Browsing by Subject "PLACEBO"

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  • Holster, Savanne; Hooiveld, Guido J.; Repsilber, Dirk; de Vos, Willem M.; Brummer, Robert J.; König, Julia (2019)
    Faecal microbiota transfer (FMT) consists of the introduction of new microbial communities into the intestine of a patient, with the aim of restoring a disturbed gut microbiota. Even though it is used as a potential treatment for various diseases, it is unknown how the host mucosa responds to FMT. This study aims to investigate the colonic mucosa gene expression response to allogenic (from a donor) or autologous (own) FMT in patients with irritable bowel syndrome (IBS). In a recently conducted randomised, double-blinded, controlled clinical study, 17 IBS patients were treated with FMT by colonoscopy. RNA was isolated from colonic biopsies collected by sigmoidoscopy at baseline, as well as two weeks and eight weeks after FMT. In patients treated with allogenic FMT, predominantly immune response-related gene sets were induced, with the strongest response two weeks after the FMT. In patients treated with autologous FMT, predominantly metabolism-related gene sets were affected. Furthermore, several microbiota genera showed correlations with immune-related gene sets, with different correlations found after allogenic compared to autologous FMT. This study shows that the microbe-host response is influenced by FMT on the mucosal gene expression level, and that there are clear differences in response to allogenic compared to autologous FMT.
  • Lintunen, Jonne; Lähteenvuo, Markku; Tanskanen, Antti; Tiihonen, Jari; Taipale, Heidi (2022)
    Background: Improved treatments for bipolar disorder (BD) are needed. Drug repurposing aims to find novel targets for drugs that have been used for other indications. This study investigated the risk of psychiatric hospitalization associated with use of calcium-channel blockers (CCBs; dihydropyridines, diltiazem, verapamil) and adenosine modulators (allopurinol, dipyridamole) in BD in within-individual design. Methods: Individuals diagnosed with BD (ICD-10: F30-F31) were identified from the inpatient, specialized outpatient, sickness absence, and disability pension registers during 1996-2018 in Finland (N = 60,045). The main outcome was hospitalization due to affective symptoms (ICD-10: F30-F39). Within-individual models in stratified Cox regression were used and adjusted hazard ratios (aHR) with 95 % confidence intervals (CIs) reported. Results: Use of CCBs was associated with a decreased risk of hospitalization due to affective symptoms (aHR 0.83, 95 % CI 0.78-0.88) when all CCBs were analyzed together. Of specific CCBs, use of diltiazem (0.71, 0.55-0.91) and dihydropyridines (0.83, 0.78-0.89) were associated with a decreased risk but verapamil was not (0.93, 0.73-1.19). Use of adenosine modulators in general was associated with a decreased risk of hospitalizations due to affective symptoms (0.87, 0.79-0.96). Both allopurinol (0.85, 0.74-0.97) and dipyridamole (0.89, 0.78-1.00) were associated with a marginally decreased risk. Thiazide diuretic use as a negative control was not associated with the risk of hospitalization due to affective symptoms (0.97, 0.83-1.13). Limitations: Due to the observational nature of this study, causation cannot be confirmed. Conclusions: Dihydropyridines and diltiazem were associated with a decreased risk of psychiatric hospitalization in bipolar disorder. Results for allopurinol and dipyridamole were inconclusive.
  • Hjortsberg, Catharina; Bergman, Annika; Bjarnason, Anton; Heikkila, Hannele; Rielmgren, Jonas; Svensson, Ake; Tennvall, Gunnel Ragnarson (2011)
  • Hemilä, Harri (2008)
    In their paper discussing the importance of double-blinding in controlled trials, Furberg and Soliman stated that one of the established and fundamental principles for avoiding the problem of bias is to keep the study participants and the investigators blinded, or masked, to the identity of the assigned interventions. As a support to this argument they described the subgroup findings of Karlowski et al.s trial, which examined the effect of vitamin C supplementation on the commoncold[2,3]. Furberg and Soliman put a great weight on the importance of double-blinding, yet they are lax on other fundamental principles of controlled trial.
  • Holster, S.; Repsilber, D.; Geng, D.; Hyotylainen, T.; Salonen, A.; Lindqvist, C. M.; Rajan, S. K.; de Vos, W. M.; Brummer, R. J.; König, J. (2021)
    Faecal microbiota transfer (FMT) consists of the infusion of donor faecal material into the intestine of a patient with the aim to restore a disturbed gut microbiota. In this study, it was investigated whether FMT has an effect on faecal microbial composition, its functional capacity, faecal metabolite profiles and their interactions in 16 irritable bowel syndrome (IBS) patients. Faecal samples from eight different time points before and until six months after allogenic FMT (faecal material from a healthy donor) as well as autologous FMT (own faecal material) were analysed by 16S RNA gene amplicon sequencing and gas chromatography coupled to mass spectrometry (GS-MS). The results showed that the allogenic FMT resulted in alterations in the microbial composition that were detectable up to six months, whereas after autologous FMT this was not the case. Similar results were found for the functional profiles, which were predicted from the phylogenetic sequencing data. While both allogenic FMT as well as autologous FMT did not have an effect on the faecal metabolites measured in this study, correlations between the microbial composition and the metabolites showed that the microbe-metabolite interactions seemed to be disrupted after allogenic FMT compared to autologous FMT. This shows that FMT can lead to altered interactions between the gut microbiota and its metabolites in IBS patients. Further research should investigate if and how this affects efficacy of FMT treatments.
  • Murtojärvi, Mika; Halkola, Anni S.; Airola, Antti; Laajala, Teemu D.; Mirtti, Tuomas; Aittokallio, Tero; Pahikkala, Tapio (2020)
    Introduction Predictive survival modeling offers systematic tools for clinical decision-making and individualized tailoring of treatment strategies to improve patient outcomes while reducing overall healthcare costs. In 2015, a number of machine learning and statistical models were benchmarked in the DREAM 9.5 Prostate Cancer Challenge, based on open clinical trial data for metastatic castration resistant prostate cancer (mCRPC). However, applying these models into clinical practice poses a practical challenge due to the inclusion of a large number of model variables, some of which are not routinely monitored or are expensive to measure. Objectives To develop cost-specified variable selection algorithms for constructing cost-effective prognostic models of overall survival that still preserve sufficient model performance for clinical decision making. Methods Penalized Cox regression models were used for the survival prediction. For the variable selection, we implemented two algorithms: (i) LASSO regularization approach; and (ii) a greedy cost-specified variable selection algorithm. The models were compared in three cohorts of mCRPC patients from randomized clinical trials (RCT), as well as in a real-world cohort (RWC) of advanced prostate cancer patients treated at the Turku University Hospital. Hospital laboratory expenses were utilized as a reference for computing the costs of introducing new variables into the models. Results Compared to measuring the full set of clinical variables, economic costs could be reduced by half without a significant loss of model performance. The greedy algorithm outperformed the LASSO-based variable selection with the lowest tested budgets. The overall top performance was higher with the LASSO algorithm. Conclusion The cost-specified variable selection offers significant budget optimization capability for the real-world survival prediction without compromising the predictive power of the model.
  • Cork, Michael J.; Eckert, Laurent; Simpson, Eric L.; Armstrong, April; Barbarot, Sebastien; Puig, Luis; Girolomoni, Giampiero; de Bruin-Weller, Marjolein; Wollenberg, Andreas; Kataoka, Yoko; Remitz, Anita; Beissert, Stefan; Mastey, Vera; Ardeleanu, Marius; Chen, Zhen; Gadkari, Abhijit; Chao, Jingdong (2020)
    Background: Atopic dermatitis (AD) profoundly affects quality of life (QoL). Dupilumab significantly improves clinical outcomes, is well tolerated, and approved to treat inadequately controlled moderate-to-severe AD in adults; however, its effect on patient-reported outcomes (PROs) is not fully characterized. Objective: To evaluate the impact of dupilumab on patient-reported AD symptoms and QoL. Methods: Pooled data were analyzed from two identically designed phase 3 studies, LIBERTY AD SOLO 1 (NCT02277743) and SOLO 2 (NCT02277769), assessing the following PROs: Peak Pruritus Numerical Rating Scale (NRS), Pruritus Categorical Scale, SCORing AD (SCORAD), Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), five-dimension EuroQoL questionnaire (EQ-5D), and patient-assessed disease status and treatment effectiveness. Results: Dupilumab rapidly improved (vs. placebo) Peak Pruritus NRS scores by day 2 (p <.05), anxiety and depression (HADS), and QoL (DLQI) by week 2, and maintained through week 16 (p <.0001). At week 16, more dupilumab-treated than placebo-treated patients reported improvement in SCORAD itch and sleep, and no pain/discomfort (EQ-5D) (p <.0001). Limitations: Cultural differences of translated PROs. Conclusion: Dupilumab had a significant, positive impact on AD symptoms, including itch, sleep, pain, anxiety and depression, and QoL in adults with moderate-to-severe AD.
  • Lehtisalo, Jenni; Rusanen, Minna; Solomon, Alina; Antikainen, Riitta; Laatikainen, Tiina; Peltonen, Markku; Strandberg, Timo; Tuomilehto, Jaakko; Soininen, Hilkka; Kivipelto, Miia; Ngandu, Tiia (2022)
    Aims Joint prevention of cardiovascular disease (CVD) and dementia could reduce the burden of both conditions. The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) demonstrated a beneficial effect on cognition (primary outcome) and we assessed the effect of this lifestyle intervention on incident CVD (pre-specified secondary outcome). Methods and results FINGER enrolled 1259 individuals aged 60-77 years (ClinicalTrials.gov NCT01041989). They were randomized (1:1) to a 2-year multi-domain intervention with diet, physical and cognitive activity, and vascular monitoring (n = 631), or general health advice (n = 628). National registries provided data on CVD including stroke, transient ischaemic attack (TIA), or coronary heart event. During an average of 7.4 years, 229 participants (18%) had at least one CVD diagnosis: 107 in the intervention group and 122 in the control group. The incidence of cerebrovascular events was lower in the intervention than the control group: hazard ratio (HR) for combined stroke/TIA was 0.71 [95% confidence interval (CI): 0.51-0.99] after adjusting for background characteristics. Hazard ratio for coronary events was 0.84 (CI: 0.56-1.26) and total CVD events 0.80 (95% CI: 0.61-1.04). Among those with history of CVD (n = 145), the incidence of both total CVD events (HR: 0.50, 95% CI: 0.28-0.90) and stroke/TIA (HR: 0.40, 95% CI: 0.20-0.81) was lower in the intervention than the control group. Conclusion A 2-year multi-domain lifestyle intervention among older adults was effective in preventing cerebrovascular events and also total CVD events among those who had history of CVD. Key question Can a 2-year multi-domain lifestyle intervention, primarily designed for prevention of cognitive impairment, prevent new cardiovascular events among older adults over an extended follow-up? Key finding Among the 1259 participants aged 60-77 years, the intervention resulted in 13-20% lower cardiovascular disease (CVD) event rates (unadjusted and adjusted analyses), but with large degree of uncertainty. Cerebrovascular event rates were lower but for total CVD only among those with earlier CVD events. Take-home message A 2-year multi-domain lifestyle intervention among older adults was effective in preventing cerebrovascular events and also total CVD events among those with a history of CVD.
  • Lauper, Kim; Ludici, Michele; Mongin, Denis; Bergstra, Sytske Anne; Choquette, Denis; Codreanu, Catalin; Cordtz, Rene; De Cock, Diederik; Dreyer, Lene; Elkayam, Ori; Hauge, Ellen-Margrethe; Huschek, Doreen; Hyrich, Kimme L.; Iannone, Florenzo; Inanc, Nevsun; Kearsley-Fleet, Lianne; Kristianslund, Eirik Klami; Kvien, Tore K.; Leeb, Burkhard F.; Lukina, Galina; Nordström, Dan C.; Pavelka, Karel; Pombo-Suarez, Manuel; Rotar, Ziga; Santos, Maria Jose; Strangfeld, Anja; Verschueren, Patrick; Courvoisier, Delphine Sophie; Finckh, Axel (2022)
    Background JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers. Methods In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk. Results We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA. Conclusion The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.
  • Matikainen, Niina; Söderlund, Sanni; Björnson, Elias; Pietiläinen, Kirsi; Hakkarainen, Antti; Lundbom, Nina; Taskinen, Marja-Riitta; Boren, Jan (2019)
    Aims Patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) exhibit considerable residual risk for cardiovascular disease (CVD). There is, therefore, increasing interest in targeting postprandial lipid metabolism and remnant cholesterol. Treatment with the glucagon-like peptide 1 (GLP-1) analogue liraglutide reduces CVD risk by mechanisms that remain unexplained in part. Here we investigated the effects of liraglutide intervention on ectopic fat depots, hepatic lipogenesis and fat oxidation, postprandial lipid metabolism and glycaemia in humans with type 2 diabetes. Methods The effect of liraglutide was investigated in 22 patients with adequately controlled type 2 diabetes. Patients were randomly allocated, in a single-blind fashion, to either liraglutide 1.8 mg or placebo once daily for 16 weeks. Because liraglutide is known to promote weight loss, the study included dietary counselling to achieve similar weight loss in the liraglutide and placebo groups. Cardiometabolic responses to a high-fat mixed meal were measured before and at the end of the liraglutide intervention. Results Weight loss at Week 16 was similar between the groups: -2.4 kg (-2.5%) in the liraglutide group and -2.1 kg (-2.2%) in the placebo group. HBA1c improved by 6.4 mmol/mol (0.6%) in the liraglutide group (P = 0.005). Liver fat decreased in both groups, by 31% in the liraglutide group and by 18% in the placebo group, but there were no significant changes in the rate of hepatic de novo lipogenesis or beta-hydroxybutyrate levels, a marker of fat oxidation. We observed significant postprandial decreases in triglycerides only in plasma, chylomicrons and VLDL, and remnant particle cholesterol after treatment in the liraglutide group. Fasting and postprandial apoCIII concentrations decreased after liraglutide intervention and these changes were closely related to reduced glycaemia. In relative importance analysis, approximately half of the changes in postprandial lipids were explained by reductions in apoCIII concentrations, whereas less than 10% of the variation in postprandial lipids was explained by reductions in weight, glycaemic control, liver fat or postprandial insulin responses. Conclusions Intervention with liraglutide for 16 weeks produces multiple improvements in cardiometabolic risk factors that were not seen in the placebo group, despite similar weight loss. Of particular importance was a marked reduction in postprandial atherogenic remnant particles. The underlying mechanism may be improved glycaemic control, which leads to reduced expression of apoCIII, a key regulator of hypertriglyceridaemia in hyperglycaemic patients.
  • Thyssen, Jacob P.; Heegaard, Steffen; Ivert, Lena; Remitz, Anita; Agner, Tove; De Bruin-Weller, Marjolein; Huldt-Nystrom, Theis; Korhonen, Laura; Ivert, Lina U.; Leinonen, Pekka; Mandelin, Johanna; Sarnhult, Tore; Schopf, Thomas; Sundlisaeter, Eirik; Thomsen, Simon F.; Tzellos, Thrasyvoulos; Vestergaard, Christian; von Kobyletzki, Laura; Bradley, Maria (2020)
    There is a need for unified guidance on the management of ocular manifestations of atopic dermatitis and ocular manifestations associated with dupilumab in the Nordic region (Denmark, Finland, Norway and Sweden). This initiative gathered Nordic dermatologists and ophthalmologists to identify consensus in this area using a modified Delphi process. The initiative was led by a Nordic expert panel who developed a questionnaire that was circulated to a wider group. The results informed an agenda consisting of 24 statements to be voted on using a 5-point Likert scale at a meeting in Copenhagen on 24 April 2019. A facilitator moderated discussion and revised statements according to expert feedback for a second vote when required to reach consensus. Consensus was reached for 23 statements regarding the diagnosis, treatment and referral of these patients, which we hope will improve patient management in the Nordic region.
  • Komulainen, Kaisla; Airaksinen, Jaakko; Savelieva, Kateryna; Gluschkoff, Kia; García Velázquez, Regina; Elovainio, Marko; Jokela, Markus (2021)
    Depression can be viewed as a network of depressive symptoms that tend to reinforce each other via feedback loops. Specific symptoms of depression may be differently responsive to antidepressant treatment, and some symptoms may be more important than others in the overall improvement of depression associated with treatment. We pooled prospective data from eight industry-sponsored placebo-controlled trials for paroxetine, fluoxetine and imipramine (totaln = 3559) to examine whether improvements in specific depressive symptoms were more strongly related to improvements in other depressive symptoms among patients on active antidepressant treatment as compared to placebo. Depressive symptoms were assessed with the 17-item Hamilton Depression Rating Scale. Data on treatment was dichotomized into active treatment (receiving any antidepressant agent) vs. placebo. Time-lagged longitudinal analyses suggested that improvement in three symptoms-depressed mood, insomnia, and suicidality-had a broader overall impact on subsequent improvement in other depressive symptoms in the antidepressant condition compared to placebo (i.e., greater out-strength). Moreover, improvements in depressed mood and insomnia were more likely to follow the improvements in other symptoms in the antidepressant condition compared to placebo (i.e., greater in-strength). These results from clinical trial data suggest that depressed mood, insomnia, and suicidality may be particularly important in accounting for the remission and recovery in response to antidepressant treatment.
  • HAROSA II Study Grp; Dauvilliers, Yves; Verbraecken, Johan; Partinen, Markku; Pepin, Jean-Louis (2020)
    Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome. Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment. Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mgld over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire. Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P <0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns. Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.
  • HAROSA I Study Grp; Pepin, Jean-Louis; Georgiev, Ognian; Tiholov, Rumen; Partinen, Markku; Dauvilliers, Yves (2021)
    BACKGROUND: Excessive daytime sleepiness (EDS) in individuals with OSA syndrome persisting despite good adherence to CPAP is a disabling condition. Pitolisant is a selective histamine H3-receptor antagonist with wake-promoting effects. RESEARCH QUESTION: Is pitolisant effective and safe for reducing daytime sleepiness in individuals with moderate to severe OSA adhering to CPAP treatment but experiencing residual EDS? STUDY DESIGN AND METHODS: In a multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was titrated individually at up to 20 mg/day and taken over 12 weeks. The primary end point was change in the Epworth Sleepiness Scale (ESS) score in the intention-to treat population. Key secondary end points were maintenance of wakefulness assessed by the Oxford Sleep Resistance Test, Clinical Global Impressions scale of severity, the patient's global opinion, EuroQoL quality-of-life questionnaire score, Pichot fatigue questionnaire score, and safety. RESULTS: Two hundred forty-four OSA participants (82.8% men; mean age, 53.1 years; mean Apnea Hypopnea Index with CPAP, 4.2/h; baseline ESS score, 14.7) were randomized to pitolisant (n = 183) or placebo (n = 61). ESS significantly decreased with pitolisant compared with placebo (-2.6; 95% CI, -3.9 to -1.4; P < .001), and the rate of responders to therapy (ESS # 10 or change in ESS $ 3) was significantly higher with pitolisant (71.0% vs 54.1%; P = .013). Adverse event occurrence (mainly headache and insomnia) was higher in the pitolisant group compared with the placebo group (47.0% and 32.8%, respectively; P = .03). No cardiovascular or other significant safety concerns were reported. INTERPRETATION: Pitolisant used as adjunct to CPAP therapy for OSA with residual sleepiness despite good CPAP adherence significantly reduced subjective and objective sleepiness and improved participant-reported outcomes and physician-reported disease severity.
  • Guinney, Justin; Wang, Tao; Laajala, Teemu D.; Winner, Kimberly Kanigel; Bare, J. Christopher; Neto, Elias Chaibub; Khan, Suleiman A.; Peddinti, Gopal; Airola, Antti; Pahikkala, Tapio; Mirtti, Tuomas; Yu, Thomas; Bot, Brian M.; Shen, Liji; Abdallah, Kald; Norman, Thea; Friend, Stephen; Stolovitzky, Gustavo; Soule, Howard; Sweeney, Christopher J.; Ryan, Charles J.; Scher, Howard I.; Sartor, Oliver; Xie, Yang; Aittokallio, Tero; Zhou, Fang Liz; Costello, James C.; Prostate Canc Challenge DREAM Comm (2017)
    Background Improvements to prognostic models in metastatic castration-resistant prostate cancer have the potential to augment clinical trial design and guide treatment strategies. In partnership with Project Data Sphere, a not-for-profit initiative allowing data from cancer clinical trials to be shared broadly with researchers, we designed an open-data, crowdsourced, DREAM (Dialogue for Reverse Engineering Assessments and Methods) challenge to not only identify a better prognostic model for prediction of survival in patients with metastatic castration-resistant prostate cancer but also engage a community of international data scientists to study this disease. Methods Data from the comparator arms of four phase 3 clinical trials in first-line metastatic castration-resistant prostate cancer were obtained from Project Data Sphere, comprising 476 patients treated with docetaxel and prednisone from the ASCENT2 trial, 526 patients treated with docetaxel, prednisone, and placebo in the MAINSAIL trial, 598 patients treated with docetaxel, prednisone or prednisolone, and placebo in the VENICE trial, and 470 patients treated with docetaxel and placebo in the ENTHUSE 33 trial. Datasets consisting of more than 150 clinical variables were curated centrally, including demographics, laboratory values, medical history, lesion sites, and previous treatments. Data from ASCENT2, MAINSAIL, and VENICE were released publicly to be used as training data to predict the outcome of interest-namely, overall survival. Clinical data were also released for ENTHUSE 33, but data for outcome variables (overall survival and event status) were hidden from the challenge participants so that ENTHUSE 33 could be used for independent validation. Methods were evaluated using the integrated time-dependent area under the curve (iAUC). The reference model, based on eight clinical variables and a penalised Cox proportional-hazards model, was used to compare method performance. Further validation was done using data from a fifth trial-ENTHUSE M1-in which 266 patients with metastatic castration-resistant prostate cancer were treated with placebo alone. Findings 50 independent methods were developed to predict overall survival and were evaluated through the DREAM challenge. The top performer was based on an ensemble of penalised Cox regression models (ePCR), which uniquely identified predictive interaction effects with immune biomarkers and markers of hepatic and renal function. Overall, ePCR outperformed all other methods (iAUC 0.791; Bayes factor >5) and surpassed the reference model (iAUC 0.743; Bayes factor >20). Both the ePCR model and reference models stratified patients in the ENTHUSE 33 trial into high-risk and low-risk groups with significantly different overall survival (ePCR: hazard ratio 3.32, 95% CI 2.39-4.62, p Interpretation Novel prognostic factors were delineated, and the assessment of 50 methods developed by independent international teams establishes a benchmark for development of methods in the future. The results of this effort show that data-sharing, when combined with a crowdsourced challenge, is a robust and powerful framework to develop new prognostic models in advanced prostate cancer.
  • Almangush, Alhadi; De Keukeleire, Stijn; Rottey, Sylvie; Ferdinande, Liesbeth; Vermassen, Tijl; Leivo, Ilmo; Mäkitie, Antti A. (2022)
    Simple Summary The immune response has been shown to be a promising indicator to predict the clinical behavior of many cancers, including head and neck cancer. Tumor-infiltrating lymphocytes (TILs) were widely introduced as an important tool to reveal the status of the immune response. This review discusses the significance of TILs in head and neck cancers. The evaluation of tumor-infiltrating lymphocytes (TILs) has received global attention as a promising prognostic cancer biomarker that can aid in clinical decision making. Proof of their significance was first shown in breast cancer, where TILs are now recommended in the classification of breast tumors. Emerging evidence indicates that the significance of TILs extends to other cancer types, including head and neck cancer. In the era of immunotherapy as a treatment choice for head and neck cancer, assessment of TILs and immune checkpoints is of high clinical relevance. The availability of the standardized method from the International Immuno-oncology Biomarker Working Group (IIBWG) is an important cornerstone toward standardized assessment. The aim of the current article is to summarize the accumulated evidence and to establish a clear premise for future research toward the implementation of TILs in the personalized management of head and neck squamous cell carcinoma patients.
  • Almangush, Alhadi; Jouhi, Lauri; Atula, Timo; Haglund, Caj; Mäkitie, Antti A.; Hagström, Jaana; Leivo, Ilmo (2022)
    Background The evaluation of immune response can aid in prediction of cancer behaviour. Here, we assessed the prognostic significance of tumour-infiltrating lymphocytes (TILs) in oropharyngeal squamous cell carcinoma (OPSCC). Methods A total of 182 patients treated for OPSCC were included in this study. Assessment of TILs was conducted on tumour sections stained with standard haematoxylin and eosin (HE) staining. We used the scoring criteria proposed by the International Immuno-Oncology Biomarker Working Group. Results The multivariable analysis showed that TILs associated with disease-specific survival with a hazard ratio (HR) of 2.13 (95% CI 1.14-3.96; P = 0.017). Similarly, TILs associated significantly with overall survival with HR of 1.87 (95% CI 1.11-3.13; P = 0.018). In a sub-analysis of HPV-positive and HPV-negative cases separately, TILs showed a significant prognostic value in both groups (P < 0.05). Conclusion The evaluation of TILs as proposed by the International Immuno-Oncology Biomarker Working Group is a simple and promising method in prediction of survival of OPSCC. It is easily applicable and after further validation can be implemented in the routine pathological report as a basic immune parameter.
  • Hemilä, Harri; Chalker, Elizabeth (2020)
    Background Our recent meta-analysis indicated that vitamin C may shorten the length of ICU stay and the duration of mechanical ventilation. Here we analyze modification of the vitamin C effect on ventilation time, by the control group ventilation time (which we used as a proxy for severity of disease in the patients of each trial). Methods We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials and reference lists of relevant publications. We included controlled trials in which the administration of vitamin C was the only difference between the study groups. We did not limit our search to randomized trials and did not require placebo control. We included all doses and all durations of vitamin C administration. One author extracted study characteristics and outcomes from the trial reports and entered the data in a spreadsheet. Both authors checked the data entered against the original reports. We used meta-regression to examine whether the vitamin C effect on ventilation time depends on the duration of ventilation in the control group. Results We identified nine potentially eligible trials, eight of which were included in the meta-analysis. We pooled the results of the eight trials, including 685 patients in total, and found that vitamin C shortened the length of mechanical ventilation on average by 14% (P = 0.00001). However, there was significant heterogeneity in the effect of vitamin C between the trials. Heterogeneity was fully explained by the ventilation time in the untreated control group. Vitamin C was most beneficial for patients with the longest ventilation, corresponding to the most severely ill patients. In five trials including 471 patients requiring ventilation for over 10 h, a dosage of 1-6 g/day of vitamin C shortened ventilation time on average by 25% (P <0.0001). Conclusions We found strong evidence that vitamin C shortens the duration of mechanical ventilation, but the magnitude of the effect seems to depend on the duration of ventilation in the untreated control group. The level of baseline illness severity should be considered in further research. Different doses should be compared directly in future trials.