Systemic Treatment for Metastatic Biliary Tract Cancer: State of the Art and a Glimpse to the Future

Recent years have seen some breakthroughs in the therapeutic landscape of advanced biliary tract cancer (BTC). Firstly, a better understanding of the molecular background of BTC has led to important improvements in the management of these hepatobiliary malignancies, with the advent of targeted agents representing an unprecedented paradigm shift, as witnessed by the FDA approval of pemigatinib and infigratinib for FGFR2-rearranged and ivosidenib in IDH1-mutant cholangiocarci-noma. In addition, several novel treatments are under assessment, including immune checkpoint inhibitors and combination chemotherapies. In the current review, we provide an overview of systemic treatment for metastatic BTC, summarizing recent clinical data on chemotherapy as well as the main results of targeted therapies and immunotherapy

MKRN3 and KISS1R mutations in precocious and early puberty

Background Pubertal timing is known to be influenced by interactions among various genetic, nutritional, environmental and socio-economic factors, although the ultimate mechanisms underlying the increase in pulsatile GnRH secretion at puberty have yet to be fully elucidated. The aim of our research was to verify the role of KISSR1 (previously named GPR54) and MKRN3 genes on pubertal timing. Methods We analyzed the DNA sequence of these genes in 13 girls affected by central precocious puberty (CPP) who showed onset of puberty before 8 years of age, and in 6 girls affected by early puberty (EP) between 8 and 10 years of age. Results Direct sequencing of the KISS1R (GPR54) gene revealed two SNPs. One SNP is a missense variant (rs 350,132) that has been previously reported in connection to CPP in Korean girls. The other variant that we found in the GPR54 gene (rs764046557) was a missense SNP located in exon 5 at position 209 of the aminoacid. We identified this variant in only one CPP patient. Automatic sequencing of MKRN3 in all patients revealed three variants in eight subjects. In 6 out of 19 (31.5%) patients (3/13 CPP patients and 3/6 EP patients) we found the synonymous variant c.663C > T (rs2239669). Another synonymous variant (rs140467331) was found in one of our CPP patients, as well as one missense variant (rs760981395) in another CPP patient. Conclusion In conclusion, we identified sequence variations of the KISS1R and MKRN3 genes, two of the most frequent genetic causes of ICPP. Our results suggest that these variants might be inducible factors in the pathogenesis of CPP

Intraoperative assessment of fluid responsiveness in normotensive dogs under isoflurane anaesthesia

The aim of this study was to evaluate the incidence of fluid responsiveness (FR) to a fluid challenge (FC) in normotensive dogs under anaesthesia. The accuracy of pulse pressure variation (PPV), systolic pressure variation (SPV), stroke volume variation (SVV), and plethysmographic variability index (PVI) for predicting FR was also evaluated. Dogs were anaesthetised with methadone, propofol, and inhaled isoflurane in oxygen, under volume-controlled mechanical ventilation. FC was performed by the administration of 5 mL/kg of Ringer’s lactate within 5 min. Cardiac index (CI; L/min/m2), PPV, (%), SVV (%), SPV (%), and PVI (%) were registered before and after FC. Data were analysed with ANOVA and ROC tests (p < 0.05). Fluid responsiveness was defined as 15% increase in CI. Eighty dogs completed the study. Fifty (62.5%) were responders and 30 (37.5%) were nonresponders. The PPV, PVI, SPV, and SVV cut-off values (AUC, p) for discriminating responders from nonresponders were PPV >13.8% (0.979, <0.001), PVI >14% (0.956, <0.001), SPV >4.1% (0.793, <0.001), and SVV >14.7% (0.729, <0.001), respectively. Up to 62.5% of normotensive dogs under inhalant anaesthesia may be fluid responders. PPV and PVI have better diagnostic accuracy to predict FR, compared to SPV and SVV

Electron neutrino tagging through tertiary lepton detection

We discuss an experimental technique aimed at tagging electron neutrinos in multi-GeV artificial sources on an event-by-event basis. It exploits in a novel manner calorimetric and tracking technologies developed in the framework of the LHC experiments and of rare kaon decay searches. The setup is suited for slow-extraction, moderate power beams and it is based on an instrumented decay tunnel equipped with tagging units that intercept secondary and tertiary leptons from the bulk of undecayed \pi^+ and protons. We show that the taggers are able to reduce the \nue contamination originating from K_e3 decays by about one order of magnitude. Only a limited suppression (~60%) is achieved for \nue produced by the decay-in-flight of muons; for low beam powers, similar performance as for K_e3 can be reached supplementing the tagging system with an instrumented beam dump.Comment: 19 pages, 7 figures; minor changes, version to appear in EPJ

Late-Proterozoic to Paleozoic history of the peri-Gondwana Calabria–Peloritani Terrane inferred from a review of zircon chronology

U–Pb analyses of zircon from ten samples of augen gneisses, eight mafic and intermediate metaigneous rocks and six metasediments from some tectonic domains along the Calabria–Peloritani Terrane (Southern Italy) contribute to knowledge of peri-Gondwanan evolution from Late-Proterozoic to Paleozoic times. All samples were equilibrated under amphibolite to granulite facies metamorphism during the Variscan orogeny. The zircon grains of all considered samples preserve a Proterozoic memory suggestive of detrital, metamorphic and igneous origin. The available data fit a frame involving: (1) Neoproterozoic detrital input from cratonic areas of Gondwana; (2) Pan-African/Cadomian assemblage of blocks derived from East and West African Craton; (3) metamorphism and bimodal magmatism between 535 and 579 Ma, within an active margin setting; (4) rifting and opening of Ordovician basins fed by detrital input from the assembled Cadomian blocks. The Paleozoic basins evolved through sedimentation, metamorphism and magmatism during the Variscan orogeny involving Palaeozoic and pre-Paleozoic blocks. The Proterozoic zircon records decidedly decrease in the high grade metamorphic rocks affected by Variscan pervasive partial melting. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40064-016-1839-8) contains supplementary material, which is available to authorized users

Pre- and post-transplant minimal residual disease predicts relapse occurrence in children with acute lymphoblastic leukaemia

Relapse remains the leading cause of treatment failure in children with acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem cell transplantation (HSCT). We retrospectively investigated the prognostic role of minimal residual disease (MRD) before and after HSCT in 119 children transplanted in complete remission (CR). MRD was measured by polymerase chain reaction in bone marrow samples collected pre-HSCT and during the first and third trimesters after HSCT (post-HSCT1 and post-HSCT3). The overall event-free survival (EFS) was 50%. The cumulative incidence of relapse and non-relapse mortality was 41% and 9%. Any degree of detectable pre-HSCT MRD was associated with poor outcome: EFS was 39% and 18% in patients with MRD positivity <1 × 10−3 and ≥1 × 10−3, respectively, versus 73% in MRD-negative patients (P < 0·001). This effect was maintained in different disease remissions, but low-level MRD had a very strong negative impact only in patients transplanted in second or further CR. Also, MRD after HSCT enabled patients to be stratified, with increasing MRD between post-HSCT1 and post-HSCT3 clearly defining cohorts with a different outcome. MRD is an important prognostic factor both before and after transplantation. Given that MRD persistence after HSCT is associated with dismal outcome, these patients could benefit from early discontinuation of immunosuppression, or pre-emptive immuno-therapy

Mesenchymal Stromal Cell on Liver Decellularised Extracellular Matrix for Tissue Engineering

Background: In end-stage chronic liver disease, transplantation represents the only curative option. However, the shortage of donors results in the death of many patients. To overcome this gap, it is mandatory to develop new therapeutic options. In the present study, we decellularised pig livers and reseeded them with allogeneic porcine mesenchymal stromal cells (pMSCs) to understand whether extracellular matrix (ECM) can influence and/or promote differentiation into hepatocyte-like cells (HLCs). Methods: After decellularisation with SDS, the integrity of ECM-scaffolds was examined by histological staining, immunofluorescence and scanning electron microscope. DNA quantification was used to assess decellularisation. pMSCs were plated on scaffolds by static seeding and maintained in in vitro culture for 21 days. At 3, 7, 14 and 21 days, seeded ECM scaffolds were evaluated for cellular adhesion and growth. Moreover, the expression of specific hepatic genes was performed by RT-PCR. Results: The applied decellularisation/recellularisation protocol was effective. The number of seeded pMSCs increased over the culture time points. Gene expression analysis of seeded pMSCs displayed a weak induction due to ECM towards HLCs. Conclusions: These results suggest that ECM may address pMSCs to differentiate in hepatocyte-like cells. However, only contact with liver-ECM is not enough to induce complete differentiation

Muon and Cosmogenic Neutron Detection in Borexino

Borexino, a liquid scintillator detector at LNGS, is designed for the detection of neutrinos and antineutrinos from the Sun, supernovae, nuclear reactors, and the Earth. The feeble nature of these signals requires a strong suppression of backgrounds below a few MeV. Very low intrinsic radiogenic contamination of all detector components needs to be accompanied by the efficient identification of muons and of muon-induced backgrounds. Muons produce unstable nuclei by spallation processes along their trajectory through the detector whose decays can mimic the expected signals; for isotopes with half-lives longer than a few seconds, the dead time induced by a muon-related veto becomes unacceptably long, unless its application can be restricted to a sub-volume along the muon track. Consequently, not only the identification of muons with very high efficiency but also a precise reconstruction of their tracks is of primary importance for the physics program of the experiment. The Borexino inner detector is surrounded by an outer water-Cherenkov detector that plays a fundamental role in accomplishing this task. The detector design principles and their implementation are described. The strategies adopted to identify muons are reviewed and their efficiency is evaluated. The overall muon veto efficiency is found to be 99.992% or better. Ad-hoc track reconstruction algorithms developed are presented. Their performance is tested against muon events of known direction such as those from the CNGS neutrino beam, test tracks available from a dedicated External Muon Tracker and cosmic muons whose angular distribution reflects the local overburden profile. The achieved angular resolution is 3-5 deg and the lateral resolution is 35-50 cm, depending on the impact parameter of the crossing muon. The methods implemented to efficiently tag cosmogenic neutrons are also presented.Comment: 42 pages. 32 figures on 37 files. Uses JINST.cls. 1 auxiliary file (defines.tex) with TEX macros. submitted to Journal of Instrumentatio

The OPERA experiment Target Tracker

The main task of the Target Tracker detector of the long baseline neutrino oscillation OPERA experiment is to locate in which of the target elementary constituents, the lead/emulsion bricks, the neutrino interactions have occurred and also to give calorimetric information about each event. The technology used consists in walls of two planes of plastic scintillator strips, one per transverse direction. Wavelength shifting fibres collect the light signal emitted by the scintillator strips and guide it to both ends where it is read by multi-anode photomultiplier tubes. All the elements used in the construction of this detector and its main characteristics are described.Comment: 25 pages, submitted to Nuclear Instrument and Method

Muon and Cosmogenic Neutron Detection in Borexino

Borexino, a liquid scintillator detector at LNGS, is designed for the detection of neutrinos and antineutrinos from the Sun, supernovae, nuclear reactors, and the Earth. The feeble nature of these signals requires a strong suppression of backgrounds below a few MeV. Very low intrinsic radiogenic contamination of all detector components needs to be accompanied by the efficient identification of muons and of muon-induced backgrounds. Muons produce unstable nuclei by spallation processes along their trajectory through the detector whose decays can mimic the expected signals; for isotopes with half-lives longer than a few seconds, the dead time induced by a muon-related veto becomes unacceptably long, unless its application can be restricted to a sub-volume along the muon track. Consequently, not only the identification of muons with very high efficiency but also a precise reconstruction of their tracks is of primary importance for the physics program of the experiment. The Borexino inner detector is surrounded by an outer water-Cherenkov detector that plays a fundamental role in accomplishing this task. The detector design principles and their implementation are described. The strategies adopted to identify muons are reviewed and their efficiency is evaluated. The overall muon veto efficiency is found to be 99.992% or better. Ad-hoc track reconstruction algorithms developed are presented. Their performance is tested against muon events of known direction such as those from the CNGS neutrino beam, test tracks available from a dedicated External Muon Tracker and cosmic muons whose angular distribution reflects the local overburden profile. The achieved angular resolution is 3-5 deg and the lateral resolution is 35-50 cm, depending on the impact parameter of the crossing muon. The methods implemented to efficiently tag cosmogenic neutrons are also presented.Comment: 42 pages. 32 figures on 37 files. Uses JINST.cls. 1 auxiliary file (defines.tex) with TEX macros. submitted to Journal of Instrumentatio