Survival trends over 20 years in patients with advanced cholangiocarcinoma: Results from a national retrospective analysis of 922 cases in Italy

: Cholangiocarcinoma is a rare group of tumors that involve the hepatic biliary tree. Prognosis for patients with cholangiocarcinoma remains dismal. Herein, we present survival trends over a long time period spanning almost 20 years in patients with advanced cholangiocarcinoma receiving systemic chemotherapy. We retrospectively analyzed a large multicenter dataset of cholangiocarcinoma outpatients evaluated in 14 centers within the Cholangiocarcinoma Italian Group Onlus (Gruppo Italiano Colangiocarcinoma Onlus, G.I.C.O.) between 2000 and 2017 (first-line), and 2002 and 2017 (second-line). Three time periods were considered: 2000-2009, 2010-2013, and 2014-2017. A total of 922 patients (51.19% male) with cholangiocarcinoma undergoing first-line therapy were evaluated. The median durations of follow-up for progression-free survival (PFS) and overall survival (OS) were 37 and 57 months, respectively. PFS at 12 months in the three periods of starting first-line therapy was similar, ranging from 11.71% to 15.25%. OS at 12 months progressively improved (38.30%, 44.61% and 49.52%, respectively), although the differences were not statistically significant after adjusting for age, disease status, and primary tumor site. A total of 410 patients (48.5% male) underwent second-line chemotherapy. The median durations of follow-up for PFS and OS were 47.6 and 41.90 months, respectively. An OS of 24.3%, 32.3%, and 33.1% was observed in 2002-2009, 2010-2013, and 2014-2017, respectively. Despite incremental benefits across years, our clinical experience confirms that modest overall advances have been achieved with first- and second-line chemotherapy in advanced cholangiocarcinoma. Efforts should focus on the identification of patients who derive the greatest benefit from treatment

Chimeric Rat/Human HER2 Efficiently Circumvents HER2 Tolerance in Cancer Patients.

Purpose: Despite the great success of HER2 vaccine strategies in animal models, effective clinical results have not yet been obtained. We studied the feasibility of using DNA coding for chimeric rat/human HER2 as a tool to break the unresponsiveness of T cells from patients with HER2-overexpressing tumors (HER2-CP). Experimental Design: Dendritic cells (DCs) generated from patients with HER2-overexpressing breast (n = 28) and pancreatic (n = 16) cancer were transfected with DNA plasmids that express human HER2 or heterologous rat sequences in separate plasmids or as chimeric constructs encoding rat/human HER2 fusion proteins and used to activate autologous T cells. Activation was evaluated by IFN-γ ELISPOT assay, perforin expression, and ability to halt HER2+ tumor growth in vivo. Results: Specific sustained proliferation and IFN-γ production by CD4 and CD8 T cells from HER2-CP was observed after stimulation with autologous DCs transfected with chimeric rat/human HER2 plasmids. Instead, T cells from healthy donors ( n = 22) could be easily stimulated with autologous DCs transfected with any human, rat, or chimeric rat/human HER2 plasmid. Chimeric HER2-transfected DCs from HER2-CP were also able to induce a sustained T-cell response that significantly hindered the in vivo growth of HER2+ tumors. The efficacy of chimeric plasmids in overcoming tumor-induced T-cell dysfunction relies on their ability to circumvent suppressor effects exerted by regulatory T cells (Treg) and/or interleukin (IL)-10 and TGF-β1. Conclusions: These results provide the proof of concept that chimeric rat/human HER2 plasmids can be used as effective vaccines for any HER2-CP with the advantage of being not limited to specific MHC

South China Sea Rifted Margin Testing hypotheses for lithosphere thinning during continental breakup: Drilling at the South China Sea rifted margin

International Ocean Discovery Program Expedition 368 is the second of two consecutive cruises that form the South China Sea Rifted Margin program. Expeditions 367 and 368 share the common key objectives of testing scientific hypotheses of breakup of the northern South China Sea (SCS) margin and comparing its rifting style and history to other nonvolcanic or magma-poor rifted margins. Four primary sites were selected for the overall program: one in the outer margin high (OMH) and three seaward of the OMH on distinct, margin-parallel basement ridges. These three ridges are informally labeled A, B, and C. They are located within the continent-ocean transition (COT) zone ranging from the OMH to the interpreted steady-state oceanic crust (Ridge C) of the SCS. The main scientific objectives include 1. Determining the nature of the basement within crustal units across the COT of the SCS that are critical to constrain style of rifting, 2. Constraining the time interval from initial crustal extension and plate rupture to the initial generation of igneous ocean crust, 3. Constraining vertical crustal movements during breakup, and 4. Examining the nature of igneous activity from rifting to seafloor spreading. In addition, the sediment cores from the drill sites targeting primarily tectonic and basement objectives will provide information on the Cenozoic regional environmental development of the Southeast Asia margin. Expedition 368 was planned to drill at two primary sites (U1501 and U1503) at the OMH and Ridge C, respectively. However, based on drilling results from Expedition 367, Expedition 368 chose to insert an alternate site on Ridge A (Site U1502). In total, the expedition completed operations at four sites (U1501, U1502, U1504, and U1505). Site U1503, however, was not completed beyond casing to 990 m because of mechanical problems with the drilling equipment that limited the expedition from 25 May 2017 to the end of the expedition to operate with a drill string not longer than 3400 m. New alternate Site U1504 proposed during Expedition 367 met this condition. Site U1505 also met the operational constraints of the 3400 m drill string (total) and was an alternate site for the already drilled Site U1501. At Site U1501, we cored to 697.1 m in 9.4 days, with 78.5% recovery. We also drilled ahead for 433.5 m in Hole U1501D and then logged downhole data from 78.3 to 399.3 m. In 19.3 days at Site U1502, we penetrated 1679.0 m, set 723.7 m of casing and cored a total of 576.3 m with 53.5% recovery, and collected downhole log data from 785.3 to 875.3 m and seismic data through the 10¾ inch casing. At Site U1503, we penetrated 995.1 m, setting 991.5 m of 10¾ inch casing, but no cores were taken. At Site U1504, we took 40 rotary core barrel (RCB) cores over two holes. The cored interval between both holes was 277.3 m with 26.8% recovery. An 88.2 m interval was drilled in Hole U1504B. At Site U1505, we cored 668.0 m with 101.1% recovery. Logging data was collected from 80.1 to 341.2 m. Operations at this site covered 6.1 days. Except for Site U1505, we drilled to acoustic basement, which prior to the expedition, except for Site U1501, had been interpreted to be crystalline basement. A total of 6.65 days were lost due to mechanical breakdown or waiting on spare supplies for repair of drilling equipment. At Site U1501 on the OMH, coring ~45 m into the acoustic basement sampled highly lithified sandstone to conglomerate of presumed Mesozoic age overlain by siliciclastic Eocene pre- to synrift sediments of Oligocene age and topped by primarily carbonaceous postrift sediments of early Miocene to Pleistocene age. Site U1502 on Ridge A was cased to 723.7 m. At this site, we recovered 180 m of hydrothermally altered brecciated basalts comprising sheet and pillow lavas below deep-marine sediments of Oligocene to late Miocene age. Coring was not performed within the upper 380 m (~Pliocene-Pleistocene) at Site U1502. At Site U1503 on Ridge C, 991.5 m of casing was installed in preparation for the planned deep drilling to ~1800 m, but no coring was performed due to mechanical failures, and the site was abandoned without further activity. Coring at Site U1504 on the OMH ~45 km east of Site U1501 recovered metamorphic schist to gneiss (greenschist facies) below late Eocene (?) carbonate rocks (partly reef debris) and early Miocene to Pleistocene sediments. At Site U1505, we cored to 480.15 m through Pleistocene to late Oligocene mainly carbonaceous ooze followed at depth by early Oligocene to late Eocene siliciclastic sediments. Efforts were made at every drill site to correlate the core with the seismic data and seismic stratigraphic unconformities interpreted within the Eocene to Plio-Pleistocene sedimentary sequence prior to drilling. The predrilling interpretation of ages of these unconformities was in general confirmed by drilling results. As a result of the constraints on the length of drill string that could be deployed during the later part of Expedition 368, the secondary expedition objectives addressing the environmental history of the SCS and Southeast Asia received more focus than planned because these sites are located in shallower water depths and required less penetration depth. This forced change in emphasis, however, was without fatal consequences for the primary tectonic objectives. The two expeditions together provided solid evidence for a process of breakup that included vigorous synrift magmatism as opposed to the often-favored interpretation of the SCS margin as a magma-starved margin

The 125–150 Ma high-resolution Apparent Polar Wander Path for Adria from magnetostratigraphic sections in Umbria–Marche (Northern Apennines, Italy): Timing and duration of the global Jurassic–Cretaceous hairpin turn

International audienceA new high-resolution Apparent Polar Wander Path (APWP) segment has been obtained from the magnetostratigraphy of four Kimmeridgian to Lower Aptian sections in the Northern Apennines (Italy). The use of paleomagnetic data for determination of the Adria APWP was hampered by the large local rotations linked to Apennine tectonics, characterized by folds and thrusts developed during the Neogene. To overcome this problem, we have computed relative rotations between time overlapping sections and realigned them in a common declination reference frame (namely the Bosso section). We synthesized a new high-resolution 150 to 125 Ma APWP for Adria, which has a similar shape to the time-equivalent segment of the synthetic APWP of Africa of Besse and Courtillot [J., Besse, V., Courtillot, Apparent and true polar wander and the geometry of the geomagnetic field over the last 200 Myr, J. Geophys. Res. 107(B11) (2002), doi:10.1029/200JB000050]. A 26° clockwise rotation of our combined Adria APWP places it in almost perfect overlap with African data of same age, confirming that the Adria promontory moved coherently with Africa during this time span, whereas the counterclockwise rotation of Adria with respect to Africa was introduced later, most probably during Apennines orogenesis. Finally, we discuss in relation with worldwide plate evolution the peculiar shape of our APWP, which displays a hairpin turn during Berriasian time, and dates the main Late Jurassic/Early Cretaceous change in plate motion at around anomaly M16

The Lower Toarcian Serrone Marls (Northern Apennines, Italy): A 3.5 Myr record of marl deposition in the aftermath of the T-OAE

The early Toarcian sedimentary record is frequently characterized by the occurrence of marls, shales, and organic rich facies comprising the Toarcian oceanic anoxic event (T-OAE), which are broadly synchronous to the emplacement of the Karoo-Ferrar large igneous province (LIP) with a main pulse at ~181.7 Ma. Here we describe the chronology and rock magnetic properties of the early Toarcian Marne del Serrone Formation (Serrone Marls) from the Monte Serrone section in the Northern Apennines of Italy, and interpret them as reflecting the local environmental response to the transient CO2 rise and accelerated hydrological cycle most likely induced by the emplacement of the Karoo-Ferrar LIP. The studied 62 m-thick section is characterized by a succession of micritic limestones and marls, interrupted by a few slumps, and contains a record of the T-OAE represented by posidonia beds and a ~40 cm-thick black shale interval. The age of the section has been constrained using magnetostratigraphy and ammonite biostratigraphy to the Spinatum to Variabilis zones. Rock-magnetic properties have been used to characterize fluctuations in the magnetite and hematite input throughout the section. Spectral analysis of continuous IRM2.5T and IRM0.1T/IRM2.5T records indicates a duration of the studied marly interval of ca. 3.5 Myr, regarded as a first-order estimate of the duration of the response of the environmental system (hydrological cycle) to the transient climate perturbation triggered by the emplacement of the Karoo-Ferrar LIP, and a duration of the Bifrons zone of ca. 3.4 Myr