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Recent regulatory initiatives, such as the EU Non-Financial Reporting Directive and the UK Companies Act, require companies to mobilise the business model concept as a framework to disclose non-financial information in the annual report. These regulatory initiatives are based on a reflexive legal approach that avoids specifying what should be disclosed or articulating minimum disclosure requirements. In this context, this study investigates whether and to what extent preparers and users of non-financial information have a shared understanding of the business model concept and its role in reporting. An exploratory survey was conducted involving 35 users and 13 preparers, followed by 13 in-depth interviews, with both stages of research conducted from Searle's perspective of institutional reality. The findings present a somewhat divergent picture, indicating a lack of widespread consensus around a specific definition of a business model, its constitutive elements, and its reporting function. Thus, we conclude that the business model remains a concept under social construction in this domain and highlights areas of intervention. This study contributes to the existing literature by discussing how the absence of a common definition might hinder the otherwise positive effects of business model disclosure regulation from enhancing corporate transparency. Archival studies on business model reporting generally show low levels of disclosure, indicating poor informativeness. Our evidence adds to the accounting literature by considering the role of a shared view of the business model among market participants as a determinant of business model reporting quality and informativeness.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer in patients with liver cirrhosis of various etiologies. In recent years, there has been an advance in the knowledge of molecular mechanisms and a better staging definition of patients which has allowed the development of new therapies that have entered the therapeutic workup of these patients. Deep information on molecular drivers of HCC contributed to the development of targeted therapies with remarkable benefits. The novel strategies of targeting immune evasion using immune checkpoint inhibitors and CAR-T and TCR-T therapeutics have also shown promising results. For advanced diseases, the therapeutic algorithm has been recently updated, thanks to the efficacy of combining immunotherapy and antiangiogenic therapy in the first-line setting, and new drugs, both as single-agents or combinations, are currently under investigation.

Background Novel androgen receptor signaling inhibitors for prostate cancer (PC) impose the burden of self-administration on older patients overwhelmed by the requirement of many other concomitant medications. Patients and Methods This study evaluated the proportion of non-adherence in a 12-month follow-up period and the first 3 months to abiraterone (ABI) or enzalutamide (ENZ). In a prospective multicenter observational cohort study, patients with metastatic castration-resistant PC (mCRPC) aged ≥70 years receiving ABI or ENZ pre- or post-docetaxel were enrolled. Treatment monitoring included pill counting, a self-assessment questionnaire, and clinical diaries at each clinical visit. Non-adherence rates were based on proportions of missed/prescribed pills ratios by pill counting. Results Overall, 234 patients were recruited with median age of 78 years (range, 73–82); 86 (37%) were treated with ABI, and 148 (63%) with ENZ. The median follow-up for adherence was seven monthly cycles (IQR: 4–12). The two cohorts were well balanced for baseline characteristics. The percentage of non-adherence by pill counting was slightly higher for ABI than ENZ (5.2% vs. 4.2%, P < .001). By self-reporting, patients on ENZ tended to report more frequently than those with ABI forgetfulness as the reason for missing events (42% vs. 17%, P < .001). A lower Geriatric G8 score correlated with non-adherence (P = .004). Overall survival (OS) was 48.8 months. Patients on ABI had radiographic progression-free survival (rPFS) of 28.4 [24.2–32.5], while for ENZ patients, we reported a median rPFS of 23.1 [18.2–28.1] months. Conclusion Physicians tend to treat older mCRPC patients with ENZ. Non-adherence rate is relatively low overall but can be higher with ABI than with ENZ and correlates with the Geriatric G8 score. Forgetfulness is a potential barrier for ENZ.

Introduction: Androgen receptor pathway inhibitors (ARPIs) have been increasingly offered to older patients with prostate cancer (PC). However, prognostic factors relevant to their outcome with ARPIs are still little investigated. Methods and Materials: The Meet-URO network ADHERE was a prospective multicentre observational cohort study evaluating and monitoring adherence to ARPIs metastatic castrate-resistant PC (mCRPC) patients aged ≥70. Cox regression univariable and multivariable analyses for radiographic progression-free (rPFS) and overall survival (OS) were performed. Unsupervised median values and literature-based thresholds where available were used as cut-offs for quantitative variables. Results: Overall, 234 patients were enrolled with a median age of 78 years (73–82); 86 were treated with abiraterone (ABI) and 148 with enzalutamide (ENZ). With a median follow-up of 15.4 months (mo.), the median rPFS was 26.0 mo. (95% CI, 22.8–29.3) and OS 48.8 mo. (95% CI, 36.8–60.8). At the MVA, independent prognostic factors for both worse rPFS and OS were Geriatric G8 assessment ≤ 14 (p < 0.001 and p = 0.004) and PSA decline ≥50% (p < 0.001 for both); time to castration resistance ≥ 31 mo. and setting of treatment (i.e., post-ABI/ENZ) for rPFS only (p < 0.001 and p = 0.01, respectively); age ≥78 years for OS only (p = 0.008). Conclusions: Baseline G8 screening is recommended for mCRPC patients aged ≥70 to optimise ARPIs in vulnerable individuals, including early introduction of palliative care.

BackgroundSecond and third-generation ALK inhibitors (ALKIs) have been recently approved for ALK-translocated lung cancer treatment, improving - and expanding - the first-line scenario.MethodsIn this systematic review and metanalysis, we investigated the efficacy and safety of next-generation ALKIs in untreated advanced ALK-translocated lung cancer patients, searching for randomized phase III controlled trials through databases (PubMed, EMBASE, and the Cochrane Library). Inclusion and exclusion of studies, quality assessment, data extraction, and synthesis were independently accomplished by two reviewers, with discrepancies adjudicated by a third reviewer. Stata (StataCorp., v.16) software was used for the metanalysis.ResultsIn total, seven randomized controlled trials met our inclusion criteria. Comparing the results of next-generation ALKIs and control therapy (crizotinib or chemotherapy), next-generation ALKIs significantly improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), any lesion (aCNSRR) and measurable lesions of central nervous system response rate (mCNSRR). Safety results were similar between the experimental and control groups.ConclusionOur analysis confirmed that next-generation ALKIs are the preferred first-line treatment option for ALK-translocated lung cancer. They are superior to crizotinib or chemotherapy in several clinical endpoints, including OS, PFS, ORR and CNS disease control, without increased toxicity. In the absence of head-to-head data, the choice between these molecules should be guided by physician experience and preference, drug-specific safety profile and schedule.

Small cell lung cancer (SCLC) is still a lethal disease. Three phase III randomized clinical trials (IMpower133, CASPIAN, and KEYNOTE-604) have highlighted the survival gain of adding immune checkpoint inhibitors to first-line standard chemotherapy in advanced SCLC patients. In this review, we discuss the data from the three trials above. Furtherly, we analyze issues that still need to be elucidated, like the role of biomarkers, poor performance status at baseline, the presence of brain metastases, and the platinum compound's choice. Moreover, we depict the future of SCLC first-line therapy management, focusing on new therapeutic strategies currently under investigation.

Anti-PD-1 antibodies revolutionized the treatment of advanced melanoma patients. However, one out of three do not respond to this therapy, with an overall poor prognosis. Identification of predictive biomarkers in patients receiving immune-based therapies is necessary for minimizing risk of toxicity and optimizing patient benefit and is still an important unmet clinical need. Recently, many studies have evaluated peripheral blood markers as potential biomarkers, but none so far have been validated. We collected at baseline peripheral blood samples from 18 consecutive advanced melanoma patients treated with anti-PD-1 therapy. Main pro- and anti-inflammatory cytokines were studied in PBMCs from baseline blood samples both evaluating mRNA expression by qRT-PCR and identifying PBMCs subpopulations by FACS analysis. We found that IFN-γ mRNA expression levels were significantly higher in responder patients compared to non-responder ones. Moreover, to better validate its role, we evaluated the IFN-γ/IL-10 ratio. This value was higher in responder patients. FACS analysis confirmed that CD4 + IFN-γ + PBMCs percentage was higher in responders. Our data suggest an interesting correlation between IFN-γ/IL-10 ratio and response to anti-PD-1 therapy in advanced melanoma patients, suggesting a new biomarker that could be easily incorporated in clinical practice.

Immunotherapy has shifted the therapeutic landscape in thoracic cancers. However, assessment of biomarkers for patient selection and disease monitoring remain challenging, especially considering the lack of tissue sample availability for clinical and research purposes. In this scenario, liquid biopsy (LB), defined as the study and characterization of biomarkers in body fluids, represents a useful alternative strategy. In other malignancies such as colorectal cancer, breast cancer or melanoma, the potential of LB has been more extensively explored for monitoring minimal residual disease or response to treatment, and to investigate mechanisms of resistance to targeted agents. Even if various experiences have already been published about the applications of LB in immunotherapy in thoracic cancers, the standardization of methodology and assessment of its clinical utility is still pending. In this review, the authors will focus on the applications of LB in immunotherapy in non-small cell lung cancer, small cell lung cancer, and malignant pleural mesothelioma, describing available data and future perspectives.

Background FKBP51 immunophilin is abundantly expressed by immune cells. Co-inhibitory immune receptor signalling generates the splicing isoform FKBP51s. Tregs stained by FKBP51s are increased in melanoma patients and their counts are associated with anti-CTLA-4 response. An expansion of FKBP51s+PD-L1+ monocytes was measured in a group of non-responding patients to anti-CTLA-4. The aim of this work was to confirm the predictive value of response of FKBP51s+Tregs in a cohort of patients undergoing anti-PD1 treatment and shed light on a monocyte subset co-expressing PD-L1/FKBP51s. Methods Co-cultures of organoids and autologous lymphocytes were used to confirm that tumour T-cell interaction can induce FKBP51s. PBMC immunophenotype and flow cytometry served to assess and monitor FKBP51s+Treg and FKBP51s+PD-L1+ monocytes in 22 advanced melanoma patients treated with anti-PD1. Silencing and overexpression of FKBP51s in human macrophages served to address the protein role in the tolerant macrophages’ behaviour. Results FKBP51s+Tregs count was increased in responders and had a prognostic value. Non-responders showed an early increase in FKBP51s+ PD-L1+ monocytes during anti-PD1 treatment. Manipulation of FKBP51s modulated the macrophage–phenotype, with forced protein expression promoting aspects associated with tolerance. Conclusions FKBP51s may guide in the selection and monitoring of melanoma patient candidates to immune-checkpoint-targeted therapy. Manipulation of FKBP51s may overcome resistance.

Background: Cutaneous melanoma is one of the most severe skin diseases. Nodular melanoma is the second melanoma subtype in order of frequency. The prognosis of skin melanoma depends on the vertical growth of the tumor (Breslow index). For this measurement, excisional biopsy is strongly recommended. This is, however, an invasive procedure and may cause damage to the lymphatic drainage system. The HFUS system, , can be extremely useful for determining tumor thickness in the preoperative phase, given its high resolution capacity. The aim of this preliminary study is to define the role of HFUS for the nodular skin melanoma Breslow thickness in adults before surgery by making a comparison with histological features. Methods: In this study, 14 melanocytic lesions (8 male and 6 female) were evaluated with dermatoscopic clinical features strongly indicative of nodular melanoma. Out of these, excisional biopsy of 7 lesions was requested. The ultrasounds were performed preoperatively. The images were acquired through the first ultrasound scanner with ultra-high frequency probes (range from 50MHz to 70 MHz) available on the market under the EEC mark (Vevo "MD, FUJIFILM Visual Sonics, Amsterdam, the Netherlands) equipped with a linear probe of 50-70 MHz. Results: From the ultrasonographic analysis of 14 nodular melanoma thickness was determined for the presence of two hyperechogenic laminae, separated by a hypo / anechoic space. The twelve lesions were in situ while the other two lesions showed ultrasonography for example; the satellite lesions (less than two centimeters from the primary lesion) and in transit (localizable to more than two centimeters from the primary lesion). Four of these lesions were ulcerated. A comparsion was made the 7 lesions on between the thickness calculated with this method, and that obtained on the bioptic piece. The presence of a positive concordance has been evident in all of the cases. Conclusions: If further studies are needed to support its widespread clinical use, its is believed that, in expert hands and with an interdisciplinary team, HFUS is already capable to reliably calculate a Breslow index in a large majority of patients with cutaneous melanoma.

Biliary tract cancer (BTC) is an aggressive tumor characterized by a poor prognosis. In the latest years, targetable genetic alterations have been discovered in BTC patients, leading to the approval of new targeted therapies. Liquid biopsy, which is a non-invasive method for detecting tumor biomarkers from fluid samples, is a useful tool for diagnosis and molecular characterization, but also for prognosis assessment and monitoring of treatment response. In this review, recent works on liquid biopsy in BTC patients were analyzed, focusing on some relevant aspects for clinical use and trying to depict the future role of this technique. Moreover, differences between plasma and bile samples were pointed out, in light of the peculiar biology of BTC and the possibility of using bile as an alternative source of cell-free DNA (cfDNA) for genomic analysis. In the era of precision oncology, the increasing adoption of liquid biopsy in BTC patients will certainly improve the management of this disease.

Background: Liquid biopsy is a potentially useful tool for melanoma patients, also for detecting BRAS/NRAS mutations, even if the tissue analysis remains the current standard. Methods: In this work, we tested ctDNA on plasma samples from 56 BRAF-V600/NRAS mutant stage III/IV melanoma patients using a real-time quantitative PCR (qPCR)-based platform. The study population was divided into two cohorts: the first including 26 patients who had undergone radical resection (resected cohort) and the second including 30 patients who had unresected measurable disease (advanced cohort). Moreover, for 10 patients in the advanced cohort, ctDNA assessment was repeated at specified timepoints after baseline testing. Data were analyzed and correlated to the clinicopathologic characteristics and outcomes. Results: In the baseline cohort, a higher tissue–plasma concordance was seen in patients with high burden of disease (sum of diameters ≥30 mm, ≥2 metastatic sites, elevated LDH levels); furthermore, monitoring of these patients through ctDNA analysis was informative for therapeutic responses. On the other hand, the low sensitivity of this technique did not allow for clinically valuable prediction of relapses in radically resected stage III/IV patients. Conclusions: Overall, our data suggest that qPCR-based ctDNA analysis could be informative in a subset of locally advanced and metastatic melanoma patients with specific clinical–radiological characteristics, supporting further investigations in this setting.

Mucosal melanomas (MM) are rare tumors, being less than 2% of all diagnosed melanomas, comprising a variegated group of malignancies arising from melanocytes in virtually all mucosal epithelia, even if more frequently found in oral and sino-nasal cavities, ano-rectum and female genitalia (vulva and vagina). To date, there is no consensus about the optimal management strategy of MM. Furthermore, the clinical rationale of molecular tumor characterization regarding BRAF, KIT or NRAS, as well as the therapeutic value of immunotherapy, chemotherapy and targeted therapy, has not yet been deeply explored and clearly established in MM. In this overview, focused on anorectal and genital MM as models of rare melanomas deserving of a multidisciplinary approach, we highlight the need of referring these patients to centers with experts in melanoma, anorectal and uro-genital cancers treatments. Taking into account the rarity, the poor outcomes and the lack of effective treatment options for MM, tailored research needs to be promptly promoted.

Simple Summary Prostate cancer research has been recently characterized by the discovery of several prognostic and predictive molecular factors, which ultimately improve patients’ management. In this review, we present the clinical impact of such factors and the methods to detect them, both on tissue and blood, in advanced prostate cancer patients. The aim of this review is ultimately to depict the role of these molecular factors in the era of precision oncology. Abstract Prostate cancer (PCa) therapy has been recently revolutionized by the approval of new therapeutic agents in the metastatic setting. However, the optimal therapeutic strategy in such patients should be individualized in the light of prognostic and predictive molecular factors, which have been recently studied: androgen receptor (AR) alterations, PTEN-PI3K-AKT pathway deregulation, homologous recombination deficiency (HRD), mismatch repair deficiency (MMRd), and tumor microenvironment (TME) modifications. In this review, we highlighted the clinical impact of prognostic and predictive molecular factors in PCa patients’ outcomes, identifying biologically distinct subtypes. We further analyzed the relevant methods to detect these factors, both on tissue, i.e., immunohistochemistry (IHC) and molecular tests, and blood, i.e., analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Moreover, we discussed the main pros and cons of such techniques, depicting their present and future roles in PCa management, throughout the precision medicine era.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease even in the early stages, despite progresses in surgical and pharmacological treatment in recent years. High potential for metastases is the main cause of therapeutic failure in localized disease, highlighting the current limited knowledge of underlying pathological processes. However, nowadays research is focusing on the search for personalized approaches also in the adjuvant setting for PDAC, by implementing the use of biomarkers and investigating new therapeutic targets. In this context, the aim of this narrative review is to summarize the current treatment scenario and new potential therapeutic approaches in early stage PDAC, from both a preclinical and clinical point of view. Additionally, the review examines the role of target therapies in localized PDAC and the influence of neoadjuvant treatments on survival outcomes.

Cutaneous melanoma is a lethal disease, even when diagnosed in advanced stages. Although recent progress in biology and treatment has dramatically improved survival rates, new therapeutic approaches are still needed. Deregulation of epigenetics, which mainly controls DNA methylation status and chromatin remodeling, is implied not only in cancer initiation and progression, but also in resistance to antitumor drugs. Epigenetics in melanoma has been studied recently in both melanoma preclinical models and patient samples, highlighting its potential role in different phases of melanomagenesis, as well as in resistance to approved drugs such as immune checkpoint inhibitors and MAPK inhibitors. This review summarizes what is currently known about epigenetics in melanoma and dwells on the recognized and potential new targets for testing epigenetic drugs, alone or together with other agents, in advanced melanoma patients.

OBJECTIVE: The aim of this review is to analyze feasibility and toxicities of high-dose chemotherapy (HDCT) in comparison to standard dose chemotherapy (SDCT) in patients affected by mediastinal germ cell tumors (MGCTs), discussing factors that may affect therapeutic choices, such as: management of residual disease, early response predictors for chemotherapeutic efficacy and determinants of chemotherapeutic resistance. In this review, we discuss the main clinical experiences with HDCT and SDCT in germ cell tumor (GCT) patients specifically in those affected by MGCT. BACKGROUND: MGCTs represent a very small subset characterized by a poor prognosis, despite improvements in their clinical management and in understanding their biology. From early 1970s, HDCT has become an alternative to SDCT for both first-line and salvage therapeutic settings in advanced GCT patients. Several HDCT schedules—either cisplatin or carboplatin-based—have been tested so far, both in clinical randomized trial and in single-center experiences, with divergent results in terms of clinical outcomes and tolerability. Moreover, the majority of these studies included, but were not exclusively designed for, advanced MGCT patients, making difficult to infer data for this specific subset. METHODS: an extended review of literature through PubMed was conducted using the keywords “mediastinal germinal cell tumors”, “standard dose chemotherapy” and “high dose chemotherapy”. CONCLUSIONS: HDCT regimens could not be considered to date a standard option as first-line therapy in advanced MGCT patients, whilst they could be an alternative to SDCT regimens in relapsed tumors after proper patient selection.

The cure rate of germ cell tumours (GCTs) has significantly increased from the late 1970s since the introduction of cisplatin-based therapy, which to date remains the milestone for GCTs treatment. The exquisite cisplatin sensitivity has been mainly explained by the over-expression in GCTs of wild-type TP53 protein and the lack of TP53 somatic mutations; however, several other mechanisms seem to be involved, many of which remain still elusive. The findings about the role of TP53 in platinum-sensitivity and resistance, as well as the reported evidence of second cancers (SCs) in GCT patients treated only with surgery, suggesting a spectrum of cancer predisposing syndromes, highlight the need for a deepened understanding of the role of TP53 in GCTs. In the following report we explore the complex role of TP53 in GCTs cisplatin-sensitivity and resistance mechanisms, passing through several recent genomic studies, as well as its role in GCT patients with SCs, going through our experience of Center of reference for both GCTs and cancer predisposing syndromes.

Wheat grain protein concentration is an important determinant of wheat quality for human nutrition that is often overlooked in efforts to improve crop production. We tested and applied a 32‐multi‐model ensemble to simulate global wheat yield and quality in a changing climate. Potential benefits of elevated atmospheric CO2 concentration by 2050 on global wheat grain and protein yield are likely to be negated by impacts from rising temperature and changes in rainfall, but with considerable disparities between regions. Grain and protein yields are expected to be lower and more variable in most low‐rainfall regions, with nitrogen availability limiting growth stimulus from elevated CO2. Introducing genotypes adapted to warmer temperatures (and also considering changes in CO2 and rainfall) could boost global wheat yield by 7% and protein yield by 2%, but grain protein concentration would be reduced by −1.1 percentage points, representing a relative change of −8.6%. Climate change adaptations that benefit grain yield are not always positive for grain quality, putting additional pressure on global wheat production., B.L received support from the International Food Policy Research Institute (IFPRI) through the Global Futures and Strategic Foresight project, the CGIAR Research Program on Climate Change, Agriculture and Food Security (CCAFS) and the CGIAR Research Program on Wheat. A.M. received support from the EU Marie Curie FP7 COFUND People Programme, through an AgreenSkills fellowship under grant agreement no. PCOFUND‐GA‐2010‐267196. PM, A.M., D.R., and D.W. acknowledge support from the FACCE JPI MACSUR project (031A103B) through the metaprogram Adaptation of Agriculture and Forests to Climate Change (AAFCC) of the French National Institute for Agricultural Research (INRA). L.X. and Y.Z. were supported by the National High‐Tech Research and Development Program of China (2013AA100404), the National Natural Science Foundation of China (31271616), the National Research Foundation for the Doctoral Program of Higher Education of China (20120097110042), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). F.T. and Z.Z. were supported by the National Natural Science Foundation of China (41571088, 41571493 and 31561143003). R.R. received support from the German Ministry for Research and Education (BMBF) through project SPACES‐LLL. Rothamsted Research receives support from the Biotechnology and Biological Sciences Research Council (BBSRC) Designing Future Wheat programme [BB/P016855/1]. M.J. and J.E.O. were supported by Innovation Fund Denmark through the MACSUR project. L.X. and Y.G. acknowledge support from the China Scholarship Council. M.B and R.F. were funded by JPI FACCE MACSUR2 through the Italian Ministry for Agricultural, Food and Forestry Policies and thank A. Soltani from Gorgan Univ. of Agric. Sci. & Natur. Resour. for his support. R.P.R., T.P., and F.T. received financial support from the FACCE MACSUR project funded through the Finnish Ministry of Agriculture and Forestry (MMM) and from the Academy of Finland through the projects NORFASYS (decision nos. 268277 and 292944) and PLUMES (decision nos. 277403 and 292836). K.C.K. and C.N. received support from the German Ministry for Research and Education (BMBF) within the FACCE JPI MACSUR project. S.M. and C.M. acknowledge financial support from the MACMIT project (01LN1317A) funded through BMBF. G.J.O. and G.J.F. acknowledge support from the Victorian Department of Economic Development, Jobs, Transport and Resources, the Australian Department of Agriculture and Water Resources, The University of Melbourne and the Grains Research Development Corporation, Australia. P.K.A.'s work was implemented as part of the CGIAR Research Program on Climate Change, Agriculture and Food Security (CCAFS), which is carried out with support from the CGIAR Trust Fund and through bilateral funding agreements. For details please visit https://ccafs.cgiar.org/donors. The views expressed in this document cannot be taken to reflect the official opinions of these organizations.. B.B. received financial support from USDA NIFA‐Water Cap Award 2015‐68007‐23133. F.E. acknowledges support from the FACCE JPI MACSUR project through the German Federal Ministry of Food and Agriculture (2815ERA01J) and from the German Science Foundation (project EW 119/5‐1).

Clinical Practice Points • Metastatic colorectal cancer is one of the most common causes of cancer death worldwide. • Primary and acquired resistance mechanisms to anti-EGFR treatment are a challenging topic with several clinical implications. • Primary resistance is defined by the presence of activating mutations in BRAF and RAS genes before treatment initiation, while acquired resistance refers to the selection of pre-existing mutant clones or de novo acquisition of mutations under the pressure of anti EGFR treatment. • Testing mutations in RAS and BRAF genes as predictive biomarkers is mandatory. • Liquid biopsy has acquired growing importance and showed to be reliable when compared to tissue NGS. • Liquid biopsy offers a full overview of the genetic landscape of the disease, overcoming spatial and temporal heterogeneity, when compared to tissue biopsy. • Liquid biopsy can be used to capture the changes in biology of cancer cells under the selective pressure of targeted agents over time. • Using complementary techniques allows to increase the diagnostic power and the biological significance of the results.

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.

Hepatocellular carcinoma (HCC) is the primary tumour of the liver with the greatest incidence, particularly in the elderly. Additionally, improvements in the treatments for chronic liver diseases have increased the number of elderly patients who might be affected by HCC. Little evidence exists regarding HCC in old patients, and the elderly are still underrepresented and undertreated in clinical trials. In fact, this population represents a complex subgroup of patients who are hard to manage, especially due to the presence of multiple comorbidities. Therefore, the choice of treatment is mainly decided by the physician in the clinical practice, who often tend not to treat elderly patients in order to avoid the possibility of adverse events, which may alter their unstable equilibrium. In this context, the clarification of the optimal treatment strategy for elderly patients affected by HCC has become an urgent necessity. The aim of this review is to provide an overview of the available data regarding the treatment of HCC in elderly patients, starting from the definition of “elderly” and the geriatric assessment and scales. We explain the possible treatment choices according to the Barcelona Clinic Liver Cancer (BCLC) scale and their feasibility in the elderly population.

Thanks to their low fertilization requirements and high consumer demand, ancient wheats and old durum wheat cultivars represent an attractive option for the marginal areas of Mediterranean environments no longer cultivated due to the low grain yields attainable using modern wheat cultivars. Dual-purpose utilization may increase their value in these cropping systems, but no information is available on the suitability of ancient wheat species to this type of utilization. To fill this gap, Khorasan, einkorn, and emmer wheats, clipped at the terminal spikelet stage or left unclipped, were compared in a two-year field trial. The grains were sown in the month of October, in Sardinia (41°N, 80 m asl), Italy, on low-fertility soils and with low-medium fertilization rates. Einkorn cultivars produced the highest biomass yield (2–3 t ha−1), reflecting the longer time to the onset of the terminal spikelet stage (119–138 days). After clipping, all species recovered their ability to intercept radiation to the levels of the unclipped crops, but clipping lowered their radiation use-efficiency. Grain yield was not penalized by clipping: the increase in the harvest index compensated for the decrease in biomass. Here we show for the first time that ancient wheat species are suitable for dual-purpose utilization (herbage plus grain in the same season) rendering them valuable for marginal areas; this was because the early sowing adopted for dual-purpose utilization allowed them to take full advantage of their lateness in terms of herbage yield, and to bring flowering forward (i.e. make it earlier) so that a satisfactory grain yield was obtained, even under severe water stress. Dual-purpose utilization of ancient wheats increases the sustainability of mixed cropping systems, by making herbage available to animals in a critical period, without decreasing the grain yield attainable after grazing in the same season.

A few months ago, results from two randomised phase III trials of total neoadjuvant therapy (TNT) in locally advanced rectal cancer were presented (RAPIDO and PRODIGE 23), consistently showing better short- and long-term outcomes with TNT as compared with standard neoadjuvant long-course chemoradiotherapy (CRT) or short-course radiotherapy (SCRT). These results represent corroborating evidence in support of a practice that many centres had already implemented based on promising preliminary data. Also, they provide new, high-level evidence to endorse TNT as a new management option in the treatment algorithm of stage II-III rectal cancer in those centres where CRT and SCRT have long remained the only accepted standard neoadjuvant treatments. Having two consistently positive trials is certainly reassuring regarding the potential of TNT as a general treatment approach. Nevertheless, substantial differences between these trials pose important challenges in relation to the generalisability and applicability of their results, and translation of the same into practical clinical recommendations. In this article, we address a number of key questions that the RAPIDO and PRODIGE 23 trials have raised among the broad community of gastrointestinal oncologists, proposing an interpretation of the data that may help the decision making, and highlighting grey areas that warrant further investigation., SCOPUS: re.j, info:eu-repo/semantics/published

Melanoma is the most lethal form of skin cancer and its incidence is growing worldwide. In the last ten years, the therapeutic scenario of this disease has been revolutionized by the introduction of targeted therapies and immune-checkpoint inhibitors. However, in patients with many lesions and bulky tumors, in which surgery is no longer feasible, there is a need for new treatment options. Here we report, for the first time to our knowledge, a clinical case where a melanoma patient harboring the SMO p.Gln216Arg mutation has been treated with imiquimod, showing a complete and durable response. To better explain this outstanding response to the treatment, we transfected a melanoma cell line (MeWo) with the SMO p.Gln216Arg mutation in order to evaluate its role in response to the imiquimod treatment. Moreover, to better demonstrate that the antitumor activity of imiquimod was due to its role in suppressing the oncogenic SMO signaling pathway, independently of its immune modulating function, an in vivo experiment has been performed. This clinical case opens up a new scenario for the treatment of melanoma patients identifying a new potentially druggable target.

Opinion statementAbout 70–80% of early breast cancer (BC) patients receive adjuvant endocrine therapy (ET) for at least 5 years. ET includes in the majority of cases the use of aromatase inhibitors, as upfront or switch strategy, that lead to impaired bone health. Given the high incidence and also the high prevalence of BC, cancer treatment–induced bone loss (CTIBL) represents the most common long-term adverse event experimented by patients with hormone receptor positive tumours. CTIBL is responsible for osteoporosis occurrence and, as a consequence, fragility fractures that may negatively affect quality of life and survival expectancy. As recommended by main international guidelines, BC women on aromatase inhibitors should be carefully assessed for their fracture risk at baseline and periodically reassessed during adjuvant ET in order to early detect significant worsening in terms of bone health. Antiresorptive agents, together with adequate intake of calcium and vitamin D, should be administered in BC patients during all course of ET, especially in those at high risk of osteoporotic fractures, as calculated by tools available for clinicians. Bisphosphonates, such as zoledronate or pamidronate, and anti-RANKL antibody, denosumab, are the two classes of antiresorptive drugs used in clinical practice with similar efficacy in preventing bone loss induced by aromatase inhibitor therapy. The choice between them, in the absence of direct comparison, should be based on patients’ preference and compliance; the different safety profile is mainly related to the route of administration, although both types of drugs are manageable with due care, since most of the adverse events are predictable and preventable. Despite advances in management of CTIBL, several issues such as the optimal time of starting antiresorptive agents and the duration of treatment remain unanswered. Future clinical trials as well as increased awareness of bone health are needed to improve prevention, assessment and treatment of CTIBL in these long-term survivor patients.

Background Despite the advancements in new therapies for colorectal cancer (CRC), chemotherapy still constitutes the mainstay of the medical treatment. For this reason, new strategies to increase the efficacy of chemotherapy are desirable. Poly-ADP-Ribose Polymerase inhibitors (PARPi) have shown to increase the activity of DNA damaging chemotherapeutics used in the treatment of CRC, however previous clinical trials failed to validate these results and pointed out dose-limiting toxicities that hamper the use of such combinations in unselected CRC patients. Nevertheless, in these studies little attention was paid to the mutational status of homologous recombination repair (HRR) genes. Methods We tested the combination of the PARPi niraparib with either 5-fluorouracil, oxaliplatin or irinotecan (SN38) in a panel of 12 molecularly annotated CRC cell lines, encompassing the 4 consensus molecular subtypes (CMSs). Synergism was calculated using the Chou-Talalay method for drug interaction. A correlation between synergism and genetic alterations in genes involved in homologous recombination (HR) repair was performed. We used clonogenic assays, mice xenograft models and patient-derived 3D spheroids to validate the results. The induction of DNA damage was studied by immunofluorescence. Results We showed that human CRC cell lines, as well as patient-derived 3D spheroids, harboring pathogenic ATM mutations are significantly vulnerable to PARPi/chemotherapy combination at low doses, regardless of consensus molecular subtypes (CMS) and microsatellite status. The strongest synergism was shown for the combination of niraparib with irinotecan, and the presence of ATM mutations was associated to a delay in the resolution of double strand breaks (DSBs) through HRR and DNA damage persistence. Conclusions This work demonstrates that a numerically relevant subset of CRCs carrying heterozygous ATM mutations may benefit from the combination treatment with low doses of niraparib and irinotecan, suggesting a new potential approach in the treatment of ATM-mutated CRC, that deserves to be prospectively validated in clinical trials.

International audience; Grain protein content constitutes a key quality trait for durum wheat end-products and may also impact grain protein composition. A total of sixteen durum wheat cultivars were analyzed in a field trial during two seasons at two nitrogen (N) levels to evaluate whether and to what extent the variation in total grain N was associated with variation in the quantity of the various protein fractions and grain quality parameters. Genotypic variation in grain N content correlated with the variation in the content of all three protein fractions, although the strength of the correlation with gliadin and albumin-globulin was higher than that with glutenins. Genotypic variation in gliadin and glutenin content was more tightly correlated with the variation in the sulfur (S)-rich protein groups than with the S-poor protein groups and subunits. The variation in the percentage of unextractable polymeric proteins (UPP%) among genotypes was independent of their glutenin allelic composition. The significant genotypic differences in UPP% and in the ratios between protein groups and subunits were not influenced by the corresponding variation in grain N content. The final grain N content can only account for part of the variation in quality parameters and in the partitioning of total grain N between protein fractions since genotypic differences other than grain N content also contribute to these variations.

BRAF-V600 mutations occur in approximately 50% of patients with metastatic melanoma. Immune-checkpoint inhibitors and targeted therapies are both active as first-line treatments in these patients regardless of their mechanisms of action and toxicities. However, an upfront therapeutic strategy is still controversial. In fact, waiting for results of ongoing clinical trials and for new biomarkers, clinicians should base their decision on the clinical characteristics of the patient and on the biological aspects of the tumor. This review provides an overview on BRAF-V600 mutations in melanoma and will discuss their prognostic and clinical significance. Moreover, it will suggest a therapeutic algorithm that can drive therapeutic choice in a first-line setting for BRAF-V600 mutant melanoma patients.

Background The emerging role of next-generation sequencing (NGS) targeted panels is revolutionising our approach to cancer patients, providing information on gene alterations helpful for diagnosis and clinical decision, in a short time and with acceptable costs. Materials and methods In this work, we evaluated the clinical application of FoundationOne CDx test, a hybrid capture-based NGS. This test identifies alterations in 324 genes, tumour mutational burden and genomic signatures as microsatellite instability. The decision to obtain the NGS assay for a particular patient was done according to investigator's choice. Results Overall, 122 tumour specimens were analysed, of which 84 (68.85%) succeeded. The success rate was influenced by type of specimen formalin-fixed paraffin embedded (FFPE block vs FFPE slides), by origin of the sample (surgery vs biopsy) and by time of fixation (

BRAF-V600 mutations occur in approximately 50% of patients with metastatic melanoma. Immune-checkpoint inhibitors and targeted therapies are both active as first-line treatments in these patients regardless of their mechanisms of action and toxicities. However, an upfront therapeutic strategy is still controversial. In fact, waiting for results of ongoing clinical trials and for new biomarkers, clinicians should base their decision on the clinical characteristics of the patient and on the biological aspects of the tumor. This review provides an overview on BRAF-V600 mutations in melanoma and will discuss their prognostic and clinical significance. Moreover, it will suggest a therapeutic algorithm that can drive therapeutic choice in a first-line setting for BRAF-V600 mutant melanoma patients.

This article offers a methodological tool that assesses a company's commitment to sustainability by analysing its business model (which is defined here as a description of processes through which organizations implement their competitive strategies and create value). Insofar as they are considered a key driver for long-term profitability, sustainability strategies should involve a company's value creation processes — that is, a company's business model. This paper specifically examines the extent to which mining companies engage in sustainability by performing content analyses of their business model disclosures. Our empirical analysis focuses on the UK mining industry because this sector often struggles with a host of societal, organizational, and environmental issues, and because UK mining companies are obliged to describe their business model in their strategic reports. In order to determine whether (and how) companies implement sustainability strategies in their business model, we perform a content analysis of the business model disclosures of 16 FTSE All-share index UK mining companies, for a total of 1048 text units. Our results suggest that mining companies have opted for a selective and soft approach to sustainability. Although Air, Energy, Water, Local community engagement, Environmental protection, and Labour conditions are often addressed in the business models of UK mining companies, there is very little evidence to suggest that concrete initiatives were actually implemented in other areas. In fact, some topics are completely ignored (Raw materials), almost completely ignored (Waste, Corruption and Lobbying, Local employment), or discussed in a predominantly descriptive manner (Human rights, Opportunity and equality, Recruitment and bargaining, Training). The practical implications of this study are twofold. First, we offer a new means of investigating how companies engage in sustainability by performing content analyses of their business model disclosures. Secondly, we offer a detailed discussion of how sustainability affects value creation processes in the UK mining industry.

Simple Summary Despite immune checkpoint inhibitors’ (ICIs) improved overall survival in urothelial carcinoma patients, only a minority of them benefit from immunotherapy. Therefore, there is an unmet clinical need to identify biomarkers which are useful to select the patients who are most likely to respond to ICIs. This review describes the prognostic and predictive role, and potential clinical applicability, of patient- and tumour-related factors. These factors include new molecular classes, tumour mutational burden, mutational signatures, circulating tumour DNA, programmed death-ligand 1, inflammatory indices and clinical characteristics. This summary may help clinicians to assess patients who are considered for ICI treatment, and may drive further prospective research on these biomarkers. Abstract In recent years, the treatment landscape of urothelial carcinoma has significantly changed due to the introduction of immune checkpoint inhibitors (ICIs), which are the standard of care for second-line treatment and first-line platinum-ineligible patients with advanced disease. Despite the overall survival improvement, only a minority of patients benefit from this immunotherapy. Therefore, there is an unmet need to identify prognostic and predictive biomarkers or models to select patients who will benefit from ICIs, especially in view of novel therapeutic agents. This review describes the prognostic and predictive role, and clinical readiness, of clinical and tumour factors, including new molecular classes, tumour mutational burden, mutational signatures, circulating tumour DNA, programmed death-ligand 1, inflammatory indices and clinical characteristics for patients with urothelial cancer treated with ICIs. A classification of these factors according to the levels of evidence and grades of recommendation currently indicates both a prognostic and predictive value for ctDNA and a prognostic relevance only for concomitant medications and patients’ characteristics.

Understanding, and then modelling, the effects of sowing date and cultivar on maize yield is essential to develop appropriate climate change adaptation strategies. Here we test the WOFOST model and a hybrid model, based on physiological crop conditions around flowering, against observed data collected during 4 years of field experiments in a Mediterranean environment under fully irrigated conditions. We simulate sowing date and cultivar responses by using 45-year historical meteorological records from the experimental weather station and future climate conditions till 2060 as projected by a set of regional climate models. Both WOFOST and the hybrid approach reveal good performance in simulating average maize yield. However, the hybrid one outperforms WOFOST with respect to its responsiveness to changes in sowing date and cultivar. These findings, besides stressing the importance of crop conditions around flowering in determining maize yield, point to lower yields (14 %–17 %, average reduction) under future climate conditions. The estimated losses may only be partially offset by changes in phenology and sowing dates.