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Primary human hepatocytes are expanded in culture while retaining metabolic function. Hepatocytes have a critical role in metabolism, but their study is limited by the inability to expand primary hepatocytes in vitro while maintaining proliferative capacity and metabolic function. Here we describe the oncostatin M (OSM)-dependent expansion of primary human hepatocytes by low expression of the human papilloma virus (HPV) genes E6 and E7 coupled with inhibition of epithelial-to-mesenchymal transition. We show that E6 and E7 expression upregulates the OSM receptor gp130 and that OSM stimulation induces hepatocytes to expand for up to 40 population doublings, producing 10 13 to 10 16 cells from a single human hepatocyte isolate. OSM removal induces differentiation into metabolically functional, polarized hepatocytes with functional bile canaliculi. Differentiated hepatocytes show transcriptional and toxicity profiles and cytochrome P450 induction similar to those of primary human hepatocytes. Replication and infectivity of hepatitis C virus (HCV) in differentiated hepatocytes are similar to those of Huh7.5.1 human hepatoma cells. These results offer a means of expanding human hepatocytes of different genetic backgrounds for research, clinical applications and pharmaceutical development.

Fibroblastic reticular cells (FRCs) form the cellular scaffold of lymph nodes (LNs) and establish distinct microenvironmental niches to provide key molecules that drive innate and adaptive immune responses and control immune regulatory processes. Here, we have used a graph theory-based systems biology approach to determine topological properties and robustness of the LN FRC network in mice. We found that the FRC network exhibits an imprinted small-world topology that is fully regenerated within 4 wk after complete FRC ablation. Moreover, in silico perturbation analysis and in vivo validation revealed that LNs can tolerate a loss of approximately 50% of their FRCs without substantial impairment of immune cell recruitment, intranodal T cell migration, and dendritic cell-mediated activation of antiviral CD8+ T cells. Overall, our study reveals the high topological robustness of the FRC network and the critical role of the network integrity for the activation of adaptive immune responses.

Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these patients remains arguable. Given the high social toll of this aggressive occupational cancer, it is paramount to establish the real clinical benefit of these treatments. To directly compare and analyze the statistical robustness of the 3 randomized clinical trials (RCTs) of frontline therapies recommended for MPM since 2003. This comparative effectiveness study assessed the following phase 3 RCTs: the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate743 (CM743) study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed. Data collection dates for the RCTs ranged from April 1999 to April 2018. Data for this study were analyzed from February to October 2021. Patient selection criteria, superiority of the intervention groups, survival-inferred fragility index, and censoring patterns in each RCT. A total of 1501 patients were included in the analysis (1170 men [77.9%]; range of median age for treatment groups, 60 [IQR, 19-84] to 69 [IQR, 65-75] years). A virtual comparison of overall survival in MAPS vs the CM743 study showed no statistically significant difference (hazard ratio [HR], 0.97 [95% CI, 0.79-1.20]; P = .79), and the survival-inferred fragility index in the intention-to-treat (ITT) populations was as low as 0.22% of the total sample size in MPS, -0.45% of the total sample size in MAPS, and 0.99% of the total sample size in the CM743 trial. Moreover, reverse restricted mean survival time (RMST) analysis of overall survival using RMST-difference (RMST-D) demonstrated differential censoring in the ITT population of the CM743 trial favoring the control group (0.56 [95% CI, 0.18-0.94]; P = .004) and in the nonepithelioid group (reverse RMST-D, 0.90 [95% CI, 0.001-1.79]; P = .048). This comparative effectiveness study found no survival benefit in the CM743 trial over MAPS, despite the inclusion of patients with worse prognosis in the latter trial. Moreover, the statistical conclusions of all the examined trials were shown to be extremely fragile, and the findings of differential censoring in the CM743 trial and in the ITT nonepithelial subset raised additional areas of concern. These findings suggest that selection criteria, fragility, and censoring patterns may affect the original conclusions drawn for the respective trials, casting a shadow on the real benefit. This model of analysis lays a rigorous groundwork extendable to trials of all cancer treatments before their registration.

In this commentary, using existing clinical trial data and FDA approvals we propose that there is currently a critical need for an appropriate balancing between the financial impact of new cancer drugs and their actual benefit for patients. By adopting “pleural mesothelioma” as our clinical model we summarize the most relevant pertinent and available literature on this topic, and use an analysis of the reliability of the trials submitted for registration and/or recently published as a case in point to raise concerns with respect to appropriate trial design, biomarker based stratification and to highlight the ongoing need for balancing the benefit/cost ratio for both patients and healthcare providers.

[...]attempts to challenge the confidence in the superiority of anticancer drugs over control treatments are important, as significant differences in outcomes assessed using an arbitrary threshold (p<0·05) can be easily reversed with a change in designation of very few events, and might not reflect clinical benefit according to European Society for Medical Oncology or American Society of Clinical Oncology value scales.2 However, the study relies entirely on the fragility index—the minimal number of changes from non-events to events that would result in a loss of statistical significance—which does not account for the time at which events occurred. To provide a comprehensive solution, a possible alternative would be to extend the concept of the fragility index to survival analysis.3 The survival fragility index is defined as the estimated number of individuals who had an event at the average exposure time of all individuals in the study, whose addition would result in a loss of statistical significance. [...]the survival fragility index can provide a measure that both accounts for events over time and maintains all the advantages of the original fragility index. The disparity might suggest that use of the fragility index on time-to-event data is inappropriate in cases where the numbers of events in both groups are similar but the timing of events considerably differs.5 Using this approach might lead to the false conclusion that such trials are fragile.

Background Long-term survival of stage IV melanoma patients has improved significantly with the development of immune checkpoint inhibitors (CIs). Reliable biomarkers to predict response and clinical outcome are needed. Methods We investigated the role of melanoma-associated antibodies as predictive markers for CI therapy in two independent cohorts. In cohort 1, a prospective study, we measured specific antibodies before treatment, after one week and after six to nine weeks of treatment. Cohort 2 consisted of serum samples prior to CI therapy initiation. ELISA assays were performed to quantify specific IgG directed against melanocyte differentiation antigens tyrosinase-related proteins 1 and 2 (TRP1/TYRP1 and TRP2/TYRP2), glycoprotein 100 (gp100), MelanA/MART1, and the cancer-testis antigen NY-ESO-1. Response was defined as either complete or partial remission on CT scan according to RECIST 1.1. Results In cohort 1, baseline levels of these antibodies were higher in the responder group, although statistical significance was only reached for NY-ESO-1 ( p  = 0.007). In cohort 2, significantly higher antibody baseline levels for MelanA/MART1 ( p  = 0.003) and gp100 ( p  = 0.029) were found. After pooling the results from both cohorts, higher levels of MelanA/MART1 ( p  = 0.013), TRP1/TYRP1 ( p  = 0.048), TRP2/TYRP2 ( p  = 0.047) and NY-ESO-1 ( p  = 0.005) specific antibodies at baseline were independently associated with response. Conclusions Melanoma-associated antibodies may be candidate biomarkers for response and survival in metastatic melanoma patients being treated with CIs. These markers may be used to complement patient assessment, in combination with PD-L1 status, tumor-infiltrating lymphocytes and tumor mutational burden, with the aim to predict outcome of CI treatment in patients with metastatic melanoma. Trial registration Ethikkommission Ostschweiz, EKOS 16/079 https://ongoingprojects.swissethics.ch/runningProjects_list.php?q=%28BASECID~contains~2016-00998%29&orderby=dBASECID .

In phase III oncology trials, superiority is defined by statistical significance using P thresholds. However, this approach has been criticized because P is continuous. Here, we reconstruct patient-level data for 230 phase III oncology trials to model the robustness of statistical significance by estimating the survival-inferred fragility index (SIFI), defined as the smallest number of patients changing arms that alters the statistical significance interpretation. The median SIFI was 8 patients (IQR 4–19), representing 1.4% of enrollments (IQR 0.7%–3%). As a continuous statistic, P —but not the significance interpretation—was correlated with SIFI. Moreover, overall survival endpoints were more fragile than surrogate endpoints. Taken together, while phase III oncology trials are intended to robustly inform patient care, shifting the assignment of a few patients is often sufficient to upend the statistical significance interpretation. This vulnerability underscores the need for more robust strategies to identify superiority in oncology.

[...]this trajectory can be determined, patients (and clinicians) need to balance whether the possibility of being in the 20% for whom chemotherapy confers a small (or possibly no) early advantage is outweighed by being in the 80% for whom immune checkpoint inhibition confers a larger advantage. [...]this approach is being evaluated in several prospective studies of stage III mismatch repair-deficient colon cancer, including the POLEM trial,3 in which avelumab is given as a maintenance treatment after fluoropyrimidine-based chemotherapy, and the ATOMIC trial,4 in which atezolizumab is combined with FOLFOX (leucovorin, fluorouracil, and oxaliplatin) therapy. The immunostimulatory potential of chemotherapeutic agents can be explained by both on-target effects on tumour cells that increase their immunogenicity, and off-target effects on immune cell subsets that modulate cancer immunosurveillance.5 To summarise, the restricted mean survival time is a useful method to evaluate effect size, especially in non-parametric settings, or when the proportional hazards assumption is violated.