Browsing by Subject "SAFETY"

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  • Rantanen, Jorma; Lehtinen, Suvi; Valenti, Antonio; Iavicoli, Sergio (2017)
    Background: The United Nations General Assembly (UNGA), the International Labour Organization (ILO), the World Health Organization (WHO), the International Commission on Occupational Health (ICOH), and the European Union (EU) have encouraged countries to organize occupational health services (OHS) for all working people irrespective of the sector of economy, size of enterprise or mode of employment of the worker. The objective of this study was to survey the status of OHS in a sample of countries from all continents. Methods: A questionnaire focusing on the main aspects of OHS was developed on the basis of ILO Convention No. 161 and several other questionnaire surveys used in various target groups of OHS. The questionnaire was sent to 58 key informants: ICOH National Secretaries. Results: A total of 49 National Secretaries responded (response rate 84.5%), from countries that employ 70% of the total world labour force. The majority of the respondent countries, 67%, had drawn up an OHS policy and implement it with the help of national occupational safety and health (OSH) authorities, institutes of occupational health or respective bodies, universities, and professional associations. Multidisciplinary expert OHS resources were available in the majority (82%) of countries, but varied widely in quantitative terms. The average OHS coverage of workers was 24.8%, with wide variation between countries. In over two thirds (69%) of the countries, the content of services was mixed, consisting of preventive and curative services, and in 29% preventive only. OHS financing was organized according to a mixed model among 63% and by employers only among 33% of the respondents. Conclusions: The majority of countries have drawn up policies, strategies and programmes for OHS. The infrastructures and institutional and human resources for the implementation of strategies, however, remain insufficient in the majority of countries (implementation gap). Qualitatively, the content and multidisciplinary nature of OHS corresponds to international guidance, but the coverage, comprehensiveness and content of services remain largely incomplete due to a lack of infrastructure and shortage of multiprofessional human resources (capacity gap). The estimated coverage of services in the study group was low; only a quarter of the total employed population (coverage gap).
  • Li, Xia; Frechen, Sebastian; Moj, Daniel; Lehr, Thorsten; Taubert, Max; Hsin, Shih-hsuan; Mikus, Gerd; Neuvonen, Pertti J; Olkkola, Klaus; Saari, Teijo; Fuhr, Uwe (2020)
    Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim(R). The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (C-max), and trough concentrations for multiple dosings (C-trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregateC(max)ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregateC(max)ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to <5-6 mg/L forC(trough), while 400 mg twice daily might be more suitable for rapid metabolizers (RMs; *1/*17, *17/*17) and normal metabolizers (NMs; *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model. Conclusions Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies.
  • Hjortsberg, Catharina; Bergman, Annika; Bjarnason, Anton; Heikkila, Hannele; Rielmgren, Jonas; Svensson, Ake; Tennvall, Gunnel Ragnarson (2011)
  • Sullivan, Samaah M.; Broyles, Stephanie T.; Barreira, Tiago V.; Chaput, Jean-Philippe; Fogelholm, Mikael; Hu, Gang; Kuriyan, Rebecca; Kurpad, Anura; Lambert, Estelle V.; Maher, Carol; Maia, Jose; Matsudo, Victor; Olds, Tim; Onywera, Vincent; Sarmiento, Olga L.; Standage, Martyn; Tremblay, Mark S.; Tudor-Locke, Catrine; Zhao, Pei; Katzmarzyk, Peter T.; ISCOLE Res Grp (2017)
    We investigated whether associations of neighborhood social environment attributes and physical activity differed among 12 countries and levels of economic development using World Bank classification (low/lower-middle-, upper-middle- and high- income countries) among 9-11 year old children (N=6161) from the International Study of Childhood Obesity, Lifestyle, and the Environment (ISCOLE). Collective efficacy and perceived crime were obtained via parental/guardian report. Moderate-to-vigorous physical activity (MVPA) was assessed with waist-worn Actigraph accelerometers. Neighborhood environment by country interactions were tested using multi-level statistical models, adjusted for covariates. Effect estimates were reported by country and pooled estimates calculated across World Bank classifications for economic development using meta-analyses and forest plots. Associations between social environment attributes and MVPA varied among countries and levels of economic development. Associations were more consistent and in the hypothesized directions among countries with higher levels economic development, but less so among countries with lower levels of economic development.
  • Bonaros, Nikolaos; Kofler, Markus; Frank, Derk; Cocchieri, Riccardo; Jagielak, Dariusz; Aiello, Marco; Lapeze, Joel; Laine, Mika; Chocron, Sidney; Muir, Douglas; Eichinger, Walter; Thielmann, Matthias; Labrousse, Louis; Bapat, Vinayak; Rein, Kjell Arne; Verhoye, Jean-Philippe; Gerosa, Gino; Baumbach, Hardy; Deutsch, Cornelia; Bramlage, Peter; Thoenes, Martin; Romano, Mauro (2018)
    Objective: It has been reported that balloon aortic valvuloplasty immediately before transfemoral or transapical transcatheter aortic valve implantation has mostly little to no clinical value. We aimed to provide data on the need for balloon aortic valvuloplasty in patients undergoing transaortic transcatheter aortic valve implantation. Methods: Patients undergoing transaortic transcatheter aortic valve implantation with the Edwards SAPIEN XT (Nyon, Switzerland) or 3 transcatheter heart valve were prospectively included at 18 sites across Europe. In the present analysis, we compare the periprocedural and 30-day outcomes of patients undergoing conventional (thorn balloon aortic valvuloplasty) versus direct (-balloon aortic valvuloplasty) transaortic transcatheter aortic valve implantation. Results: Of the 300 patients enrolled, 222 underwent conventional and 78 underwent direct transaortic transcatheter aortic valve implantation. Peak and mean transvalvular gradients were improved in both groups with no significant difference between groups. Procedural duration, contrast agent volume, and requirement for postdilation were also comparable. A trend toward fewer periprocedural complications was evident in the direct group (3.9% vs 11.3%; P = .053), with significantly lower rates of permanent pacemaker implantation (0% vs 5.0%; P = .034). Balloon aortic valvuloplasty omission had no significant effect on any of the 30-day safety and efficacy outcomes, including Valve Academic Research Consortium-2 composite end points (early safety events: 22.7% vs 17.4%, odds ratio, 1.17, 95% confidence interval, 0.53-2.62; clinical efficacy events: 20.5% vs 18.7%, odds ratio, 1.14, 95% confidence interval, 0.51-2.55). Conclusions: For many patients, balloon aortic valvuloplasty predilation seems to have little clinical value in transaortic transcatheter aortic valve implantation using a balloon expandable transcatheter valve and may result in a higher rate of periprocedural complications, particularly in terms of permanent pacemaker implantation.
  • Lakanmaa, Riitta-Liisa; Suominen, Tarja; Ritmala-Castren, Marita; Vahlberg, Tero; Leino-Kilpi, Helena (2015)
    Critical care patients benefit from the attention of nursing personnel with a high competence level. The aim of the study was to describe and evaluate the self-assessed basic competence of intensive care unit nurses and related factors. A cross-sectional survey design was used. A basic competence scale (Intensive and Critical Care Nursing Competence Scale version 1, Likert scale 1-5, 1 = poor and 5 = excellent) was employed among Finnish intensive care unit nurses (n = 431). Intensive care unit nurses' self-assessed basic competence was good (mean 4.19, SD 0.40). The attitude and value base of basic competence was excellent whereas experience base was the poorest compared to the knowledge base and skill base of intensive and critical care nursing. The strongest factor explaining nurses' basic competence was their experience of autonomy in nursing care (F value 60.85, beta 0.11, SE 0.01, and P
  • Cavalli, Emma; Levinson, Clara; Hertl, Matthias; Broguiere, Nicolas; Brück, Oscar; Mustjoki, Satu; Gerstenberg, Anja; Weber, Daniel; Salzmann, Gian; Steinwachs, Matthias; Barreto, Goncalo; Zenobi-Wong, Marcy (2019)
    Treating cartilage injuries and degenerations represents an open surgical challenge. The recent advances in cell therapies have raised the need for a potent off-the-shelf cell source. Intra-articular injections of TGF-beta transduced polydactyly chondrocytes have been proposed as a chronic osteoarthritis treatment but despite promising results, the use of gene therapy still raises safety concerns. In this study, we characterized infant, polydactyly chondrocytes during in vitro expansion and chondrogenic redifferentiation. Polydactyly chondrocytes have a steady proliferative rate and re-differentiate in 3D pellet culture after up to five passages. Additionally, we demonstrated that polydactyly chondrocytes produce cartilage-like matrix in a hyaluronan-based hydrogel, namely transglutaminase cross-linked hyaluronic acid (HA-TG). We utilized the versatility of TG cross-linking to augment the hydrogels with heparin moieties. The heparin chains allowed us to load the scaffolds with TGF-beta 1 which induced cartilage-like matrix deposition both in vitro and in vivo in a subcutaneous mouse model. This strategy introduces the possibility to use infant, polydactyly chondrocytes for the clinical treatment of joint diseases.
  • Vuorinen, Aino-Maija; Pakarinen, Sami; Jaakkola, Ilkka; Holmström, Miia; Kivisto, Sari; Kaasalainen, Touko (2019)
    Background Magnetic resonance imaging (MRI) in patients with cardiac pacing devices has become available despite previously being considered absolutely contraindicated. However, most institutional safety protocols have included several limitations on patient selection, leaving MRI unavailable for many patients. Purpose To evaluate the first 1000 MRI examinations conducted on patients with cardiac pacing devices at Helsinki University Hospital for any potential safety hazards and also to evaluate the long-term functionality of the safety protocol in "real-life" clinical practice. Material and Methods A total of 1000 clinically indicated MRI scans were performed with a 1.5-T MRI scanner according to the safety protocol. The following information was collected from the electronic medical record (EMR): patients' date of birth; sex; pacing device generator model; date of MRI scan; date of the latest pacing device generator implantation; and the body region scanned. The EMR of these patients was checked and especially searched for any pacing device related safety hazards or adverse outcomes during or after the MRI scan. Results Only one potentially dangerous adverse event was noted in our study group. In addition, patients with abandoned leads, temporary pacing devices, and newly implanted pacing device generators were scanned successfully and safely. Conclusion MRI scans can be performed safely in patients with cardiac pacing devices if the dedicated safety protocol is followed.
  • Törmä, K.; Fredriksson-Ahomaa, M.; Lunden, J. (2019)
    Small-scale slaughterhouses (SHs) face many challenges, not least due to the requirements of food safety legislation. Food business operators' (FBOs') own-check system is very important for food safety, but its proper implementation can be quite difficult and laborious for small-scale SHs. In the European Union, the importance not only of food safety but also facilitation of local food production, including small-scale slaughtering, is highlighted. The aim of our study was to assess compliance with legislation of own-check systems, including six own-check programmes and HACCP, in small-scale SHs. The FBOs' opinions of the implementation of own-check systems were also sought to elucidate possible obstacles in implementation. Our results showed that the best compliance in own-check programmes was achieved in temperature of storage rooms and traceability. FBOs also evaluated these programmes as necessary. However, FBOs' perceived necessity of own-check programmes did not always lead to compliance, as was the case with labelling and HACCP. Instead, in HACCP laboriousness and compliance showed a negative correlation (p <0.05). In addition to laboriousness, costs of own-check programmes, specifically concerning microbiological sampling requirements, appeared to influence compliance, with many of the small-scale SHs poorly following sampling requirements. FBOs also noted the high costs of the non-edible by-product programme. Moreover, the results show that official veterinarians' assessment of compliance was significantly higher than that of the researcher, which warrants further investigation. This study reveals that many small-scale SHs in Finland struggle with food safety requirements. Amendments of some of the requirements to ease the burden of FBOs are proposed. HACCP in particular is suggested to be simplified. In addition, ways to improve food safety and official control in small-scale SHs are discussed.
  • Kettunen, Karoliina; Pesonen, Susanna; Lunden, Janne; Nevas, Mari (2018)
    Consistency and risk-basis are core elements of effective enforcement of food safety legislation. In Finland, inspections of food retail premises have been conducted since 2013 based on new national guidelines for evaluation and grading. According to the guidelines, food control authorities should initiate an administrative enforcement process to ensure compliance if the food business operator (FBO) is given the poorest grade in the inspection. In this study, we examined the consistency within and between local food control units on the threshold of initiating an enforcement process. The study was conducted through an analysis of inspection reports of FBOs and by an electronic survey and interviews of local food control officials. The results reveal that most officials consider the national evaluation guidelines as helpful in improving the consistency of using enforcement measures. However, inconsistencies exist between and within the local food control units in the alignments of initiating an enforcement process. Enforcement measures are mainly used on a risk-basis and gradually, as in most enforcement cases the FBO had multiple non-compliances and the FBO had been given a prior request to correct the non-compliance before initiating an enforcement process. The results, however, revealed rather weak compliance and repeated violations among some FBOs. Based on the observed persistence of non -compliances and the efficacy of enforcement measures in inducing compliance, a lower threshold of initiating an enforcement process towards FBOs with repeated violations appears beneficial in enhancing the correction of violations. Increasing the consistency of the enforcement process begins with unifying the practices within the local food control units by establishing clear procedures for enforcement and ensuring adequate orientation of personnel. Further strengthening of cooperation, peer-review and discussion on interpretations of required control actions between the units is needed for nationally consistent implementation of the evaluation and disclosure system and use of enforcement measures. (C) 2017 Elsevier Ltd. All rights reserved.
  • Puhakka, Riikka; Ollila, Sari; Valve, Raisa; Sinkkonen, Aki Tapio (2019)
    A health effect is a credence quality feature which is difficult for consumers to detect, and they need to be convinced of its trustworthiness. This study explores the role of trust-related arguments in Finnish, German, and British consumers' willingness to try a novel health-enhancing, non-edible product. Scientific evidence in particular would convince consumers, particularly Finnish ones, to try a product. Receiving recommendations from other users was more important for younger than for older respondents when it came to trying this type of product. Different marketing strategies may be needed to convince potential users of the benefits of a novel product.
  • Huoponen, Saara; Aaltonen, Kalle J.; Viikinkoski, Jaana; Rutanen, Jarno; Relas, Heikki; Taimen, Kirsi; Puolakka, Kari; Nordström, Dan; Blom, Marja (2019)
    Objectives The objective of this study was to evaluate the cost-effectiveness of abatacept, tocilizumab, and tumor necrosis factor (TNF) inhibitors as compared with rituximab in Finnish rheumatoid arthritis patients, who have previously been treated with TNF inhibitors. Methods A patient-level simulation model was developed to predict costs and outcomes associated with four biological drugs (abatacept, tocilizumab, rituximab and TNF inhibitors) in the treatment of rheumatoid arthritis. Following lack of efficacy or adverse events, the patients were switched to another biological drug until all four options were exhausted. After that, the patients were assumed to receive a 6th line treatment until death. The patients' baseline characteristics and regression models used in the simulation were based on observational data from the National Register for Biological Treatments in Finland. Direct costs comprised drug costs, administration costs, costs of switching, and outpatient and inpatient care, while indirect costs included disability pension and sick leaves due to rheumatoid arthritis. Several subgroup and deterministic sensitivity analyses were conducted. Results Drug costs were the lowest for rituximab, but when administration costs and costs of switching were included, drug costs were the lowest for TNF inhibitors. Abatacept was associated with the highest drug costs, whereas rituximab was associated with the highest healthcare costs. In total, TNF inhibitors had the lowest direct costs, while rituximab had the highest direct costs. The amount of quality-adjusted life years (QALY) gained ranged from 9.405 for rituximab to 9.661 for TNF inhibitors. TNF inhibitors, abatacept, and tocilizumab were dominant in comparison to RTX. Conclusions TNF inhibitors, abatacept, and tocilizumab had lower costs and higher QALYs than rituximab, and therefore, they were dominant in comparison to rituximab. As TNF inhibitors had the lowest costs and highest QALYs, they were the most cost-effective treatment option.
  • EFSA Panel Dietetic Prod Nutr; Heinonen, Marina (2017)
    Following an application from Suomen Terveysravinto Oy, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Finland, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to curcumin and normal functioning of joints. The food that is proposed as the subject of the health claim is curcumin. The Panel considers that curcumin is sufficiently characterised. The claimed effect proposed by the applicant is 'normal functioning of joints by reducing the biomarkers of inflammation'. The target population proposed by the applicant is the general population. Upon a request from EFSA to clarify whether the claimed effect is related to the normal function of joints or rather to the reduction of inflammation, the applicant did not address this issue in the reply. The Panel assumes that the claimed effect refers to the maintenance of joint function. The Panel considers that maintenance of joint function is a beneficial physiological effect. The Panel considers that no conclusions can be drawn from 15 human intervention studies conducted in patients with osteoarthritis or rheumatoid arthritis and from one study in obese subjects on serum cytokines for the scientific substantiation of the claim. In the absence of evidence for an effect of curcumin on the normal function of joints in humans, the results of the human studies on curcumin pharmacokinetics, safety and mechanistic studies, the animal studies and the in vitro studies submitted by the applicant cannot be used as a source of data for the scientific substantiation of the claim. The Panel concludes that a cause and effect relationship has not been established between the consumption of curcumin and maintenance of joint function. (C) 2017 European Food Safety Authority.
  • Pesonen, Ida; Carlson, Lisa; Murgia, Nicola; Kaarteenaho, Riitta; Skold, Carl Magnus; Myllärniemi, Marjukka; Ferrara, Giovanni (2018)
    Background: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive loss of lung function with high mortality within the first 5 years from diagnosis. In 2011-2014, two drugs, pirfenidone and nintedanib, have been approved worldwide for prevention of IPF progression. National IPF-registries have been established in both Finland and Sweden. Our study explored potential differences in the care of IPF in these two countries. Methods: Patients included consecutively in the Finnish and Swedish IPF-registries from January 1, 2014 through December 31, 2016 were included in the study. Data on demographics and lung function at the time of inclusion were collected. Access to antifibrotic drugs and data on disease outcomes, mortality and the proportion of patients who underwent lung transplantation, was collected during a 3-year follow up. Results: One-hundred and fifty-two patients from the Finnish and 160 patients from the Swedish IPF-cohorts were included in the study. At inclusion, Finnish patients were significantly older than the Swedish patients (74.6 years vs 72.5 years, p = 0.017). The proportion of non-smokers was significantly higher in the Finnish cohort (41.7% vs 26.9%, p = 0.007). Forced vital capacity (FVC), % of predicted (78.2 vs 71.7 for Finnish and Swedish patients, respectively, p = 0.01) and diffusion capacity for carbon monoxide (DLCO), % of predicted (53.3 vs 48.2 for Finnish and Swedish patients, respectively, p = 0.002) were significantly higher in the Finnish cohort compared to the Swedish cohort at the time of inclusion. During the 3-year follow up period, 45 (29.6%) Finnish and 111 (69.4%) Swedish patients, respectively, were initiated on treatment with an antifibrotic drug (pirfenidone or nintedanib) (p <0.001). When comparing possible determinants of treatment, patients with higher FVC % were less likely to start antifibrotic drugs (OR 0.96, 95% CI 0.93-1.00, p <0.024). To be resident in Sweden was the main determinant for receiving antifibrotic drugs (OR 5.48, 95% CI 2.65-11.33, p <0.0001). No significant difference in number of deaths and lung transplantation during the follow up period was found. Conclusions: This study highlights differences concerning how IPF patients are treated in Finland and Sweden. How these differences will influence the long-term outcome of these patients is unknown.
  • Luukkanen, Jenni; Nevas, Mari; Fredriksson-Ahomaa, Maria; Lundén, Janne (2018)
    In the European Union, competent authorities are obligated to arrange audits to ensure that the official control (comprising meat and food safety inspections) in slaughterhouses is performed according to legislation. Previous information on the functionality of these audits and on non-conformities observed in the official control of slaughterhouses is limited. In this study, non-conformities of the official control of slaughterhouses and their correction were analysed from the internal audit reports of the Finnish Food Safety Authority Evira. To further assess the benefits and needs for improvement of the audits, we conducted interviews with the chief official veterinarians (OVs) responsible for the controls in slaughterhouses and the auditors of Evira. According to our results, non-conformities, especially in the inspection of intestines of bovines and swine, were common. Regarding food safety inspections, OVs should develop their documentation, perform the follow-up of the correction of non-compliances more systematically, and improve the enforcement, especially in smaller red meat slaughterhouses. Based on our results, internal audits appeared to be beneficial, as non-conformities in the official control were noticed, most non-conformities were corrected or corrective measures had been taken, and the audits were assessed as necessary by both the auditors and auditees. Our results can be utilized in improving the official control and audit procedures in slaughterhouses. In the future, the uniformity of meat inspection could be improved by auditing also differences in the rejections and their reasons between official auxiliaries in post-mortem inspection.
  • Jansen, Y. J. L.; Rozeman, E. A.; Mason, R.; Goldinger, S. M.; Foppen, M. H. Geukes; Hoejberg, L.; Schmidt, H.; van Thienen, J.; Haanen, J. B. A. G.; Tiainen, L.; Svane, I. M.; Mäkelä, S.; Seremet, T.; Arance, A.; Dummer, R.; Bastholt, L.; Nyakas, M.; Straume, O.; Menzies, A. M.; Long, G.; Atkinson, Jeffrey; Blank, C. U.; Neyns, B. (2019)
    Background Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. Patients and Methods This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N=167) or nivolumab (N=18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. Results Median time on treatment was 12months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. Conclusions In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients. Clinical trial registration NCT02673970 (https://clinicaltrials.gov/ct2/show/NCT02673970?cond=melanoma&cntry=BE&city=Jette&rank=3)
  • Joensuu, Heikki; Blay, Jean-Yves; Comandone, Alessandro; Martin-Broto, Javier; Fumagalli, Elena; Grignani, Giovanni; Del Muro, Xavier Garcia; Adenis, Antoine; Valverde, Claudia; Pousa, Antonio Lopez; Olivier, Bouche; Italiano, Antoine; Bauer, Sebastian; Barone, Carlo; Weiss, Claudia; Crippa, Stefania; Camozzi, Maura; Castellana, Ramon; Le Cesne, Axel (2017)
    Background: This multicentre phase II trial (DOVIGIST) evaluated the antitumour activity of dovitinib as second-line treatment of patients with gastrointestinal stromal tumour (GIST) refractory to imatinib or who do not tolerate imatinib. Methods: Patients received oral dovitinib 500 mg day(-1), 5 days on/2 days off, until GIST progression or unacceptable toxicity, with an objective to evaluate efficacy, assessed as the disease control rate (DCR) at 12 weeks. Tumour assessment and response to dovitinib therapy were evaluated by Response Evaluation Criteria In Solid Tumours (RECIST v1.1) and the Choi criteria. Secondary objectives included assessment of progression-free survival (PFS), safety and tolerability, and DCR at the end of treatment. Results: Thirty-eight of the 39 patients enrolled had histologically confirmed GIST. The DCR at 12 weeks was 52.6% (90% confidence interval (CI), 38.2-66.7%) meeting the preset efficacy criterion for the primary end point. The objective response rate (complete response+partial response) was 2.6% (1 of 38; 90% CI, 0.1-11.9%), and 5.3% (n = 2; 90% CI, 0.9-15.7%) at the end of the study. The median PFS was 4.6 months (90% CI, 2.8-7.4 months). Dose interruption was required in 26 patients (66.7%), of which 18 (69.2%) were due to adverse events. The most frequently observed grade 3 adverse events included hypertension (n = 7), fatigue (n = 5), vomiting (n = 4), hypertriglyceridaemia (n = 4), and gamma-glutamyltransferase increase (n = 4). Conclusions: Dovitinib is an active treatment for patients with GIST who are intolerant to imatinib or whose GIST progresses on imatinib.
  • NEO-RACo Study Group; Rantalaiho, Vappu; Sandström, Tia; Koski, Juhani; Hannonen, Pekka; Mottonen, Timo; Kaipiainen-Seppänen, Oili; Yli-Kerttula, Timo; Kauppi, Markku J.; Uutela, Toini; Malmi, Timo; Julkunen, Heikki; Laasonen, Leena; Kautiainen, Hannu; Leirisalo-Repo, Marjatta (2019)
    Objective The short-term outcomes of remission-targeted treatments of rheumatoid arthritis (RA) are well-established, but the long-term success of such strategies is speculative, as is the role of early add-on biologics. We assessed the 10-year outcomes of patients with early RA treated with initial remission-targeted triple combination of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), 7.5-mg prednisolone, and additional infliximab (IFX) or placebo infusions. Methods Ninety-nine patients with early, DMARD-naive RA were treated with a triple combination of csDMARDs and prednisolone and randomized to double-blind receipt of infusions of either IFX (the Finnish Rheumatoid Arthritis Combination Therapy Trial [FIN-RACo] + IFX) or placebo (FIN-RACo + placebo) during the first 6 months. After 2 years, the treatment strategies became unrestricted, but the treatment goal was strict remission in the TNF-Blocking Therapy in Combination With Disease-Modifying Antirheumatic Drugs in Early Rheumatoid Arthritis (NEO-RACo) study. At 10 years, the clinical and radiographic outcomes and the drug treatments used between 5 and 10 years were assessed. Results Ninety patients (91%) were followed after 2 years, 43 in the FIN-RACo + IFX and 47 in the FIN-RACo + placebo group. At 10 years, the respective proportions of patients in strict NEO-RACo remission and in Disease Activity Score using 28 joints remission in the FIN-RACo + IFX and FIN-RACo + placebo groups were 46% and 38% (P = 0.46) and 82% and 72% (P = 0.29), respectively. The mean total Sharp/van der Heijde score was 9.8 in the FIN-RACo + IFX and 7.3 in the FIN-RACo + placebo group (P = 0.34). During the 10-year follow-up, 26% of the FIN-RACo + IFX group and 30% of the FIN-RACo + placebo group had received biologics (P = 0.74). Conclusion In early RA, excellent results can be maintained up until 10 years in most patients treated with initial combination csDMARDs and remission-targeted strategy, regardless of initial IFX/placebo infusions.
  • Joensuu, Heikki; Fraser, Judith; Wildiers, Hans; Huovinen, Riikka; Auvinen, Päivi; Utriainen, Meri; Nyandoto, Paul; Villman, Kenneth K.; Halonen, Päivi; Granstam-Björneklett, Helena; Lundgren, Lotta; Sailas, Liisa; Turpeenniemi-Hujanen, Taina; Tanner, Minna; Yachnin, Jeffrey; Ritchie, Diana; Johansson, Oskar; Huttunen, Teppo; Neven, Patrick; Canney, Peter; Harvey, Vernon J.; Kellokumpu-Lehtinen, Pirkko-Liisa; Lindman, Henrik (2018)
    IMPORTANCE Trastuzumab plus chemotherapy is the standard adjuvant treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. While the standard duration of trastuzumab treatment is 12 months, the benefits and harms of trastuzumab continued beyond the chemotherapy are unclear. OBJECTIVE To evaluate the efficacy and safety of adjuvant trastuzumab continued beyond chemotherapy in women treated with up-front chemotherapy containing a taxane and trastuzumab. DESIGN, SETTING, AND PARTICIPANTS Open-label, randomized (1: 1) clinical trial including women with HER2-positive breast cancer. Chemotherapy was identical in the 2 groups, consisting of 3 cycles of 3-weekly docetaxel (either 80 or 100 mg/m(2)) plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide. Thereafter, no trastuzumab was administered in the 9-week group, whereas controls received trastuzumab to complete 1 year of administration. Disease-free survival (DFS) was compared between the groups using a Cox model and the noninferiority approach. The estimated sample size was 2168 patients (1-sided testing, with a relative noninferiority margin of 1.3). From January 3, 2008, to December 16, 2014, 2176 patients were accrued from 7 countries. INTERVENTION Docetaxel plus trastuzumab for 9 weeks, followed by 3 cycles of fluorouracil, epirubicin, and cyclophosphamide in both groups. Controls continued trastuzumab to 1 year. MAIN OUTCOMES AND MEASURES The primary objectivewas DFS; secondary objectives included distant disease-free survival, overall survival, cardiac DFS, and safety. RESULTS In the 2174 women analyzed, median age was 56 (interquartile range [IQR], 48-64) years. The median follow-up was 5.2 (IQR, 3.8-6.7) years. Noninferiority of the 9-week treatment could not be demonstrated for DFS (hazard ratio, 1.39; 2-sided 90% CI, 1.12-1.72). Distant disease-free survival and overall survival did not differ substantially between the groups. Thirty-six (3%) and 21 (2%) patients in the 1-year and the 9-week groups, respectively, had cardiac failure; the left ventricle ejection fraction was better maintained in the 9-week group. An interaction was detected between the docetaxel dose and DFS; patients in the 9-week group treated with 80 mg/m(2) had inferior and those treated with 100 mg/m(2) had similar DFS as patients in the 1-year group. CONCLUSIONS AND RELEVANCE Nine weeks of trastuzumab was not noninferior to 1 year of trastuzumab when given with similar chemotherapy. Cardiac safety was better in the 9-week group. The docetaxel dosing with trastuzumab requires further study.
  • Isokuortti, Nanne; Aaltio, Elina; Laajasalo, Taina; Barlow, Jane (2020)
    Background: Attempts to improve child protection outcomes by implementing social work practice models embedded in a particular theory and practice approach, have increased internationally over the past decade. Objective: To assess the evidence of the effectiveness of child protection practice models in improving outcomes for children and families. Participants and setting: Children <18 years and their families involved in child protection services. Methods: A systematic review was conducted to synthesize evidence regarding the effectiveness of child protection practice models. Systematic searches across 10 electronic databases and grey literature were conducted to identify quasi-experimental studies minimally. Included studies were critically appraised and the findings summarized narratively. Results: Five papers, representing six studies, focusing on three practice models (Solution-Based Casework; Signs of Safety; and Reclaiming Social Work) met the inclusion criteria. All studies applied a quasi-experimental design. Overall, the quality of the evidence was rated as being poor, with studies suffering from a risk of selection bias, small sample sizes and short-term follow up. Conclusions: Despite the popularity of practice models, the evidence base for their effectiveness is still limited. The results suggest that high-quality studies are urgently needed to evaluate the impact of practice models in improving the outcomes of child-protection-involved families. The findings also illustrate the difficulties of conducting high-quality outcome evaluations in children's social care, and these challenges and future directions for research, are discussed.