Treatment allocation in patients with hepatocellular carcinoma: Need for a paradigm shift?

Letter

Development and Validation of a New Prognostic System for Patients with Hepatocellular Carcinoma

BACKGROUND: Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients with HCC. METHODS AND FINDINGS: Prospective collected databases from Italy (training cohort, n = 3,628; internal validation cohort, n = 1,555) and Taiwan (external validation cohort, n = 2,651) were used to develop the ITA.LI.CA prognostic system. We first defined ITA.LI.CA stages (0, A, B1, B2, B3, C) using only tumor characteristics (largest tumor diameter, number of nodules, intra- and extrahepatic macroscopic vascular invasion, extrahepatic metastases). A parametric multivariable survival model was then used to calculate the relative prognostic value of ITA.LI.CA tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, Child-Pugh score (CPS), and alpha-fetoprotein (AFP) in predicting individual survival. Based on the model results, an ITA.LI.CA integrated prognostic score (from 0 to 13 points) was constructed, and its prognostic power compared with that of other integrated systems (BCLC, HKLC, MESIAH, CLIP, JIS). Median follow-up was 58 mo for Italian patients (interquartile range, 26-106 mo) and 39 mo for Taiwanese patients (interquartile range, 12-61 mo). The ITA.LI.CA integrated prognostic score showed optimal discrimination and calibration abilities in Italian patients. Observed median survival in the training and internal validation sets was 57 and 61 mo, respectively, in quartile 1 (ITA.LI.CA score 64 1), 43 and 38 mo in quartile 2 (ITA.LI.CA score 2-3), 23 and 23 mo in quartile 3 (ITA.LI.CA score 4-5), and 9 and 8 mo in quartile 4 (ITA.LI.CA score > 5). Observed and predicted median survival in the training and internal validation sets largely coincided. Although observed and predicted survival estimations were significantly lower (log-rank test, p < 0.001) in Italian than in Taiwanese patients, the ITA.LI.CA score maintained very high discrimination and calibration features also in the external validation cohort. The concordance index (C index) of the ITA.LI.CA score in the internal and external validation cohorts was 0.71 and 0.78, respectively. The ITA.LI.CA score's prognostic ability was significantly better (p < 0.001) than that of BCLC stage (respective C indexes of 0.64 and 0.73), CLIP score (0.68 and 0.75), JIS stage (0.67 and 0.70), MESIAH score (0.69 and 0.77), and HKLC stage (0.68 and 0.75). The main limitations of this study are its retrospective nature and the intrinsically significant differences between the Taiwanese and Italian groups. CONCLUSIONS: The ITA.LI.CA prognostic system includes both a tumor staging-stratifying patients with HCC into six main stages (0, A, B1, B2, B3, and C)-and a prognostic score-integrating ITA.LI.CA tumor staging, CPS, ECOG performance status, and AFP. The ITA.LI.CA prognostic system shows a strong ability to predict individual survival in European and Asian populations

A Liver Index and its Relationship to Indices of HCC Aggressiveness

A Hepatocellular (HCC) Aggressiveness Index was recently constructed, consisting of the sum of the scores for the 4 clinical parameters of maximum tumor size, multifocality, presence of portal vein thrombus and blood alphafetoprotein levels. It was observed that there was an association with several liver function tests. We have now formed a Liver Index from the 4 liver parameters with the highest hazard ratios with respect to HCC aggressiveness, namely: blood total bilirubin, gamma glutamyl transpeptidase (GGTP), albumin and platelet levels (cirrhosis surrogate). We found that the scores for the Liver Index related significantly to survival, but also to the Aggressiveness Index and to its individual HCC components as well as showing significant trends with the components. These results support the hypothesis that liver function is not only an important prognostic factor in HCC patients, but may also be involved in HCC biology and aggressiveness. Blood albumin, GGTP, albumin and platelet levels were used to create a Liver Index that related significantly to parameters of HCC aggressiveness

PixFEL: development of an X-ray diffraction imager for future FEL applications

A readout chip for diffraction imaging applications at new generation X-ray FELs (Free Electron Lasers) has been designed in a 65 nm CMOS technology. It consists of a 32 × 32 matrix, with square pixels and a pixel pitch of 110 µm. Each cell includes a low-noise charge sensitive amplifier (CSA) with dynamic signal compression, covering an input dynamic range from 1 to 104 photons and featuring single photon resolution at small signals at energies from 1 to 10 keV. The CSA output is processed by a time-variant shaper performing gated integration and correlated double sampling. Each pixel includes also a small area, low power 10-bit time-interleaved Successive Approximation Register (SAR) ADC for in-pixel digitization of the amplitude measurement. The channel can be operated at rates up to 4.5 MHz, to be compliant with the rates foreseen for future X-ray FEL machines. The ASIC has been designed in order to be bump bonded to a slim/active edge pixel sensor, in order to build the first demonstrator for the PixFEL (advanced X-ray PIXel cameras at FELs) imager

Plasma cholesterol and lipoprotein levels in relation to tumor aggressiveness and survival in HCC patients

open13Hepatocellular carcinoma is associated with several chronic liver diseases, especially chronic hepatitis B virus, hepatitis C virus, and alcoholism. It is increasingly appreciated that obesity/metabolic syndrome is also associated with chronic liver disease and subsequent hepatocellular carcinoma.openCarr, Brian I; Giannelli, Gianluigi; Guerra, Vito; Giannini, Edoardo G; Farinati, Fabio; Rapaccini, Gian Ludovico; Marco, Maria Di; Zoli, Marco; Caturelli, Eugenio; Masotto, Alberto; Virdone, Roberto; Sacco, Rodolfo; Trevisani, FrancoCarr, Brian I; Giannelli, Gianluigi; Guerra, Vito; Giannini, Edoardo G; Farinati, Fabio; Rapaccini, Gian Ludovico; Marco, Maria Di; Zoli, Marco; Caturelli, Eugenio; Masotto, Alberto; Virdone, Roberto; Sacco, Rodolfo; Trevisani, Franc

A Sedimentological Record of Early Miocene Ice Advance and Retreat, AND-2A drill hole, McMurdo Sound, Antarctica

The lowest 501 m (∼1139–638 m) of the AND-2A core from southern McMurdo Sound is the most detailed and complete record of early Miocene sediments in Antarctica and indicates substantial variability in Antarctic ice sheet activity during early Miocene time. There are two main pulses of diamictite accumulation recorded in the core, and three significant intervals with almost no coarse clasts. Each diamictite package comprises several sequences consistent with ice advance-retreat episodes. The oldest phase of diamictite deposition, Composite Sequence 1 (CS1), has evidence for grounded ice at the drill site and has been dated around 20.2–20.1 Ma. It likely coincides with cooling associated with isotope event Mi1aa. This is overlain by a diamictite-free, sandstone-dominated interval, CS2 that includes three coarsening-upward deltaic cycles, is inferred to mark substantial warming, and has an inferred age range between 20.1 and 20.05 Ma. Above this is an interval with variable amounts of diamictite (CS3), with indicators of ice grounding, that is inferred to record ice advance relative to CS2, and is overlain by an ∼100-m-thick mud-rich interval (CS4) with no sedimentological evidence for direct glacial influence at the drill site (ca. 19.4–18.7 Ma). A third overlying diamictite-rich interval (CS5) overlies an unconformity spanning 18.7–17.8 Ma (coinciding with isotope event Mi1b), and records a return to more ice-influenced conditions at the drill site in late early Miocene time. The overall picture for the early Miocene (spanning the period 20.2–17.35 Ma) is one of ice advance alternating with periods of ice retreat and hence significant global climate fluctuations after the permanent establishment of the Antarctic ice sheet at the Eocene/Oligocene boundary, and preceding the relative warmth of the middle Miocene climatic optimum (ca. 17.5–14.5 Ma). Sedimentary cyclicity in CS1 and CS2 is consistent with ∼21 k.y. precession but in CS3 the frequency is closer to 100 k.y. (consistent with eccentricity), with a possible change to 20 k.y. precession in CS4. CS5 cyclicity is consistent with obliquity forcing. Provenance data are consistent with local Transantarctic Mountains glacial activity under precessional control in CS1 and more southerly ice-cap build up under 100 k.y. eccentricity and obliquity control during CS3 and CS5, respectively

Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia

Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions. Thus, a much more striking degree of structural restriction of the entire BCR and a much higher frequency of receptor sharing exists among patients than appreciated previously. The data imply that either a significant fraction of B-CLL cells was selected by a limited set of antigenic epitopes at some point in their development and/or that they derive from a distinct B cell subpopulation with limited Ig V region diversity. These shared, stereotyped Ig molecules may be valuable probes for antigen identification and important targets for cross-reactive idiotypic therapy

Expanding The Knowledge On Lignocellulolytic And Redox Enzymes Of Worker And Soldier Castes From The Lower Termite Coptotermes Gestroi

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Termites are considered one of the most efficient decomposers of lignocelluloses on Earth due to their ability to produce, along with its microbial symbionts, a repertoire of carbohydrate-active enzymes (CAZymes). Recently, a set of Pro-oxidant, Antioxidant, and Detoxification enzymes (PAD) were also correlated with the metabolism of carbohydrates and lignin in termites. The lower termite Coptotermes gestroi is considered the main urban pest in Brazil, causing damage to wood constructions. Recently, analysis of the enzymatic repertoire of C. gestroi unveiled the presence of different CAZymes. Because the gene profile of CAZy/PAD enzymes endogenously synthesized by C. gestroi and also by their symbiotic protists remains unclear, the aim of this study was to explore the eukaryotic repertoire of these enzymes in worker and soldier castes of C. gestroi. Our findings showed that worker and soldier castes present similar repertoires of CAZy/PAD enzymes, and also confirmed that endo-glucanases (GH9) and beta-glucosidases (GH1) were the most important glycoside hydrolase families related to lignocellulose degradation in both castes. Classical cellulases such as exo-glucanases (GH7) and endo-glucanases (GH5 and GH45), as well as classical xylanases (GH10 and GH11), were found in both castes only taxonomically related to protists, highlighting the importance of symbiosis in C. gestroi. Moreover, our analysis revealed the presence of Auxiliary Activity enzyme families (AAs), which could be related to lignin modifications in termite digestomes. In conclusion, this report expanded the knowledge on genes and proteins related to CAZy/PAD enzymes from worker and soldier castes of lower termites, revealing new potential enzyme candidates for second-generation biofuel processes.7FAPESP (The State of Sao Paulo Research Foundation) [11/20977-3, 15/06971-3, 12/19040-0, 14/10351-8, 06/59086-8, 14/20576-7, 13/03061-0, 10/11469-1]National Council for Scientific and Technological Development (CNPq) [140796/2013-4][08/58037-9][14/50371-8][08/50114-4][310186/2014-5][442333/2014-5]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq