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This new classification highlights the importance of assessing and identifying the dynamic changes in the quality of fibrosis, especially relevant in the era of antiviral therapy.(Hepatology 2017;65:1438-1450).

Purpose: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4)-blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. Experimental Design: Autologous DC were pulsed with MART-1 26-35 peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. Results: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. The CTL-associated antigen 4 (CTLA4) is a main negative regulator of the immune system, which inhibits costimulatory signaling provided by dendritic cells (DC) to activate T lymphocytes. Antibodies to CTLA4 block this negative signaling, which allows a dominant positive signaling provided by costimulatory molecules on DCs recognized by CD28 on T cells (1). In animal models, administration of CTLA4-blocking antibodies alone induced rejection of established tumors, provided that these were immunogenic tumor models (1, 2). However, in poorly immunogenic tumor models, which may more closely resemble human disease, prior immunization with tumor vaccines, including DC-based vaccines, was required for CTLA4 blockade to exert robust antitumor effects (1).Tremelimumab 206) is a fully human CTLA4-blocking monoclonal antibody being developed for the treatment of cancer (3). In phase I testing, plasma levels of antibody of 30 μg/mL, which corresponds to levels predicted to result in continuous CTLA4 blockade in vitro, were achieved for at least 1 month at doses beyond 6 mg/kg (4). Cumulative clinical data suggests that single agent tremelimumab has antitumor activity in ∼10% of patients with advanced melanoma, and these responses tend to be long

Spatially ordered embryo-like structures self-assembled from blastocyst-derived stem cells can be generated to mimic embryogenesis in vitro. However, the assembly system and developmental potential of such structures needs to be further studied. Here, we devise a nonadherent-suspension-shaking system to generate self-assembled embryo-like structures (ETX-embryoids) using mouse embryonic, trophoblast and extra-embryonic endoderm stem cells. When cultured together, the three cell types aggregate and sort into lineage-specific compartments. Signaling among these compartments results in molecular and morphogenic events that closely mimic those observed in wild-type embryos. These ETX-embryoids exhibit lumenogenesis, asymmetric patterns of gene expression for markers of mesoderm and primordial germ cell precursors, and formation of anterior visceral endoderm-like tissues. After transplantation into the pseudopregnant mouse uterus, ETX-embryoids efficiently initiate implantation and trigger the formation of decidual tissues. The ability of the three cell types to self-assemble into an embryo-like structure in vitro provides a powerful model system for studying embryogenesis.

GPC3 protein is a sensitive and specific serum marker for diagnosis of early HCC. Its expression in liver tissues can be used to discriminate tumor cells from benign hepatic cells.

Purpose To determine the incidence of and risk factors for radiation pneumonitis (RP) after stereotactic ablative radiation therapy (SABR) to the lung in patients who had previously undergone conventional thoracic radiation therapy. Methods and Materials Seventy-two patients who had previously received conventionally fractionated radiation therapy to the thorax were treated with SABR (50 Gy in 4 fractions) for recurrent disease or secondary parenchymal lung cancer (T <4 cm, N0, M0, or Mx). Severe (grade ≥3) RP and potential predictive factors were analyzed by univariate and multivariate logistic regression analyses. A scoring system was established to predict the risk of RP. Results At a median follow-up time of 16 months after SABR (range, 4-56 months), 15 patients had severe RP (14 [18.9%] grade 3 and 1 [1.4%] grade 5) and 1 patient (1.4%) had a local recurrence. In univariate analyses, Eastern Cooperative Oncology Group performance status (ECOG PS) before SABR, forced expiratory volume in 1 second (FEV1), and previous planning target volume (PTV) location were associated with the incidence of severe RP. The V10 and mean lung dose (MLD) of the previous plan and the V10-V40 and MLD of the composite plan were also related to RP. Multivariate analysis revealed that ECOG PS scores of 2-3 before SABR (P=.009), FEV1 ≤65% before SABR (P=.012), V20 ≥30% of the composite plan (P=.021), and an initial PTV in the bilateral mediastinum (P=.025) were all associated with RP. Conclusions We found that severe RP was relatively common, occurring in 20.8% of patients, and could be predicted by an ECOG PS score of 2-3, an FEV1 ≤ 65%, a previous PTV spanning the bilateral mediastinum, and V20 ≥30% on composite (previous RT + SABR) plans. Prospective studies are needed to validate these predictors and the scoring system on which they are based.

ObjectiveWe conducted a prospective, randomized, open-label, multicenter study to compare busulfan plus fludarabine (BuFlu) with busulfan plus cyclophosphamide (BuCy) as the conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) in first complete remission (CR1).MethodsTotally 108 AML-CR1 patients undergoing allo-HSCT were randomized into BuCy (busulfan 1.6 mg/kg, q12 hours, -7 ~ -4d; cyclophosphamide 60 mg/kg.d, -3 ~ -2d) or BuFlu (busulfan 1.6 mg/kg, q12 hours, -5 ~ -2d; fludarabine 30 mg/m2.d, -6 ~ -2d) group. Hematopoietic engraftment, regimen-related toxicity (RRT), graft-versus-host disease (GVHD), transplant related mortality (TRM), and overall survival were compared between the two groups.ResultsAll patients achieved hematopoietic reconstitution except for two patients who died of RRT during conditioning. All patients obtained complete donor chimerism by day +30 post-transplantation. The incidence of total and III-IV RRT were 94.4% and 81.5% (P = 0.038), and 16.7% and 0.0% (P = 0.002), respectively, in BuCy and BuFlu group. With a median follow up of 609 (range, 3–2130) days after transplantation, the 5-year cumulative incidence of TRM were 18.8 ± 6.9% and 9.9 ± 6.3% (P = 0.104); the 5-year cumulative incidence of leukemia relapse were 16.5 ± 5.8% and 16.2 ± 5.3% (P = 0.943); the 5-year disease-free survival and overall survival were 67.4 ± 7.6% and 75.3 ± 7.2% (P = 0.315), and 72.3 ± 7.5% and 81.9 ± 7.0% (P = 0.177), respectively in BuCy and BuFlu group.ConclusionCompared with BuCy, BuFlu as a myeloablative condition regimen was associated with lower toxicities and comparable anti-leukemic activity in AML-CR1 patients undergoing allo-HSCT.

Background: GLV-1h68 is an attenuated recombinant vaccinia virus (VACV) that selectively colonizes established human xenografts inducing their complete regression.