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A Consensus Conference of clinicians, researchers, public health specialists and users was convened in Italy to review efficacy, effectiveness, treatment appropriateness and access to care for anxiety and depression, and to consider the role of psychological therapies. Expert opinion was sought concerning identification of people requiring psychological therapies according to levels of symptom severity matched to corresponding levels of treatment intensity, suitability of psychological therapies for subclinical anxiety or depression, definition of a minimum level of information on evidence-based psychotherapies to be provided by university medical and psychology courses, initiatives to raise awareness among potential users and decision makers on the role and effectiveness of psychological therapies in healthcare. The expert jury concluded that a number of psychological therapy models endorsed by most authoritative guidelines are supported by research showing their effectiveness at least equal to the drugs used in common mental disorders (CMDs). Such therapies are under-represented in the Italian public health system, leading many people to resort to the private sector, resulting in unacceptable wealth discrimination. The difficulty of accessing psychological treatments often entails the use of drug therapies in cases where they are not indicated. Starting from these assumptions, the experts recommended the promotion of better and timely recognition of anxiety and depressive disorders and their classification in terms of symptom intensity and functional impairment, differentiating subthreshold mood swings from clinical forms, to foster outcome studies of psychotherapies in CMDs in Italy, to introduce a stepped care model structured according to levels of intensity of treatment, based on wellbeing support strategies in nonmedical contexts for subthreshold situations, self-help, support and psychoeducation as frontline interventions in mild clinical forms, evidence-based psychotherapies in moderate and severe forms, with the option of combining psychological treatment and appropriate drug therapy in the most severe cases.

This editorial describes the clinical trials related to antidiabetic drugs, most of them following an "add-on" design of where the new drug is added to metformin and the comparative arm is metformin plus placebo. Many drugs are already approved for therapy following this design; the authors believe that it is unethical to continue this trend because it makes it impossible to stratify the many antidiabetic drugs according to their efficacy and toxicity.

Introduction Prevalence of cancer patients is dramatically increasing. We aimed at quantifying the oncology workload generated by each new cancer patient in the two years following first consultation. Methods In this record-based retrospective study, we retrieved data of all newly diagnosed patients treated at the Oncology Department of Udine Academic Hospital between 01.01.2012 and 31.12.2017. We calculated mean number and standard deviation of the activity type generated by each new cancer patient during the following 2 years. Results Seven thousand four hundred fifty-two cancer patients generated a total of 85,338 clinical episodes. The two-years mean number of oncology episodes generated was 11.31 (i.e., for every 1,000 new cancer patients, 11,310 oncology activities are generated overall in the following two-year lapse). Patients with advanced disease generated the highest workload (24.3; SD 18.8) with a statistically significant difference compared to adjuvant and follow-up patients (p p p Conclusion This is the first study reporting on the mean oncology workload generated during the 2 years following first consultation. Workload is the highest for patient with advanced disease, especially in the first months and in patients in active treatment. A detailed analysis of workloads in oncology is feasible and could be crucial for planning a sustainable framework for cancer care in the next future.

IntroductionUp to one-fifth of patients with colorectal cancer will develop peritoneal metastases, frequently without other districts’ involvement. Despite the recent unsuccesses of hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer peritoneal metastases treatment, the rationale in the prophylactic setting remains strong. Several clinical and pharmacokinetic data suggest that the efficacy of intraperitoneal chemotherapy is highest when the disease is microscopic. However, robust evidence demonstrating whether the addition of HIPEC for high-risk colorectal cancers offers better control of local recurrence is lacking.Methods and analysisThis is a multicentre randomised phase 3 trial comparing prophylactic surgery plus HIPEC CO2 with mitomycin, over standard surgical excision in patients with colorectal cancer at high risk of peritoneal carcinomatosis; 388 patients will be included in this study. The primary objective is to compare the efficacy of prophylactic surgery (radical colorectal resection, omentectomy, appendectomy, round ligament of the liver resection and bilateral adnexectomy) plus HIPEC CO2 with mitomycin and standard surgery in terms of local recurrence-free survival. The main secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. The primary endpoint will be described with a cumulative incidence function and will be analysed with Grey test to take account of the competing risks. DFS and OS will be described with the Kaplan-Meier method.Ethics and disseminationThis trial has been evaluated by the Italian Medicines Agency, local ethics committees and will be submitted to the Ministry of Health to notify the start of the trial according to the regulation of trials on devices with CE mark/certification.The results will be submitted for presentation at academic meetings and for publication in a peer-reviewed journal, whatever the findings.Trial registration numberNCT03914820.

Introduction At the time of diagnosis, 15–20% of gastric carcinomas are in stage T4 or T4b. Furthermore, 5–20% of patients undergoing potentially curative surgery suffer from synchronous or metachronous peritoneal metastases. To date, neither surgery nor systemic chemotherapy successfully controls peritoneal dissemination, offering a limited impact on survival. Peritoneal metastases are in fact responsible for death in around 60% of gastric cancer patients. Several Eastern studies in the past have focused on hyperthermic intraperitoneal chemotherapy (HIPEC) as a prophylactic measure in patients with serosal extension, nodal involvement, and positive peritoneal fluid cytology. Therefore, a new multimodal therapeutic strategy based on aggressive surgery plus new locoregional treatment may prolong survival in this particular clinical scenario. Methods This study compares the efficacy of prophylactic surgery (radical gastric resection, appendectomy, resection of the round ligament of the liver, and bilateral adnexectomy) plus hybrid CO2 HIPEC system versus standard surgery in patients with T3-T4 N0-N + gastric adenocarcinoma. Patients will be randomly assigned (1:1 ratio) to the experimental arm or standard surgery. The primary endpoint is to establish the difference in disease-free survival between the groups. The secondary objective is to compare the safety and tolerability of prophylactic surgery plus HIPEC CO2 versus standard surgery. Discussion Considering the poor prognosis of patients with peritoneal dissemination from gastric cancer, a prophylactic strategy to prevent peritoneal metastases may be beneficial. In patients with gastric cancer at high risk of peritoneal carcinomatosis, we propose aggressive surgical treatment with radical gastrectomy, removal of organs at risk of harbouring tumour cells, and HIPEC. Trial registration ClinicalTrials.gov NCT03917173. Registered on 16 April 2019. Protocol version: v1, March 27, 2019. Protocol number: IRFMN-GCC-7813. EudraCT number: 2019–001478-27.

Trastuzumab is a human epidermal growth factor receptor 2 (HER2) inhibitor used to treat HER2+ metastatic gastric cancer (mGC). The present study aims to investigate the relationship between CDH1 mRNA expression and HER2-positivity in mGC using a multiplexed gene expression profile in two series of gastric cancer (GC): Series 1 (n = 38): HER2+ and HER2- mGC; Series 2 (n = 36) HER2- GC with and without metastasis. To confirm the results, the same expression profiles were analyzed in 354 GC from The Cancer Genome Atlas (TCGA) dataset. The difference in gene expression connected HER2 overexpression with canonical wingless-type (Wnt)/β-catenin pathway and immunohistochemical (IHC) expression loss of E-cadherin (E-CAD). CDH1 mRNA expression was simultaneously associated with the rs16260-A variant and an increase in E-CAD expression. Differences in retinoic acid receptor alfa (RARA), RPL19 (coding for the 60S ribosomal L19 protein), catenin delta 1 (CTNND1), and epidermal growth factor (EGF) mRNA levels—all included in the Wnt/β-catenin pathway—were found associated with overall survival (OS). RARA, CTNND1, and EGF resulted in independent OS prognostic factors. EGF was confirmed as an independent factor along with TNM stage in HER2-overpressed mGC from TCGA collection. Our study highlighted factors involved in the WNT/β-catenin pathway that interconnected E-CAD with HER2 overexpression and patient survival.

Background Brain injury and neurological deficit are consequences of cardiac arrest (CA), leading to high morbidity and mortality. Peripheral activation of the kynurenine pathway (KP), the main catabolic route of tryptophan metabolized at first into kynurenine, predicts poor neurological outcome in patients resuscitated after out‐of‐hospital CA. Here, we investigated KP activation in hippocampus and plasma of rats resuscitated from CA, evaluating the effect of KP modulation in preventing CA‐induced neurological deficit. Methods and Results Early KP activation was first demonstrated in 28 rats subjected to electrically induced CA followed by cardiopulmonary resuscitation. Hippocampal levels of the neuroactive metabolites kynurenine, 3‐hydroxy‐anthranilic acid, and kynurenic acid were higher 2 hours after CA, as in plasma. Further, 36 rats were randomized to receive the inhibitor of the first step of KP, 1‐methyl‐DL‐tryptophan, or vehicle, before CA. No differences were observed in hemodynamics and myocardial function. The CA‐induced KP activation, sustained up to 96 hours in hippocampus (and plasma) of vehicle‐treated rats, was counteracted by the inhibitor as indicated by lower hippocampal (and plasmatic) kynurenine/tryptophan ratio and kynurenine levels. 1‐Methyl‐DL‐tryptophan reduced the CA‐induced neurological deficits, with a significant correlation between the neurological score and the individual kynurenine levels, as well as the kynurenine/tryptophan ratio, in plasma and hippocampus. Conclusions These data demonstrate the CA‐induced lasting activation of the first step of the KP in hippocampus, showing that this activation was involved in the evolving neurological deficit. The degree of peripheral activation of KP may predict neurological function after CA.

Therapeutic drug and immunogenicity monitoring (TDIM) is increasingly proposed to guide therapy with biologics, characterised by high inter-individual variability of their blood levels, to permit objective decisions for the management of non-responders and reduce unnecessary interventions with these expensive treatments. However, TDIM has not yet entered clinical practice partly because of uncertainties regarding the accuracy and precision of enzyme-linked immunosorbent assays (ELISA). Here we report the characterisation of a novel surface plasmon resonance (SPR)-based TDIM, applied to the measurement of serum concentrations of infliximab, an antibody against tumour necrosis factor α (anti-TNFα), and anti-infliximab antibodies. SPR has the obvious advantages of directly detecting and measuring serum antibodies in minutes, avoiding the long incubation/separation/washing/detection steps of the methods proposed so far, reducing complexity and variability. Moreover, drug and anti-drug antibodies can be measured simultaneously. This new method was validated for sensitivity and reproducibility, and showed cost-effectiveness over commercial ELISA kits. This method may be applied to other biotherapeutics. These data pave the way for the development of SPR-based point-of-care devices for rapid on-site analysis.

Measurements of serum concentrations of therapeutic antibodies and anti-drug antibodies (ADA) can support clinical decisions for the management of non-responders, optimizing the therapy. In the present study we compared the results obtained by classical ELISA and a recently proposed surface plasmon resonance (SPR)-based immunoassay, in 76 patients receiving infliximab for inflammatory bowel diseases. The two methods indicated very similar serum concentrations of the drug, but there were striking differences as regards ADA. All the sera showing ADA by ELISA (14) also showed ADA by SPR, but the absolute amounts were different, being 7–490 times higher with SPR, with no correlation. Eight patients showed ADA only with SPR, and these ADA had significantly faster dissociation rate constants than those detectable by both SPR and ELISA. The underestimation, or the lack of detection, of ADA by ELISA is likely to reflect the long incubation steps which favor dissociation of the patient’s low-affinity ADA, while the commercial, high-affinity anti-infliximab antibodies used for the calibration curve do not dissociate. This problem is less important with SPR, which monitors binding in real time. The possibility offered by SPR to detect ADA in patients otherwise considered ADA-negative by ELISA could have important implications for clinicians.

Never before has the central role of medicines and other health care interventions for society been so recognized. Europe’s pharmaceutical sector is a major contributor to the European Union’s economy. According to the European Federation of Pharmaceutical Industries and Associations (EFPIA), it contributes with more than €110 billion to the EU trade balance and employs almost 800,000 people across Europe. In 2019, it invested an estimated € 37,500 million in R&D in Europe (European Federation of Pharmaceutical Industries and Associations, 2020). However, despite these investments, the drug market is not without some low-value drugs and alleged innovations, resulting in an excess of public and private spending that could be reduced in favour of other health-related activities. A survey by the independent scientific journal Prescrire found that only 10% of the new authorisations in 2019 presented a notable therapeutic advance (Prescrire, 2020), a view shared by the German Institute for Quality and Efficiency in Health Care (IQWiG) (Wieseler et al., 2019). On 25 November 2020, in the midst of the COVID-19 pandemic, the European Commission adopted a new “Pharmaceutical strategy for Europe,” after intense rounds of consultation with stakeholders and the public between July and September 2020. This pharmaceutical strategy “aims to ensure the quality and safety of medicines, while boosting the sector’s global competitiveness” (European Commission, 2020a). It is a roadmap based on four specific pillars (Table 1), an inventory of actions. Some will make the legislative cut by the end of the current European Commission’s term. Unquestionably, this document offers an opportunity for thorough reflection on drug development, regulation, and policies. TABLE 1 Pillars of the pharmaceutical strategy and key proposals.

There is a need of comparative studies to understand the differences in term of efficacy and safety of drugs with different mechanisms of action but similar therapeutic indications. This requires changes in the European Legislation of criteria for drug approval.

Objective:Previous studies from European countries noted that food products promoted on TV for children did not comply with international guidelines, including the World Health Organization European Nutrient Profile Model (WHO-ENPM) and the EU Pledge Nutrition Criteria (EU-PNC, an initiative developed by leading food companies). We aim to provide new data from Italy.Design:Evaluation of Italian TV advertisements. Data on nutritional values for food product advertised were compared with nutritional standards issued by the WHO-ENPM and the EU-PNC.Setting:In total, 180 h of TV programmes from six Italian channels, 2016–2017.Participants:Eight hundred and ten consecutive advertisements during children’s programmes.Results:Out of 810 advertisements, 90 (11·1 %) referred to food products. Among these, 84·5 % of the foods promoted did not meet the WHO-ENPM and 55·6 % the EU-PNC guidelines. Advertisements promoting sweet and salty snacks (i.e. ≥ 70 % of all foods) v. other food products showed higher non-compliance with both the WHO-ENPM (OR: 73·8; 95 % CI: 4·09, 1330) and the EU-PNC (OR: 9·21; 95 % CI: 2·82, 30·1).Conclusions:In Italy, most food advertisements during children’s programmes are not compliant with European nutritional standards. Almost all the advertisements for snacks do not meet international guidelines. As the WHO-ENPM guidelines do not propose standards for all the food products, including meals, there is an urgent need to define independent and easy-to-read guidelines for food advertisements targeting children. As a first step towards the complete ban of food advertisements targeting children recommended by other researchers, these guidelines should be enforced by all the TV broadcasts.

Today, personalized medicine is essentially based on individual “omics.” However there is a need to integrate this approach with a number of data such as pharmacokinetics, optimal dose and duration of drug treatments, age and gender differences, and drug interactions, which are relevant in terms of benefits and risks but are frequently unknown. This requires independent research that should be supported by governments in order to make personalized medicine a reality.

Background Pulmonary arterial hypertension (PAH) is a life-threatening rare disease. Between 2001 and 2016 the European Medicines Agency (EMA) approved nine drugs to treat PAH. Considering the poor prognosis of patients with PAH it would be useful to understand whether the approved therapies can change the natural history of the disease. We assessed the therapeutic value and the quality of the evidence on medicines that have been authorized by the EMA in the 2000s. Methods Information about drug approval was obtained from the EMA website and the European Public Assessment Reports. MedLine, Embase, and Cochrane databases were systematically searched for published randomized clinical trials and meta-analyses of the selected drugs and their combinations. Results At the time of approval no medicine had been proved to reduce mortality or slow the progression of the disease or to improve patients' quality of life. Recent meta-analyses concluded that, compared to placebo, active treatments reduced mortality but there was no conclusion on any preferred therapeutic option. Approvals of monotherapies in the absence of best evidence of their efficacy, have prompted the search for better efficacy of their combinations. Three meta-analyses found no advantage in survival from combinations as opposed to monotherapies. Conclusions This model case confirms previous analyses that marketing authorizations granted in spite of low evidence of therapeutic efficacy not only expose patients to treatments with unknown benefit-risk profiles but also hamper post-marketing research aimed at filling the information gap.

There is a need of comparative studies to understand the differences in term of efficacy and safety of drugs with different mechanisms of action but similar therapeutic indications. This requires changes in the European Legislation of criteria for drug approval

Background Medical devices play an important role in the diagnosis, prevention, treatment and care of diseases. However, compared to pharmaceuticals, there is no rigorous formal regulation for demonstration of benefits and exclusion of harms to patients. The medical device industry argues that the classical evidence hierarchy cannot be applied for medical devices, as randomised clinical trials are impossible to perform. This article aims to identify the barriers for randomised clinical trials on medical devices. Methods Systematic literature searches without meta-analysis and internal European Clinical Research Infrastructure Network (ECRIN) communications taking place during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. Results In addition to the barriers that exist for all trials, we identified three major barriers for randomised clinical trials on medical devices, namely: (1) randomisation, including timing of assessment, acceptability, blinding, choice of the comparator group and considerations on the learning curve; (2) difficulties in determining appropriate outcomes; and (3) the lack of scientific advice, regulations and transparency. Conclusions The present review offers potential solutions to break down the barriers identified, and argues for applying the randomised clinical trial design when assessing the benefits and harms of medical devices. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2168-0) contains supplementary material, which is available to authorized users.

Introduction The approval or rejection of scientific publications can have important consequences for scientific knowledge, so considerable responsibility lies on those who have to assess or review them. Today it seems that the peer review process, far from being considered an outdated system to be abandoned, is experiencing a new upturn. Aim and methods This article proposes criteria for the conduct of reviewers and of those who select them. While commenting on new emerging models, it provides practical recommendations for improving the peer-review system, like strengthening the role of guidelines and training and supporting reviewers. Conclusions The process of peer review is changing, it is getting more open and collaborative, but those same ethical principles which guided it from its very origin should remain untouched and be firmly consolidated. The paper highlights how the ethics of reviewing scientific publications is needed now more than ever, in particular with regard to competence, conflict of interest, willingness to discuss decisions, complete transparency and integrity.

The Food and Drug Administration (FDA) and European Medicines Agency (EMA) now have expedited review procedures for new drugs. We compared the review times of medicines licensed by the 2 agencies and explored differences in the evidence submitted. In 2015-2017 the FDA licensed 113 drugs, 66 of which reached Europe. The median review time was longer at the EMA than FDA and was shorter for drugs undergoing FDA-expedited programmes compared to the same drugs approved by the EMA through the standard procedure. We identified differences regarding the evidence submitted to the 2 regulators for 7 drugs. The greater use of expedited programmes by the FDA and administrative time at the European Commission mainly explain the later access of new drugs to the European market. The additional evidence submitted to the EMA is generally scant and limited to a few drugs.

To review the marketing authorization of biosimilars and provide a critical analysis of the pivotal trials supporting their approval by the European Medicines Agency (EMA). EMA website to identify the biosimilars approved up to July 2019 and the European Public Assessment Report for information on pivotal trial design, duration, intervention and control, primary outcome, data on immunogenicity, and comparability margins. The EMA has approved 55 biosimilars (62% in 2017–2019) of 16 biologic products, used in several clinical indications. Some biosimilars were licensed as multiple products, with different commercial names, by the same or different companies. The comparability exercise and subsequent approval of 49/55 (89%) biosimilars were based on one or more pivotal phase III trials testing their clinical efficacy. In all, biosimilars were approved on the basis of 55 trials, mostly phase III (42/55, 76%) assessing clinical efficacy; these were mainly equivalence trials (31/55, 56%). The pivotal phase III trials assessed surrogate measures of clinical effect, and 71% reported immunogenicity data. Analysis of the approval of biosimilars in Europe depicts a complex and heterogeneous scenario. The requirement for showing similarity in terms of clinical efficacy and safety provides a robust demonstration of comparable clinical outcomes but lays a burden on biosimilar manufacturers and may delay the introduction of the drugs. The development, licensing, and monitoring of biosimilars would benefit from new strategies to accelerate access to these drugs while reducing uncertainties about their use in practice.

Different de-escalation strategies have been proposed to limit the risk of cumulative toxicity and guarantee quality of life during the treatment trajectory of patients with metastatic colorectal cancer (mCRC). Programmed treatment interruptions, defined as drug holidays (DHs), have been implemented in clinical practice. We evaluated the association between DHs and overall survival (OS). This was a retrospective study, conducted at the University Hospital of Udine and the IRCCS CRO of Aviano. We retrieved records of 608 consecutive patients treated for mCRC from 1 January 2005 to 15 March 2017 and evaluated the impact of different de-escalation strategies (maintenance, DHs, or both) on OS through uni- and multivariate Cox regression analyses. We also looked at attrition rates across treatment lines according to the chosen strategy. In our study, 19.24% of patients received maintenance therapy, 16.12% DHs, and 9.87% both, while 32.07% continued full-intensity first-line treatment up to progression or death. In uni- and multivariate analyses first-line continuous treatment and early discontinuation (treatment for less than 3 months) were associated to worse OS compared to non-continuous strategies (HR, 1.68, 95% CI, 1.22–2.32, p = 0.002 and HR,4.89, 95% CI, 3.33–7.19, p &lt, 0.001, respectively). Attrition rates were 22.8%, 20.61%, and 19.64% for maintenance, DHs, or both, respectively. For continuous therapy and for treatment of less than 3 months it was 21.57% and 49%. De-escalation strategies are safe and effective options. DHs after initial induction chemotherapy may be considered in clinically selected patients with metastatic colorectal cancer.

Since patients with advanced gastric cancer (GC), a worldwide leading cause of cancer-related death, still have a dismal prognosis and a very limited 5-year life expectancy, novel treatment options are urgently needed. Although novel molecular classifications may help identifying potential targets, we have not reached major breakthroughs. The role of antiangiogenic strategy has recently contributed to reshape the overall management of advanced GC. Despite bevacizumab, the first clinically available VEGF-inhibitor, failed to provide convincing results in this disease, researchers did not give up. Ramucirumab, a recombinant monoclonal antibody that potently blocks VEGFR-2, was approved for clinical use based on the results of REGARD and RAINBOW studies. Apatinib, a novel orally active VEGFR-2 tyrosine kinase inhibitor, was lately tested in Chinese patients who had previously failed at least 2 systemic chemotherapies. In a recently published phase III, randomized, placebo-controlled trial, apatinib compared favorably to placebo in 273 heavily pretreated patients, and produced a 2-month increase in median overall survival (OS). Despite noteworthy, whether these results are practice changing and which degree of innovation they bring to the scientific community is still uncertain. Hopefully, ongoing studies will bring us the final picture in the near future.

Consideration of drug benefits and harms is asymmetric. Approval of drugs is mainly based on efficacy, while the assessment of their safety is left to post-marketing commitments or spontaneous reporting. Benefits are overestimated as a result of pharmaceutical companies' advertisements, the paucity of independent information, and the scant understanding of the effectiveness of medicines in real life. Polypharmacy in older adults-even during the last period of their life-reflects the tendency to assign priority to efficacy and overlook harms, although nobody knows what happens when three or more drugs are given chronically. Medical journals and public research funding projects do not pay enough attention to drug toxicity. We call for a sense of purpose by all those involved in medicine to tackle this problem. European and national agencies and health authorities should promote and support independent information and experimental and clinical studies on drug toxicity. Information should rely not just on spontaneous reporting but also on active pharmacovigilance. The benefit-harm profile of drugs should be periodically reviewed in the light of toxic effects that come to light over the years. Potential interactions within polytherapies should be sought by re-assessing the pharmacokinetics and pharmacodynamics of their components.