 melanosomal protein as the shared antigen recognized by three independent CD8+ CTL clones in HLA-A*6801-restricted fashion. This finding was confirmed by the correlation between lack of gp100/pMel17 protein in a number of HLA-A*6801-positive melanomas and their resistance to lysis/cytokine production by the specific effectors. The gp100/pMel17 antigenic epitope was identified based on recognition of subfragments and on a computer-based prediction algorithm. Among a panel of gp100/pMel17-derived synthetic peptides only the 10-mer HTMEVTVYHR (gp100/pMel17182-191) induced tumor necrosis factor (TNF) release by CTL clones when pulsed on suitable target cells whereas both the 10-mer and the shorter 9-mer gp100/pMel17183-191 sensitized the same antigen-pulsed cells to lysis. In conclusion, the identification of the HTMEVTVYHR peptide will extend to HLA-A*6801 melanoma patients the possibility to exploit gp100/pMel17 melanosomal protein for experimental and clinical studies.     

Early, reversible plasma membrane injury in galactosamine-induced liver cell death.

Administration to rats of D-galactosamine (400 mg/kg) produces liver cell death that develops during the first 24 hours. Plasma membranes isolated within the first few hours from these animals show a 40% reduction in 5'-nucleotidase activity and a two-fold increase in maximum negative ellipticity determined by circular dichroism. Simultaneous administration of uridine prevents liver cell death and these early alterations in the plasma membranes. Uridine also prevents cell death if administered for up to 3 hours after galactosamine. The 5'nucleotidase activity reduced when uridine is administered for up to 2-1/2 hours after galactosamine. Changes in the liver calcium ion concentration accompany these plasma membrane alterations. Uridine will prevent and reverse the changes in calcium content in parallel to its ability to reverse the membrane alterations. The significance of these findings with respect to the mechanism of galactosamine-induced liver cell death is discussed.