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Background:  Multicenter precision oncology real-world evidence requires a substantial long-term investment by hospitals to prepare their data and align on common Clinical Research processes and medical definitions. Our team has developed a self-assessment framework to support hospitals and hospital networks to measure their digital maturity and better plan and coordinate those investments. From that framework, we developed PRISM for Cancer Outcomes: PR: agmatic I: nstitutional S: urvey and benchM: arking., Objectives:  The primary objective was to develop PRISM as a tool for self-assessment of digital maturity in oncology hospitals and research networks; a secondary objective was to create an initial benchmarking cohort of >25 hospitals using the tool as input for future development., Methods:  PRISM is a 25-question semiquantitative self-assessment survey developed iteratively from expert knowledge in oncology real-world study delivery. It covers four digital maturity dimensions: (1) Precision oncology, (2) Clinical digital data, (3) Routine outcomes, and (4) Information governance and delivery. These reflect the four main data types and critical enablers for precision oncology research from routine electronic health records., Results:  During piloting with 26 hospitals from 19 European countries, PRISM was found to be easy to use and its semiquantitative questions to be understood in a wide diversity of hospitals. Results within the initial benchmarking cohort aligned well with internal perspectives. We found statistically significant differences in digital maturity, with Precision oncology being the most mature dimension, and Information governance and delivery the least mature., Conclusion:  PRISM is a light footprint benchmarking tool to support the planning of large-scale real-world research networks. It can be used to (i) help an individual hospital identify areas most in need of investment and improvement, (ii) help a network of hospitals identify sources of best practice and expertise, and (iii) help research networks plan research. With further testing, policymakers could use PRISM to better plan digital investments around the Cancer Mission and European Digital Health Space., Competing Interests: None declared., (Thieme. All rights reserved.)

In recent years, cancer research has highlighted the role of disrupted microbiota in carcinogenesis and cancer recurrence. However, microbiota may also interfere with drug metabolism, influencing the efficacy of cancer drugs, especially immunotherapy, and modulating the onset of adverse events. Intestinal micro-organisms can be altered by external factors, such as use of antibiotics, proton pump inhibitors treatment, lifestyle and the use of prebiotics or probiotics. The aim of our review is to provide a picture of the current evidence about preclinical and clinical data of the role of gut and local microbiota in malignancies and its potential clinical role in cancer treatments. Standardization of microbiota sequencing approaches and its modulating strategies within prospective clinical trials could be intriguing for two aims: first, to provide novel potential biomarkers both for early cancer detection and for therapeutic effectiveness; second, to propose personalized and "microbiota-tailored" treatment strategies., Competing Interests: Declaration of Competing Interest MDM reports honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, GlaxoSmithKline, Amgen, Merck, Takeda for consultancy or participation to advisory boards and direct research funding from Tesaro/GlaxoSmithKline, institutional funding for work in clinical trials/contracted research from Beigene, Exelixis, MSD, Pfizer and Roche. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Randomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms., Methods: We identified phase III studies testing active treatments in patients with solid tumours among 11 major oncology journals. Each control arm was analysed, and the standard of care was determined according to international guidelines and scientific evidence at accrual beginning and until accrual completion. We identified studies with suboptimal control arm from the beginning (type 1) and studies with an initially optimal control arm which became outdated during the accrual period (type 2)., Results: This analysis included 387 studies. Forty-three (11.1%) control arms were judged as suboptimal: 24 (6.2%) type 1 and 19 (4.9%) type 2. These rates were higher in industry-sponsored compared to academic trials: 9.3% versus 1.9% for type 1 (p = 0.003); 7.9% versus 0.6% for type 2 (p = 0.001). Rates of suboptimal control arms were higher in studies with positive results: 8.1% versus 4.0% for type 1 (p = 0.09); 7.6% versus 1.7% for type 2 (p = 0.007)., Conclusions: Many trials have suboptimal control arms, even in journals with high-impact factors, leading to suboptimal treatment of control patients and biased evaluation of trial results., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, RDL reports honoraria from Astellas Pharma and Janssen. LM reports honoraria from Gilead and Merck; research grant from AstraZeneca; travel expenses from Janssen. CP reports support for attending meetings and/or travel from Eli Lilly and Takeda; institutional research grant from IQVIA. MLR reports honoraria from Eli Lilly, AstraZeneca and Janssen. AF reports honoraria from Roche, Pfizer, Novartis, Dompè , Astra Zeneca, Seagen, Gilead, Exact Science, Eli Lilly; support for attending meetings and/or travel from Roche, Pfizer, Novartis, Dompè , Astra Zeneca, Seagen, Gilead, Exact Science, Eli Lilly; participation on advisory boards for Roche, Pfizer, Novartis, Astra Zeneca, Seagen, Gilead, Eli Lilly. FP reports honoraria from Bayer, Pierre Fabre, AstraZeneca, Incyte, Ipsen, Clovis, Astellas, Sanofi, Roche, Pfizer; institutional funding for work in clinical trials/contracted research from Roche, Bayer, AstraZeneca, Pfizer, Incyte, Tesaro/GlaxoSmithKline and Merck. MDM reports honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, Takeda for consultancy or participation to advisory boards institutional research funding from Tesaro/GlaxoSmithKline, institutional funding for work in clinical trials/contracted research from Beigene, Exelixis, MSD, Pfizer and Roche. Other authors declare no relationships or activities that could appear to have influenced the submitted work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In addition to improving survival outcomes, new oncology treatments should lead to amelioration of patients' quality of life (QoL). Herein, we examined whether QoL results correlated with PFS and OS outcomes in phase III randomized controlled trials (RCTs) investigating new systemic treatments in metastatic non-small cell lung cancer (NSCLC)., Methods: The systematic search of PubMed was conducted in October 2022. We identified 81 RCTs testing novel drugs in metastatic NSCLC and published in the English language in a PubMed-indexed journal between 2012 and 2021. Only trials reporting QoL results and at least one survival outcome between OS and PFS were selected. For each RCT, we assessed whether global QoL was "superior," "inferior," or with "non-statistically significant difference" in the experimental arm compared to the control arm., Results: Experimental treatments led to superior QoL in 30 (37.0%) RCTs and inferior QoL in 3 (3.7%) RCTs. In the remaining 48 (59.3%) RCTs, a statistically significant difference between the experimental and control arms was not found. Of note, we found a statistically significant association between QoL and PFS improvements (X 2  = 3.93, p = 0.0473). In more detail, this association was not significant in trials testing immunotherapy or chemotherapy. On the contrary, in RCTs testing target therapies, QoL results positively correlated with PFS outcomes (p = 0.0196). This association was even stronger in the 32 trials testing EGFR or ALK inhibitors (p = 0.0077). On the other hand, QoL results did not positively correlate with OS outcomes (X 2  = 0.81, p = 0.368). Furthermore, we found that experimental treatments led to superior QoL in 27/57 (47.4%) trials with positive results and in 3/24 (12.5%) RCTs with negative results (p = 0.0028). Finally, we analyzed how QoL data were described in publications of RCTs in which QoL outcomes were not improved (n = 51). We found that a favorable description of QoL results was associated with sponsorship by industries (p = 0.0232)., Conclusions: Our study reveals a positive association of QoL results with PFS outcomes in RCTs testing novel treatments in metastatic NSCLC. This association is particularly evident for target therapies. These findings further emphasize the relevance of an accurate assessment of QoL in RCTs in NSCLC., (© 2023. The Author(s).)

Background: Pancreatic ductal adenocarcinoma (PDAC) harbouring germline BRCA1-2 pathogenic variants (gBRCA1-2pv) is a distinct nosological entity. Information on second-line therapy (2LT) outcome in this setting is lacking., Methods: Data of gBRCA1-2pv metastatic PDAC patients treated with chemotherapy were collected. A primary analysis of 2LT RECIST response, median progression-free survival (mPFS 2 ) and overall survival (mOS 2 ), was performed. A secondary analysis addressed the impact of timing of platinum introduction on the outcome of patients receiving at least a first-line combination chemotherapy (1LT)., Results: Eighty-four gBRCA1-2pv metastatic PDAC patients were enrolled. The primary analysis, including 43 patients, highlighted a significant improvement of mPFS 2 and a doubled response rate, in the platinum-based 2LT subgroup as compared to the platinum-free (8.8 versus 3.7 months, p = 0.013). Seventy-seven patients were included in the secondary analysis. Median PFS 1 of 3- and 4-drug platinum-based 1LT significantly outperformed both platinum-free combinations and platinum-based doublets (11.4 versus 6.4 versus 7.9 months, p = 0.01). Albeit still immature, data on mOS paralleled those on mPFS., Conclusions: This study highlighted the beneficial role of platinum agents in gBRCA1-2pv PDAC patients also in second-line treatment setting. However, our data suggest that early use of 3- and 4-drug platinum-based chemotherapy combinations provides a survival outcome advantage., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Lung cancer (LC) tissue for immunological characterization is often scarce. We explored and compared T cell characteristics between broncho-alveolar lavage from tumor affected (t-BAL) and contralateral lung (cl-BAL), with matched peripheral blood (PB)., Methods: BAL and PB were collected during bronchoscopy for diagnostic and/or therapeutic purposes in patients with monolateral primary lesion., Results: Of 33 patients undergoing BAL and PB sampling, 21 had histologically-confirmed LC. Most cases were locally-advanced or metastatic non-small cell LC. T cell characteristics were not significantly different in t-BAL vs. cl-BAL. Compared to PB, CD8 T cells in BAL presented features of immune activation and exhaustion (high PD-1, low IFN-g production). Accordingly, regulatory CD4 T cells were also higher in BAL vs. PB. When dichotomizing T cell density in t-BAL in high and low, we found that PD-L1 expression in LC was associated with T cell density in t-BAL. T-BAL with high T cell density had higher %IFN-g+CD8 T cells and lower %T-regs., Conclusion: In BAL from advanced LC patients, T cells present features of exhaustion. T cells in t-BAL could be the best surrogate of tumor-infiltrating T cell, and future studies should evaluate T cell phenotype and density as potential biomarkers for cancer immunotherapy outcome.

Introduction: Advanced stage malignant mesothelioma (asMM) patients have poor prognosis. Several trials investigated the role of programmed cell death protein-1 (PD-1) and its ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs) in pre-treated asMM., Methods: A systematic review of the literature of clinical trials testing single-agent anti PD-1/PD-L1 ICIs in pre-treated asMM was performed. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) data were extracted. The predictive role of PD-L1 was assessed., Results: We selected 13 studies including 888 patients. ORR and DCR were 18.1% (95% confidence interval [CI] 13.9-22.8%) and 55.4% (95% CI: 48.1-62.5%), respectively. Median PFS and OS ranged from 2.1 to 5.9 and from 6.7 to 20.9 months, respectively. ORR according to PD-L1 was 27.0% (95% CI: 18.7-36.2%)., Conclusions: Anti-PD-(L)1 ICIs might be considered a treatment option for chemotherapy-resistant asMM, even if reliable predictive factors are still lacking., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aim: Trial designs using multiple primary endpoints (MPEs) are increasing in phase III cancer trials. Our objectives were to describe the incidence of MPEs in recently published phase III trials testing systemic treatments in patients with advanced cancer; the main characteristics of trials adopting MPEs; the presence of mature results for all endpoints in the primary publication; consistency between results of each endpoint and authors' conclusions., Methods: Articles of randomised phase III trials conducted in patients with advanced cancer, published between 2017 and 2020, were retrieved from PubMed. The main outcome was the proportion of trials with MPEs. In principle, according to regulatory agencies, we considered two distinct cases: (i) MPEs correspond to 'multiple chances' for the success of experimental treatment, needing adjustment for multiplicity, and (ii) a positive result depends on the success in all MPEs ('co-primary' endpoints)., Results: Out of 235 eligible trials, 27 trials (12%) adopted MPE, mostly overall survival (OS) and progression-free survival (PFS). The proportion of trials with MPEs increased over time, from 6% in 2017 to 20% in 2020 (p = 0.025). MPEs were adopted in 16% of for-profit trials versus 4% of non-profit trials (p = 0.006). The proportion of trials adopting MPEs was particularly high with immunotherapy (53%, p < 0.00001). Out of 27 trials with MPEs, 10 (37%) adopted an explicit definition of 'co-primary' endpoints, but only 1/10 declared the positivity of both endpoints critical for interpretation. Most trials (23, 85%) planned correction for multiplicity. Of 21 publications with positive conclusions, only 12 had a statistically significant positive result in both primary endpoints. In four cases (15%), positive conclusions were based on PFS results alone., Conclusions: Adoption of MPEs in randomised trials in oncology is quite common. Only a minority of trials respect recommendations by regulatory agencies about the adoption of MPEs, definition of 'co-primary' endpoints and correction for multiplicity., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Maria Lucia Reale had a role as a consultant for Eli-Lilly, outside the submitted work. Francesco Perrone reports grants, personal fees and non-financial support from Bayer, personal fees from Sandoz, grants and personal fees from Incyte, personal fees from Celgene, grants and personal fees from Astra Zeneca, personal fees from Pierre Fabre, personal fees from Janssen Cilag, grants from Roche, grants from Pfizer, outside the submitted work.Massimo Di Maio received honoraria and had roles as consultant or advisor for AstraZeneca, Pfizer, Novartis, Roche, Takeda, Eisai, Janssen, Astellas; received institutional research grant by Tesaro – GlaxoSmithKline, outside the submitted work. All remaining authors declared no conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Patients with unresectable biliary tract carcinomas (BTCs) have a poor prognosis with a median overall survival of fewer than 12 months following systemic chemotherapy. In recent years, the identification of distinct molecular alterations with corresponding targeted therapies is modifying this therapeutic algorithm. The aim of this review is to present an overview of targeted therapy for BTCs, describing published available data and potential future challenges in ongoing trials. From clinicaltrials.gov online database all ongoing trials for BTCs (any stage) was examinated in July 2021, and data regarding study design, disease characteristics and type of treatments were registered. Oncogenic-driven therapy (targeted therapy) was investigated in 67 trials. According to research, 15 ongoing trials (22.4%) are investigating fibroblast growth factor (FGF) receptor (FGFR)-inhibitors in BTCs. Three (18.7%) are open-label randomized multicenter phase 3 trials, 8 (50%) are single-arm phase two trials, and 4 (25%) are phase one studies. Twelve (17.9%) clinical trials dealt with isocitrate dehydrogenase (IDH) 1/2 targeting therapy either in combination with cisplatin (Cis) and gemcitabine (Gem) as first-line treatment for BTCs or in monotherapy in patients with IDH1 mutant advanced malignancies, including cholangiocarcinoma (CCA). Nine (13.4%) clinical trials tested human epidermal growth factor receptor (HER) 2 targeting therapy. Four (44.4%) studies are phase I trials, two (22.2%) are phase I/II trials, and three (33.3%) phase II trials. Rare molecular alterations in BTCs, such as anaplastic lymphoma kinase (ALK), c-ros oncogene1 receptor tyrosine kinase (ROS1), and v-RAF murine sarcoma viral oncogene homologue B1 (BRAF), are also under investigation in a few trials. Forty-four clinical trials (17.2%) are investigating not oncogenic-driven multitarget therapy like multireceptor tyrosin kinase inhibitors and antiangiogenetic agents. In conclusion, this review shows that BTCs management is experiencing important innovations, especially in biomarker-based patient selection and in the new emerging therapeutic approach. Many ongoing trials could answer questions regarding the role of molecular inhibitors leading to new therapeutic frontiers for molecular subcategories of BTCs., Competing Interests: The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Massimo Di Maio received honoraria and had roles as consultant or advisor for AstraZeneca, Pfizer, Novartis, Roche, Takeda, Eisai, Janssen, Astellas; received institutional research grant by Tesaro e GlaxoSmithKline, outside the submitted work. All remaining authors declared no conflicts of interest., (© The Author(s) 2021.)

Regulating the choice between neural stem cell maintenance versus differentiation determines growth and size of the developing brain. Here we identify TGF-beta signaling as a crucial factor controlling these processes. At early developmental stages, TGF-beta signal activity is localized close to the ventricular surface of the neuroepithelium. In the midbrain, but not in the forebrain, Tgfbr2 ablation results in ectopic expression of Wnt1/beta-catenin and FGF8, activation of Wnt target genes, and increased proliferation and horizontal expansion of neuroepithelial cells due to shortened cell-cycle length and decreased cell-cycle exit. Consistent with this phenotype, self-renewal of mutant neuroepithelial stem cells is enhanced in the presence of FGF and requires Wnt signaling. Moreover, TGF-beta signal activation counteracts Wnt-induced proliferation of midbrain neuroepithelial cells. Thus, TGF-beta signaling controls the size of a specific brain area, the dorsal midbrain, by antagonizing canonical Wnt signaling and negatively regulating self-renewal of neuroepithelial stem cells.

Given their accessibility, multipotent skin-derived cells might be useful for future cell replacement therapies. We describe the isolation of multipotent stem cell-like cells from the adult trunk skin of mice and humans that express the neural crest stem cell markers p75 and Sox10 and display extensive self-renewal capacity in sphere cultures. To determine the origin of these cells, we genetically mapped the fate of neural crest cells in face and trunk skin of mouse. In whisker follicles of the face, many mesenchymal structures are neural crest derived and appear to contain cells with sphere-forming potential. In the trunk skin, however, sphere-forming neural crest-derived cells are restricted to the glial and melanocyte lineages. Thus, self-renewing cells in the adult skin can be obtained from several neural crest derivatives, and these are of distinct nature in face and trunk skin. These findings are relevant for the design of therapeutic strategies because the potential of stem and progenitor cells in vivo likely depends on their nature and origin.

Beta-catenin plays a pivotal role in cadherin-mediated cell adhesion. Moreover, it is a downstream signaling component of Wnt that controls multiple developmental processes such as cell proliferation, apoptosis, and fate decisions. To study the role of beta-catenin in neural crest development, we used the Cre/loxP system to ablate beta-catenin specifically in neural crest stem cells. Although several neural crest-derived structures develop normally, mutant animals lack melanocytes and dorsal root ganglia (DRG). In vivo and in vitro analyses revealed that mutant neural crest cells emigrate but fail to generate an early wave of sensory neurogenesis that is normally marked by the transcription factor neurogenin (ngn) 2. This indicates a role of beta-catenin in premigratory or early migratory neural crest and points to heterogeneity of neural crest cells at the earliest stages of crest development. In addition, migratory neural crest cells lateral to the neural tube do not aggregate to form DRG and are unable to produce a later wave of sensory neurogenesis usually marked by the transcription factor ngn1. We propose that the requirement of beta-catenin for the specification of melanocytes and sensory neuronal lineages reflects roles of beta-catenin both in Wnt signaling and in mediating cell-cell interactions.

The transcription factor Erm is a member of the Pea3 subfamily of Ets domain proteins that is expressed in multipotent neural crest cells, peripheral neurons, and satellite glia. A specific role of Erm during development has not yet been established. We addressed the function of Erm in neural crest development by forced expression of a dominant-negative form of Erm. Functional inhibition of Erm in neural crest cells interfered with neuronal fate decision, while progenitor survival and proliferation were not affected. In contrast, blocking Erm function in neural crest stem cells did not influence their ability to adopt a glial fate, independent of the glia-inducing signal. Furthermore, glial survival and differentiation were normal. However, the proliferation rate was drastically diminished in glial cells, suggesting a glia-specific role of Erm in controlling cell cycle progression. Thus, in contrast to other members of the Pea3 subfamily that are involved in late steps of neurogenesis, Erm appears to be required in early neural crest development. Moreover, our data point to multiple, lineage-specific roles of Erm in neural crest stem cells and their derivatives, suggesting that Erm function is dependent on the cell intrinsic and extrinsic context.

Multipotent stem cells must generate various differentiated cell types in correct number and sequence during neural development. In the peripheral nervous system (PNS), this involves the formation of postmigratory progenitor cell types which maintain multipotency and are able to give rise to neural and non-neural cells in response to instructive growth factors. We propose that fate restrictions in such progenitor cells are controlled by the combinatorial interaction of different extracellular signals, including community effects in response to both neurogenic and gliogenic factors. In addition, distinct progenitor cell types display intrinsic differences which modulate their response to the extracellular environment. Thus, a progenitor cell is apparently able to integrate multiple intrinsic and extrinsic cues and thereby to choose fates appropriate for its location. Fate analysis of genetically modified progenitor cells will help to identify the molecules involved. This approach appears promising given the identification of multipotent progenitor cells from the mouse PNS and the availability of genetics in the mouse system.

Distinct glial cell types of the vertebrate peripheral nervous system (PNS) are derived from the neural crest. Here we show that the expression of the Ets domain transcription factor Erm distinguishes satellite glia from Schwann cells beginning early in rat PNS development. In developing dorsal root ganglia (DRG), Erm is present both in presumptive satellite glia and in neurons. In contrast, Erm is not detectable at any developmental stage in Schwann cells in peripheral nerves. In addition, Erm is downregulated in DRG-derived glia adopting Schwann cell traits in culture. Thus, Erm is the first described transcription factor expressed in satellite glia but not in Schwann cells. In culture, the Neuregulin1 (NRG1) isoform GGF2 maintains Erm expression in presumptive satellite cells and reinduces Erm expression in DRG-derived glia but not in Schwann cells from sciatic nerve. These data demonstrate that there are intrinsic differences between these glial subtypes in their response to NRG1 signaling. In neural crest cultures, Erm-positive progenitor cells give rise to two distinct glial subtypes: Erm-positive, Oct-6-negative satellite glia in response to GGF2, and Erm-negative, Oct-6-positive Schwann cells in the presence of serum and the adenylate cyclase activator forskolin. Thus, Erm-positive neural crest-derived progenitor cells and presumptive satellite glia are able to acquire Schwann cell features. Given the in vivo expression of Erm in peripheral ganglia, we suggest that ganglionic Erm-positive cells may be precursors of Schwann cells., (Copyright 2000 Academic Press.)

Tyramide signal amplification has successfully been applied to enhance detection limits of both immunological reactions and in situ hybridization methods. The technique uses short-range deposition of activated tyramide mediated by horseradish peroxidase. We have adapted this method to fluorescence in situ hybridization on embryonic tissue sections using fluorophore-labeled tyramide. The sensitivity of the procedure was sufficient to analyze the embryonic expression of mRNAs encoding both transcription factors and structural proteins. Combining fluorescence in situ hybridization and immunofluorescence with confocal microscopy allows the simultaneous detection of distinct mRNA species or of mRNAs together with proteins on the cellular level. Thus, the cell types expressing a particular gene at a given developmental stage can be studied even if no antibody to the gene product of interest is available. Moreover, the technique allows to study in situ the combinatorial marker expression that characterizes progenitor stages of a given cell lineage.