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Objectives: To investigate psychometric performance of the 12-item Psoriatic Arthritis Impact of Disease (PsAID-12) total and individual item scores in patients with psoriatic arthritis (PsA) and to estimate score change thresholds and scores corresponding to different levels of symptom/impact severity., Methods: Data up to week 16 from 1252 patients with active PsA enrolled in two randomised controlled trials of bimekizumab (BE OPTIMAL (NCT03895203) and BE COMPLETE (NCT03896581)) were used to assess construct validity (correlations with other patient-reported outcomes), known-groups validity (based on Minimal Disease Activity index, Disease Activity Index for Psoriatic Arthritis and Psoriatic Arthritis Disease Activity Score), reliability (Cronbach's alpha and intraclass correlation coefficients (ICCs)) and responsiveness (sensitivity to change). Clinically meaningful within-patient improvement thresholds were estimated by anchor-based and distribution-based analyses, and symptom/impact severity thresholds were estimated by receiver operating characteristic curve analyses., Results: The mean (SD) PsAID-12 total score at baseline was 4.19 (1.94). PsAID-12 scores demonstrated good convergent validity and good known-groups validity. Internal consistency reliability (Cronbach's alpha 0.95) and test-retest reliability (ICC ≥ 0.70) were also good. Responsiveness was acceptable (correlations ≥0.30 for most scores). Improvement thresholds were estimated at 1.5-2 points for the PsAID-12 total score and 2 or 3 points for item scores. Thresholds for different levels of symptom/impact severity could be derived for most PsAID-12 items., Conclusions: The PsAID-12 demonstrated robust psychometric properties in a large sample of patients with active PsA, supporting its use as a fit-for-purpose patient-reported outcome in this population. Furthermore, thresholds for score interpretation were derived., Competing Interests: Competing interests: LG: Grants from AbbVie, Biogen, Eli Lilly, Novartis, Sandoz and UCB Pharma; consulting fees from AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Sandoz and UCB Pharma. A-MO: Research grants to Johns Hopkins University from AbbVie, Amgen and Janssen; consulting fees from BMS, Janssen, Sanofi and UCB Pharma. LCC: Grants/research support from AbbVie, Amgen, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer and UCB Pharma; consultant for AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Domain, Eli Lilly, Galapagos, Gilead, Janssen, Moonlake Pharma, Novartis, Pfizer, and UCB Pharma; speaking fees from AbbVie, Amgen, Biogen, Celgene, Eli Lilly, Galapagos, Gilead, GSK, Janssen, medac, Novartis, Pfizer, and UCB Pharma. DG: Consultant and/or received grant support from Abbvie, Amgen, BMS, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer, and UCB Pharma. AO: Grant/research support from AbbVie, Amgen, Janssen, Novartis and Pfizer, consultant of AbbVie, Amgen, BMS, Celgene, CorEvitas, Eli Lilly, GSK, Gilead, Janssen, Novartis, Pfizer, Takeda and UCB Pharma. CGP: Employed by Evidera, a part of Thermo Fisher Scientific, which received funding for this research from UCB Pharma. VC, VT and JL: Employees and stockholders of UCB Pharma. BI: Employee of UCB Pharma; shareholder of AbbVie, GlaxoSmithKline and UCB Pharma. MdW: Over the last five years Stichting Tools has received fees for lectures or consultancy provided by MdW from Celgene, Eli Lilly, Janssen-Cilag, Pfizer and UCB Pharma., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Hidradenitis suppurativa (HS) has a profound negative impact on patients' health-related quality of life (HRQoL). Here we summarize the evidence on HRQoL and Patient Reported Outcomes (PROs) in patients with HS in real-world settings by conducting a systematic literature review (SLR) of observational studies., Methods: Data sources included MEDLINE, Embase & PsycINFO between January 1, 2010 and August 29, 2021, and conference proceedings between 2019 and 2021. Identified abstracts were reviewed and screened independently by two reviewers. Eligibility criteria included patients with HS of any severity, sample size ≥ 100, reporting PROs including HRQoL measures. Included studies were critically appraised., Results: Fifty-eight observational studies matched inclusion criteria. Dermatology Life Quality Index (DLQI) was the most commonly utilized instrument: 57% of included studies reported mean baseline DLQI scores, ranging between 8.4 and 16.9, indicating a very large impact on the patients' HRQoL. Higher scores were reported with increasing disease severity and among female patients. Pain was assessed mostly by an 11-point (0-10) numeric rating scale (NRS) with a mean baseline score ranging from 3.6 to 7.7 indicating moderate to high pain levels. There was a negative impact of HS on patients' psychological well-being, based on PRO scores related to depression and anxiety. A high proportion of sexual dysfunction was reported, with a larger impact on women than men. Work productivity and leisure activity were consistently found to be impaired in patients with HS., Conclusions: All included studies reported a negative impact of HS on patients' lives. A diverse set of disease- and non-disease-specific PRO instruments were utilized highlighting the need for more consistent use of HS-specific validated PRO instruments to assess the impact of HS on the different aspects of patients' HRQoL to allow for data to be more meaningfully interpreted and compared in real-world settings. Patients with HS need better disease management approaches that address the observed low quality of life., (© 2024. The Author(s).)

Background: Hidradenitis suppurativa (HS), a chronic skin condition that causes pain and physical dysfunction, can impact significantly on quality of life. Disease-specific tools have been designed to assess the impact of HS on patients, including the HS Symptom Daily Diary (HSSDD), the HS Symptom Questionnaire (HSSQ), and the HS Quality of Life (HiSQOL©) questionnaire, which have been developed into electronic instruments (eHSSDD, eHSSQ, and eHiSQOL©)., Objectives: The objective of this study was to establish the content validity of the electronic version of the HSSDD and HSSQ, and the acceptability and usability of the HSSDD, HSSQ, and HiSQOL©, using concept elicitation and cognitive debriefing interviews., Methods: This was a non-interventional qualitative video interview study involving participants aged ≥18 years with moderate to severe HS recruited from a single clinical site in the USA. Interviews gathered feedback on participants' symptom experience, followed by training and completion of the eHSSDD, eHSSQ, and eHiSQOL© questionnaires on electronic handheld devices. Participants were then interviewed on the content of the eHSSDD and eHSSQ and the acceptability and usability of all three instruments. Interviews were transcribed and qualitatively analysed., Results: Twenty participants with moderate to severe HS (median age: 41.5 [range: 20.0-64.0]; n = 16/20 female) were included. All participants found the eHSSDD, eHSSQ, and eHiSQOL© instructions clear and described the instruments as "easy", "simple" and "self-explanatory". Overall understanding of individual items within the eHSSDD and eHSSQ was high; however, 6/20 participants had difficulty in understanding the average skin pain item in the eHSSDD. All participants were able to accurately recall their symptoms within the recall periods of the eHSSDD and eHSSQ, although 4/20 participants found the 24-h recall period of the eHSSDD limiting. Completion time was quick across all instruments, and usability was high, with the majority of participants reporting no difficulty in completing questionnaires on electronic devices., Conclusion: The concepts covered in the eHSSDD and eHSSQ are relevant and important to patients, supporting their content validity. The findings also provide evidence of acceptability and usability of the eHSSDD, eHSSQ, and eHiSQOL©. A limitation was that all participants were recruited from a single site, which may have introduced selection bias and thus limited the generalisability of results., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Importance: Few simplified instruments exist for use in hidradenitis suppurativa (HS) trials., Objective: To assess psychometric properties of the Hidradenitis Suppurativa Investigator Global Assessment (HS-IGA) score using a clinical trial data set., Design, Setting, and Participants: This retrospective analysis of a phase 2 randomized double-blind, placebo-controlled, active-reference arm trial (UCB HS0001) included adults with moderate-to-severe HS., Exposures: Trial participants were randomized at baseline to receive bimekizumab, adalimumab, or placebo., Main Outcomes and Measures: The HS-IGA score at prespecified time points up to 12 weeks after randomization., Results: The HS-IGA score showed strong convergent validity with IHS4 and HS-PhGA scores at baseline (Spearman correlation, 0.86 [P < .001] and 0.74 [P < .001], respectively) and at week 12 (Spearman correlation, 0.73 [P < .001] and 0.64 [P < .001], respectively). The HS-IGA scores assessed during predosing visits at screening and baseline showed good test-retest reliability (intraclass correlation coefficient [ICC] = 0.92). At week 12, HS-IGA responders were significantly associated with HiSCR-(50/75/90) responders (χ2 = 18.45; P < .001; χ2 = 18.11; P < .001; and χ2 = 20.83; P < .001, respectively). The HS-IGA score was predictive of HiSCR-50/75/90 and HS-PhGA response at week 12 (AUC, 0.69, 0.73, 0.85, and 0.71, respectively). However, the HS-IGA as a measure of disease activity showed low predictive validity with patient-reported outcomes at week 12., Conclusions and Relevance: The HS-IGA score demonstrated good psychometric properties compared with existing measures and may be considered for use as an end point in clinical trials for HS.

Background: Given the chronic nature of psoriasis and the loss of response that can be observed with therapies over time, it is important to understand the long-term efficacy of new treatments., Objectives: To evaluate maintenance of Week 16 responses with bimekizumab (BKZ) treatment through Year 3, in patients with moderate-to-severe plaque psoriasis., Methods: Data were pooled from BKZ-treated patients in the 52-week (BE VIVID) and 56-week (BE READY and BE SURE) phase III studies, and their ongoing open-label extension (OLE), BE BRIGHT. Efficacy outcomes are reported through 3 years of BKZ treatment in patients with an efficacy response at Week 16. Missing data were imputed primarily using modified nonresponder imputation (mNRI), with nonresponder imputation and observed case data also reported., Results: A total of 989 patients were randomized to BKZ at baseline in BE VIVID, BE READY and BE SURE. At Week 16, 693 patients achieved ≥ 90% reduction from baseline in Psoriasis Area and Severity Index (PASI 90), 503 achieved 100% reduction from baseline in PASI (PASI 100), 694 achieved absolute PASI ≤ 2 and 597 achieved body surface area (BSA) ≤ 1%, and continued into the OLE. Of these, 93.0% maintained PASI 90, 80.8% maintained PASI 100, 94.0% maintained PASI ≤ 2 and 90.3% maintained BSA ≤ 1% responses through to 3 years of BKZ treatment (mNRI). Among Week 16 PASI 90 responders, 96.8% and 72.5% also achieved Investigator's Global Assessment 0/1 and PASI 100 at Week 16, respectively, and 92.2% and 73.4% achieved these responses at Year 3 (mNRI). Among Week 16 PASI 100 responders, 76.3% also achieved Dermatology Life Quality Index (DLQI) 0/1 at Week 16, and DLQI 0/1 response increased with continuous BKZ treatment to 89.0% at Year 3 (mNRI)., Conclusions: High levels of clinical response were maintained through to 3 years of BKZ treatment in the vast majority of Week 16 responders. Long-term treatment with BKZ was efficacious, with important benefits for health-related quality of life, in patients with moderate-to-severe plaque psoriasis., Competing Interests: Conflicts of interest B.S.: Consultant (honoraria) from AbbVie, Almirall, Amgen, Arcutis, Arena, Aristea, Asana, Boehringer Ingelheim, Bristol Myers Squibb, Connect Biopharma, Dermavant, Eli Lilly, EPI Health, Evelo Biosciences, Immunic Therapeutics, Janssen, LEO Pharma, Maruho, Meiji Seika Pharma, Mindera Health, Novartis, Ono, Pfizer, Regeneron, Sanofi, Sun Pharma, UCB Pharma, Union Therapeutics, Ventyxbio and vTv Therapeutics; Stock options in Connect Biopharma and Mindera Health; Speaker for AbbVie, Eli Lilly, Janssen, Regeneron and Sanofi; Scientific Co-Director (consulting fee) from CorEvitas (formerly Corrona) Psoriasis Registry; Investigator for AbbVie, Cara Therapeutics, CorEvitas Psoriasis Registry, Dermavant, Dermira and Novartis; Editor-in-Chief (honorarium) of Journal of Psoriasis and Psoriatic Arthritis. Y.T.: Honoraria and/or grants from AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Eli Lilly, Janssen, Kyowa Hakko Kirin, LEO Pharma, Maruho, Mitsubishi Tanabe Pharma, Sun Pharma, Taiho Pharmaceutical, Torii Pharmaceutical and UCB Pharma. U.M.: Served as advisor and/or clinical study investigator for, and/or received honoraria and/or grants from AbbVie, Almirall, Aristea, Boehringer Ingelheim, Celgene, Dr Reddy’s Laboratories, Eli Lilly, Foamix, Formycon, Forward Pharma, Janssen, LEO Pharma, Medac, Novartis, Phi-Stone, Pierre Fabre, Sanofi and UCB Pharma. M.L.: Employee of Mount Sinai and receives research funds from AbbVie, Amgen, Arcutis, Avotres Therapeutics, Boehringer Ingelheim, Cara Therapeutics, Dermavant, Eli Lilly, Incyte, Janssen, LLC, Ortho Dermatologics, Regeneron and UCB Pharma; Consultant for Aditum Bio, Almirall, AltruBio, AnaptysBio, Arcutis, Aristea, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, CorEvitas (formerly Corrona), Dermavant, Dr Reddy’s Laboratories, Evelo Biosciences, Evommune, Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima, LEO Pharma, Meiji Seika Pharma, Mindera Health, Pfizer, Seanergy and Verrica. P.F.: Grant support from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Sanofi and Sun Pharma; Investigator for AbbVie, Akaal, Amgen, Arcutis, Argenx, Aslan, AstraZeneca, Boehringer Ingelheim, Botanix, Bristol Myers Squibb, Celgene, Celtaxsys, CSL, Cutanea, Dermira, Eli Lilly, Evelo Biosciences, Galderma, Genentech, Geneseq, GenesisCare, GSK, Hexima, Janssen, Kymab, LEO Pharma, MedImmune, Merck, Novartis, Pfizer, Regeneron, Reistone, Roche, Sanofi, Sun Pharma, Teva, UCB Pharma and Valeant; served on advisory boards for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galderma, GSK, Janssen, LEO Pharma, Mayne Pharma, Merck, Novartis, Pfizer, Sanofi, Sun Pharma, UCB Pharma and Valeant; served as a consultant for Aslan, Bristol Myers Squibb, Eli Lilly, Galderma, GenesisCare, Janssen, LEO Pharma, Mayne Pharma, MedImmune, Novartis, Pfizer, Roche, UCB Pharma and Wintermute; received travel grants from AbbVie, Eli Lilly, Galderma, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Roche, Sun Pharma and Sanofi; served as a speaker for or received honoraria from AbbVie, Amgen, Celgene, Eli Lilly, Galderma, GSK, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Roche, Sanofi, Sun Pharma and Valeant. R.G.L.: Principal Investigator for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis, Pfizer and UCB Pharma; served on scientific advisory boards for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis, Pfizer and UCB Pharma; provided lectures for AbbVie, Amgen, Celgene, Eli Lilly, LEO Pharma, Merck, Novartis and Pfizer. R.B.W.: Consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, GSK, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi and UCB Pharma; research grants to his institution from AbbVie, Almirall, Janssen, LEO Pharma, Novartis and UCB Pharma; honoraria from Astellas, DiCE, GSK and Union. M.W., V.V., B. Szilagyi.: Employees and shareholders of UCB Pharma. V.C.: Employee of UCB Pharma. C.P.: Consulting fees and/or grants from AbbVie, Almirall, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, GSK, Janssen Cilag, LEO Pharma, Novartis, Pfizer, Pierre Fabre, Sanofi and UCB Pharma., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Aim: The present pilot RCT aimed to investigate the influence of a connective tissue graft (CTG) in combination with the immediate implant placement (IIP) on hard and soft tissue healing, without a bone replacement graft in the gap between the implant and the socket walls., Materials and Methods: Thirty patients requiring extraction of one anterior tooth (from premolar to premolar) were randomly assigned to one of the two treatment groups (test: IIP + CTG; control: IIP). Cone-beam computed tomography and optically scans were performed before tooth extraction and at 6-month follow-up. Then, DICOM files were superimposed in order to allow the evaluation of osseous ridge and buccal bone changes, while the superimposition of DICOM and Standard Tessellation Language files allowed for evaluating of soft tissue contour. For testing the differences between the two groups, the non-parametric test as Wilcoxon rank-sum test, was used., Results: Twenty-six of the 30 enrolled patients attended the 6-month follow-up visit. The four patients of the control group that were lost to follow-up were analysed under the intention-to-treat principle. No statistically significant differences between the groups were observed for the vertical buccal bone resorption (p = .90), as well as for the horizontal buccal bone resorption at all measured levels. Significant differences were found between the test and control groups in the horizontal dimensional changes of osseous ridge at the most coronal aspect (p = .0003 and p = .02). Changes in tissue contour were between -0.32 and -0.04 mm in the test group and between -1.94 and -1.08 mm in the control group, while changes in soft tissue thickness varied between 1.33 and 2.42 mm in the test group and between -0.16 and 0.88 mm in the control group, with statistically significant differences for both variables at all measured levels. At 6 months, the mean volume increase was 6.76 ± 8.94 mm 3 and 0.16 ± 0.42 mm 3 in the test and control groups, respectively, with a statistically significant difference., Conclusions: The findings of the present study indicate that the adjunct of a CTG at the time of IIP, without bone grafting, does not influence vertical bone resorption. Within the limits of this study, it can be suggested that the adjunct of a CTG at the time of IIP, without bone grafting, reduces the horizontal changes of the alveolar ridge. Moreover, it allows maintenance of the tissue contour due to an increase in soft tissue thickness., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: This analysis assessed the psychometric properties of the Psoriasis Symptoms and Impacts Measure (P-SIM), a novel patient-reported outcome (PRO) tool designed to capture patient experiences of the signs, symptoms and impacts of psoriasis., Methods: Blinded data from the BE RADIANT phase 3b trial of bimekizumab were analysed. In BE RADIANT, patients were randomised 1:1 to bimekizumab 320 mg every 4 weeks (Q4W) or secukinumab 300 mg (weekly until Week 4, then Q4W). Three items (itching, skin pain and scaling) of the P-SIM were electronically assessed throughout the trial and were scored from 0 to 10 (none to very severe signs/symptoms/impacts). Test-retest reliability was determined using intraclass correlations. Convergent validity was assessed between P-SIM and other relevant PRO and clinician-reported outcome (ClinRO) scores. Known-groups validity was assessed by comparing mean P-SIM item scores between patient subgroups based on the Psoriasis Area and Severity Index (PASI)/Investigator's Global Assessment (IGA) scores. Responsiveness was assessed via correlations between changes from baseline in P-SIM item scores and other relevant PRO and ClinRO scores. Anchor-based responder analyses and empirical cumulative distribution function (eCDF) curves determined responder thresholds., Results: The three P-SIM items yielded high intraclass coefficients (> 0.70). By Week 48, the three P-SIM items had moderate (> 0.30 and ≤ 0.50) to strong (> 0.50) correlations with other PROs and weaker correlations with ClinROs, demonstrating good convergent validity. For almost all known-group comparisons, statistically significant between-subgroup score differences were seen across all three P-SIM items. Changes from baseline in the P-SIM and other relevant outcomes were above the acceptable threshold of ≤ 0.30, demonstrating sensitivity to change. Anchor-based analyses determined a ≥ four-point reduction from baseline to indicate marked clinically meaningful improvement for the P-SIM., Conclusion: These results support the validity, reliability and sensitivity to change of the P-SIM in assessing key symptoms (itching, skin pain and scaling) in patients with moderate to severe plaque psoriasis., Trial Registration: NCT03536884., (© 2021. The Author(s).)

Introduction: Plaque psoriasis can significantly impact patients' quality of life. We assessed psychometric properties of the Psoriasis Symptoms and Impacts Measure (P-SIM), developed to capture patients' experiences of signs, symptoms and impacts of psoriasis., Methods: Pooled, blinded, 16-week data from 1002 patients in the BE VIVID and BE READY bimekizumab phase 3 trials were analysed. The suitability of the P-SIM missing score rule (weekly scores considered missing if ≥ 4 daily scores were missing) was assessed. Test-retest reliability was evaluated using intraclass correlation coefficients (ICCs). Convergent validity was assessed between P-SIM and relevant patient-reported outcome (PRO) (Dermatology Life Quality Index [DLQI], DLQI item 1 [skin symptoms], Patient Global Assessment of Psoriasis) and clinician-reported outcome (ClinRO) scores (Psoriasis Area and Severity Index [PASI], Investigator's Global Assessment [IGA]) at baseline and week 16. Known-groups validity was assessed, comparing P-SIM scores between patient subgroups predefined using PASI/IGA scores. Sensitivity to change over 16 weeks was evaluated; responder definition (RD) thresholds were explored., Results: The missing score rule used did not impact P-SIM scores. Test-retest reliability analyses demonstrated excellent score reproducibility (ICC 0.91-0.98). Inter-item correlations at baseline and week 16 were strong (> 0.5), apart from "choice of clothing" with "skin pain" and "burning" at baseline (both 0.49). All P-SIM scores were moderately to strongly correlated with other outcomes, demonstrating convergent validity, apart from ClinROs (PASI, IGA) at baseline that had low variability. P-SIM scores discriminated known groups at week 16, confirming known-groups validity. Changes from baseline to week 16 in P-SIM and other clinically relevant outcomes were strongly correlated (> 0.5; weaker with ClinROs), establishing sensitivity to change. Anchor-based RD analyses determined a four-point P-SIM item score decrease as indicative of marked clinically meaningful improvement., Conclusion: P-SIM scores demonstrated good reliability, validity and sensitivity to change. A four-point RD threshold could be used to assess 16-week treatment effects., Trial Registration: BE VIVID: NCT03370133; BE READY: NCT03410992., (© 2021. The Author(s).)

Introduction: Patients with plaque psoriasis experience a variety of signs and symptoms that can impact daily life, which may not be evaluated by clinician-reported outcomes. This study aimed to develop and assess the content validity of a new patient-reported outcome (PRO) measure to capture patient experiences of the signs, symptoms and impacts of psoriasis and aid integration of the patient perspective in treatment benefit-risk decision-making., Methods: The psoriasis symptoms and impacts measure (P-SIM) was developed based on a literature search and interviews with five clinical experts in psoriasis to identify frequent signs, symptoms and impacts of psoriasis. Hybrid concept elicitation, cognitive debriefing and usability testing interviews were conducted with moderate to severe psoriasis patients to evaluate the content validity and patient understanding of the preliminary P-SIM. The preliminary P-SIM was refined using initial quantitative analyses of phase 2b data from psoriasis patients to inform the removal of any items., Results: A preliminary 19-item P-SIM was developed for administration on a hand-held electronic tablet device using a 0-10 numerical response scale over a 24-h recall period. Patient interviews and testing demonstrated most patients interpreted the items and responses as intended, would not re-word any items, felt the responses matched the items and rated the device as easy to use. After quantitative testing, five items were removed from the preliminary 19-item measure because of conceptual overlap, floor effects and/or skewed distributions to generate the final 14-item P-SIM., Conclusions: The P-SIM questionnaire has good content validity; patients reported it was easy to understand and reflective of their experiences. Following psychometric validation, the P-SIM may be a useful PRO measure for capturing the signs, symptoms and impacts of psoriasis and may support clinician-reported outcomes when assessing treatment benefits in clinical trials.

Background: Patient-reported outcome (PRO) instruments provide robust and effective means of evaluating patients' treatment experience; however, none adequately cover experience using self-injection devices with enhanced features, such as an electromechanical autoinjector (e-Device). The aim of this study was to develop a PRO instrument that accurately assesses patient experience of using an e-Device and to evaluate its psychometric properties., Methods: A mixed-methods approach was taken; two parallel, targeted literature reviews were conducted to identify relevant concepts and existing self-injection PRO instruments that could be adapted. Patient feedback obtained from two focus groups was used to inform initial instrument development. The pilot instrument was then administered in a multicenter, open-label, phase 3 clinical study in which patients self-injected certolizumab pegol using an e-Device, to gather evidence of its psychometric qualities. Exit interviews were conducted with a sub-sample of patients enrolled in the study to confirm the appropriateness and clarity of the items included and cognitively debrief the instrument. Confirmatory factor analysis (CFA) was conducted on all items, and each domain's internal consistency was measured using Cronbach's ɑ., Results: The literature searches identified several e-Device-specific concepts related to device features, device function, side effects/reactions/pain, confidence, and interference/convenience in daily life. Seven existing PRO instruments were identified. The Self-Injection Assessment Questionnaire (SIAQ), containing pre- and post-injection questionnaire modules, was selected as most suitable and adapted using feedback from 19 patients in the two focus groups to form the pilot Assessment of Self-Injection (ASI) questionnaire. CFA resulted in some changes to the grouping of items in the post-injection module domains following psychometric evaluation of the ASI. Internal consistency was satisfactory for all pre- and post-injection domains (ɑ > 0.8). Cognitive debriefing results from 12 patient exit interviews confirmed the ASI's appropriateness and clarity., Conclusions: The ASI was developed iteratively with patient input and was evaluated in its intended clinical context of use. Psychometric analyses indicated promising cross-sectional results; the ASI was well understood and considered relevant by patients self-injecting using the e-Device, suggesting that it could be used in real-world settings to aid with clinical decision making., Trial Registration: NCT03357471.

An ultrasound (US) study is often the first imaging approach in patients with abdominal symptoms or signs related to abdominal diseases, and it is often part of the routine workup. The pancreatic gland, despite its retroperitoneal site, can be efficiently examined with US thanks to advances in US technologies. Nowadays, a pancreatic US study could be considered complete if multiparametric, including the use of Doppler imaging, US elastography, and contrast-enhanced imaging for the study of a pancreatic mass. A complete US examination could contribute to a faster diagnosis, especially if the pancreatic lesion is incidentally detected, addressing second-step imaging modalities correctly., (© 2019 by the American Institute of Ultrasound in Medicine.)

To evaluate pancreatic neuroendocrine neoplasms (panNENs) grade prediction by means of qualitative and quantitative CT evaluation, and 3D CT-texture analysis. Patients with histopathologically-proven panNEN, availability of Ki67% values and pre-treatment CT were included. CT images were retrospectively reviewed, and qualitative and quantitative images analysis were done; for quantitative analysis four enhancement-ratios and three permeability-ratios were created. 3D CT-texture imaging analysis was done (Mean Value; Variance; Skewness; Kurtosis; Entropy). Subsequently, these features were compared among the three grading (G) groups. 304 patients affected by panNENs were considered, and 100 patients were included. At qualitative evaluation, frequency of irregular margins was significantly different between tumor G groups. At quantitative evaluation, for all ratios, comparisons resulted statistical significant different between G1 and G3 groups and between G2 and G3 groups. At 3D CT-texture analysis, Kurtosis resulted statistical significant different among three G groups and Entropy resulted statistical significant different between G1 and G3 and between G2 and G3 groups. Quantitative CT evaluation of panNENs can predict tumor grade, discerning G1 from G3 and G2 from G3 tumors. CT-texture analysis can predict panNENs tumor grade, distinguishing G1 from G3 and G2 from G3, and G1 from G2 tumors.

Pancreatic neuroendocrine neoplasms (P-NENs) are the second most common solid pancreatic neoplasms. P-NENs have a wide range of imaging features presentations and they can be detected with typical and atypical imaging presentations. Typical and atypical appearances can be explained by pathologic correlations. P-NENs are generally hypervascular lesions, showing a typical enhancement behavior after contrast media injection during imaging methods, but they could also have different imaging features, creating some difficulty in differential diagnosis. For this reason, radiologists should be aware of different imaging presentations of these neoplasms. Radiological evaluation has a critical role in P-NENs identification, characterization, and staging of these neoplasms, especially in those cases in which surgery is the treatment of choice. The present paper shows, indicating the underlying pathologic correlations, typical and atypical presentations of NENs. KEY POINTS: • P-NENs have a wide range of imaging features presentations, typical and atypical. • Pathology could help in better understanding the typical P-NENs appearance at imaging. • P-NENs are generally hypervascular lesions. • Radiological evaluation has a critical role in P-NENs identification and management. • Radiologists should know every type of different imaging presentation of P-NENs to better diagnose these kinds of lesions.

Background/aim: Re-staging of ductal adenocarcinoma using computed tomography (CT) scan can be problematic so new imaging techniques and evaluation parameters are required. The aim of the study was to evaluate the added value of CT texture analysis in estimation of tissue changes in ductal adenocarcinoma downsized and resected after chemotherapy., Materials and Methods: Patients with ductal adenocarcinoma downstaged after neoadjuvant treatment, and resected, were included. A pre- and post-treatment CT was obtained. In comparison, patients with disease progression were included for texture analysis evaluation at CT pre- and post-treatment. CT texture analysis results were compared., Results: A total of 17 patients affected by un-resectable or borderline ductal adenocarcinoma reached the resectable stage after treatment. The comparison between Kurtosis pre- and Kurtosis post-treatment showed a statistically significant difference. On the contrary, in the comparison group composed of 14 patients with disease progression there was no statistical difference regarding this parameter., Conclusion: This evaluation may represent an added value in tumor tissue changes judgment and can be extremely useful to diagnose downstaging in those cases with no evident downsizing after chemotherapy., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: To assess the accuracy of unenhanced magnetic resonance imaging (MRI) immediately after the percutaneous ultrasound-guided radiofrequency ablation (RFA) of liver malignancy in predicting treatment efficacy at CT follow-up., Materials and Methods: Percutaneous ablation was prospectively performed in 23 liver malignancies (20 hepatocarcinomas and 3 metastases). After the procedure in the same day all patients were studied with unenhanced MRI. The best sequence to detect the coagulative necrosis was visually established. Pre-RFA CT and post-RFA MRI were registered with non-rigid transformation algorithm. Manual segmentation of lesions and ablated areas in pre-RFA CT, post-RFA MRI, and follow-up CT were obtained. Sensitivity, specificity, positive predictive value (PPV), negative predicitve value (NPV), and accuracy of MRI in predicting the correct centering and the complete treatment of the lesion were calculated in respect to the 1-month follow-up CT., Results: Fat-saturated T1-weighted (fs T1-w) was the sequence in which the best conspicuity of the ablated area was depicted. Coagulative necrosis was hyperintense in fs T1-w sequence in 17/23 (74%). In respect to follow-up CT, MRI predicted the correct centering of the lesions in 19/20 lesions with sensitivity, specificity, PPV, NPV, and accuracy of 100%, 75%, 95%, 100%, and 100%, respectively. MRI predicted the complete treatment of the lesions in 17/17 lesions with sensitivity, specificity, PPV, NPV, and accuracy of 100%., Conclusion: MRI with the single fs T1-w sequence was highly accurate in predicting the treatment efficacy of percutaneous ablation of liver malignancies in comparison to follow-up CT control. Unnecessary CT in case of incomplete treatment can be therefore easily avoided.

Background: The purpose of the study is to evaluate the utility of acoustic radiation force impulse (ARFI) on pancreatic tissue as a preoperative predictor of postoperative pancreatic fistula (POPF). Studied patients underwent exclusively to pancreaticoduodenectomy (PD) surgery., Methods: Shear wave velocity of pancreas was measured using ARFI in 71 patients scheduled for PD. An intraoperative pancreas palpation was made by surgeons. A postoperative clinical evaluation to detect occurrence of POPF was performed. Sensitivity, specificity, positive and negative predictive values together with the accuracy of the method were investigated., Results: Incidence of fistula observed in 17 patients with soft pancreas was approximately 53% vs. 47% without fistula. Percentage of patients without fistula was higher (66%) among 24 patients with medium parenchymal texture values, and was even higher (69%) in 26 patients with hard pancreas. Comparing ARFI and intraoperative pancreatic palpation, low wave velocity values (≤1.40 m/s) match 60% with soft parenchyma assessed by palpation and high values (>2 m/s) match 59% with hard pancreas on palpation., Conclusions: This study shows that ARFI elastography may be clinically useful as a preoperative predictor of pancreatic fistula following PD., (© 2017 S. Karger AG, Basel.)

Aim: To describe the imaging features of serous neoplasms of the pancreas using ultrasound, endoscopic ultrasound, computed tomography and magnetic resonance imaging., Methods: This multicenter international collaboration enhances a literature review to date, reporting features of 287 histologically confirmed cases of serous pancreatic cystic neoplasms (SPNs)., Results: Female predominance is seen with most SPNs presenting asymptomatically in the 5 th through 7 th decade. Mean lesion size was 38.7 mm, 98% were single, 44.2% cystic, 46% mixed cystic and solid, and 94% hypoechoic on B-mode ultrasound. Vascular patterns and contrast-enhancement profiles are described as hypervascular and hyperenhancing., Conclusion: The described ultrasound features can aid differentiation of SPN from other neoplastic lesions under most circumstances., Competing Interests: Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.

Background: Crisaborole is a novel, topical nonsteroidal, anti-inflammatory, phosphodiesterase 4 (PDE4) inhibitor for the treatment of mild to moderate atopic dermatitis., Objective: As part of a nonclinical safety testing program, these 2-year studies tested the carcinogenic potential of crisaborole., Methods: Crisaborole ointment, 2%, 5%, or 7%, was applied once daily topically to mice, and crisaborole was administered orally to rats at doses of 30, 100, or 300mg/kg/day for up to 104 weeks. Systemic exposure to crisaborole and its metabolites, moribundity/death, clinical signs, and tumor formation were assessed in each study., Results: Crisaborole treatment was not tumorigenic in mice at any of the doses administered and did not increase the incidence of neoplastic or nonneoplastic microscopic lesions compared with controls. Oral administration of crisaborole at the high dose (300mg/kg/day) to female rats increased the incidence of treatment-related benign granular cell tumors in the distal reproductive tract (uterus with cervix and vagina) but did not cause moribundity/death., Conclusion: Crisaborole was well tolerated and not tumorigenic in mice. It was not tumorigenic in male rats at 300mg/kg/day at exposures that were 3× the human area under the concentration-time curve (AUC 24 ) and was nontumorigenic in female rats at 100mg/kg/day at exposures that were 1× the human AUC 24 ., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development.

Aim: To evaluate modifications of perfusional parameters assessed by perfusion computed tomography (P-CT) of liver metastases (LM) from pancreatic neuroendocrine tumors (PanNETs) during everolimus treatment., Patients and Methods: All patients with LMs from G1-2 PanNETs undergoing everolimus treatment between January 2013 and January 2015 were prospectively evaluated with P-CT at baseline, and after 2 and 4 months of therapy. Size, perfusion, blood volume (BV), peak enhancement intensity (PEI) and time to peak for each lesion were calculated., Results: A total of 33 LMs in nine patients with G1-2 PanNETs were prospectively evaluated: 23/33 (69.7%) were responders, 10/33 (30.3%) were non-responders. Among perfusional parameters, only numerical peak enhancement intensity values significantly differed between the two groups at baseline (p=0.043). BV increase was the most significant perfusional modification identifying responding lesions, even at an early stage of treatment, with a high positive predictive value (89.47%)., Conclusion: P-CT seems to be useful for prediction of response to everolimus of LMs from PanNETs., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. The effects of tavaborole on gestation, parturition (delivery, labor), offspring development, and survival during the perinatal and postnatal periods were assessed in mated female rats. Females (F0 generation) were administered single daily oral (gavage) doses of 15, 60, or 100 mg/kg/d from gestation day 6 through lactation day 20. The females were allowed to deliver naturally and rear their offspring until lactation day 21, at which time the F0 females were euthanized. One male and female from each litter were selected (F1 generation) and retained for assessments, including growth, neurobehavior, fertility, and their ability to produce an F2 generation. Reproductive and offspring parameters were determined for the F1 and F2 generations, as applicable. F1 females and F2 pups were euthanized on postnatal day 7. In the F0 females, decreased activity was observed in the 100 mg/kg/d dose group. Excess salivation was observed in the 60 and 100 mg/kg/d dose groups (slight to moderate), however, this finding was not considered adverse. There were no tavaborole-related effects on the growth, viability, development, neurobehavioral assessments, or reproductive performance of the F1 generation. Survivability and mean body weight of the F2 pups were unaffected. The no observed adverse effect level (NOAEL) for maternal toxicity (F0 generation) was 60 mg/kg/d, based on the decreased activity observed in the 100 mg/kg/d dose group. The NOAEL for the offspring effects was ≥100 mg/kg/d, based on the lack of test article-related changes., (© The Author(s) 2016.)

Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. As part of the nonclinical development program, reproductive and developmental toxicity studies were conducted (rat oral fertility and early embryonic development, rat (oral) and rabbit (dermal) embryo-fetal development). There were no effects on fertility or reproductive performance at doses up to 300 mg/kg/d (107 times the maximum recommended human dose [MRHD] based on mean area under the plasma concentration-time curve comparisons). In the rat embryo-fetal development toxicity studies, teratogenicity was not observed at doses up to 100 mg/kg/d (29 times the MRHD). However, several treatment-related skeletal malformations and variations were observed at 300 mg/kg/d (570 times the MRHD). In rabbit embryo-fetal development toxicity studies dosed via oral or dermal administration, the no observable adverse effect level for maternal toxicity and embryo-fetal toxicity was 50 mg/kg/d (16 times the MRHD) and 5% (26 times the MRHD), respectively., (© The Author(s) 2016.)

Background: To evaluate the correlation between variations of CA 19.9 blood levels and the entity of necrosis at CT after radiofrequency ablation (RFA) of unresectable pancreatic adenocarcinoma., Methods: In this study, from June 2010 to February 2014, patients with diagnosis of unresectable and not metastatic pancreatic ductal adenocarcinoma, expressing tumor marker CA 19.9, treated with RFA procedure were included. All these patients underwent RFA. CT study was performed 1 week after RFA. The dosage of CA 19.9 levels was performed 1 month after RFA. Features of necrosis at CT, as mean entity, density and necrosis percentages compared to the original lesion, were evaluated and compared by using t-test with CA 19.9 blood levels variations after RFA procedure., Results: In this study were included 51 patients with diagnosis of unresectable and not metastatic pancreatic ductal adenocarcinoma, expressing tumor marker CA 19.9, treated with RFA procedure and with CT study and CA 19.9 available for analysis. After the procedure, CA 19.9 blood levels reduced in 24/51 (47%), remained stable in 10/51 (20%) and increased in 17/51 (33%). In patients with CA 19.9 levels reduced, the tumor marker were reduced less than 20% in 4/24 (17%) and more than 20% in 20/24 (83%); instead the tumor marker were reduced less than 30% in 8/24 (33%) and more than 30% in 16/24 (67%). At CT scan necrotic area density difference was not statistically significant. Also there was no statistically significant difference among the mean area, the mean volume and the mean ablation volume in percentage related to the treated tumor among the three different groups of patients divided depending on the CA 19.9 blood levels. But a tendency to a statistically significant difference was found in comparing the mean percentage of ablation volume between two subgroups of patients with a decrease of CA 19.9 levels with less or more than 20% reduction of tumor markers and between two subgroups with less or more than 30% reduction of CA 19.9 levels., Conclusions: RFA of unresectable pancreatic adenocarcinoma induces reduction of CA 19.9 blood levels in about half of the cases.

Crisaborole topical ointment, 2% (formerly known as AN2728) is a benzoxaborole, nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor investigational compound that recently completed phase 3 studies for the treatment of mild to moderate atopic dermatitis (AD). The unique configuration of boron within the crisaborole molecule enables selective targeting and inhibition of PDE4, an enzyme that converts the intracellular second messenger 3'5'-cyclic adenosine monophosphate (cAMP) into the active metabolite adenosine monophosphate (AMP). By inhibiting PDE4 and thus increasing levels of cAMP, crisaborole controls inflammation. The use of boron chemistry enabled synthesis of a low-molecular-weight compound (251 daltons), thereby facilitating effective penetration of crisaborole through human skin. In vitro experiments showed that crisaborole inhibits cytokine production from peripheral blood mononuclear cells in a pattern similar to other PDE4 inhibitors and distinct from corticosteroids. Crisaborole also displayed topical anti-inflammatory activity in a skin inflammation model. Once crisaborole reaches systemic circulation after topical application, it is metabolized to inactive metabolites. This limits systemic exposure to crisaborole and systemic PDE4 inhibition. In phase 1 and 2 clinical studies, crisaborole ointment, 2% was generally well tolerated and improved AD disease severity scores, pruritus, and all other AD signs and symptoms. Two large, randomized, controlled, phase 3, pivotal clinical trials assessing the efficacy and safety of crisaborole topical ointment, 2% in children, adolescents, and adults with mild to moderate AD were recently completed with positive results.

Introduction: The SOCEUS survey aims to evaluate how contrast-enhanced ultrasound (CEUS) is effectively used in the focal liver lesions characterization., Materials and Methods: In the survey were involved Verona, Brescia and Trieste Radiological Centers and Arezzo and Bologna Non-radiological Centers. Inclusion criteria were liver focal lesion detection at conventional ultrasound and studied by means of CEUS, with or without CT or MRI examinations, done previous or subsequent to CEUS., Results: 1069 forms were collected. Patients with benign lesions, who did not undergo any other studies, were 255/561 (45.5 %). Among patients with diagnosis of hemangioma at CEUS, those who had no other investigations were 129/267 (48.3 %). Patients with malignant lesions who had studies pre-CEUS (CT and/or MRI) were 328/508 (65 %), whereas those who had examinations post-CEUS (CT and/or MRI) were 218/508 (42.9 %). Concordance rate between CEUS and CT investigations pre- and post-CEUS was, respectively, 66 and 89 %. Concordance rate between CEUS and MRI studies pre- and post-CEUS was, respectively, 87.5 and 81.5 %., Conclusion: This study proves contrast-enhanced ultrasound correct application in the involved centers.

Contrast-enhanced ultrasonography (CEUS) improves the characterization of pancreatic masses. CEUS is in fact a safe and accurate imaging method to evaluate the vascularity of pancreatic lesions. CEUS should be performed when possible immediately after the ultrasound (US) detection of a pancreatic mass. CEUS is accurate in the characterization of ductal adenocarcinoma. The use of CEUS in studying pancreatic lesions found at US, especially in the same session of ultrasound examination, is therefore recommendable to promote faster diagnosis mainly of pancreatic ductal adenocarcinoma., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Tavaborole, a cyclized boronic acid, has been approved by the Food and Drug Administration for the topical treatment of toenail onychomycosis. This novel, low-molecular-weight pharmaceutical compound has broad-spectrum antifungal activity against dermatophytes, yeasts, and molds responsible for the disease. Tavaborole was tested in 2-year carcinogenicity studies in mice (once daily dermal administration) and rats (once daily by oral gavage) as part of the extensive nonclinical safety program. There was no evidence of tavaborole-related neoplasms observed in either study. Based on the data gathered from these 2 carcinogenicity studies, tavaborole is considered noncarcinogenic., (© The Author(s) 2014.)

Boron-containing compounds are being studied as potential therapeutic agents. As part of the safety assessment of these therapeutic agents, a battery of genetic toxicology studies was conducted. The battery included a bacterial reverse mutation (Ames) assay, an in vitro chromosome aberration assay in peripheral human lymphocytes, and an in vivo rat micronucleus study. The following compounds represent some of the boron-containing compounds that have been advanced to human clinical trials in various therapeutic areas. The borinic picolinate, AN0128, is an antibacterial compound with anti-inflammatory activity that has been studied in clinical trials for acne and the treatment of mild to moderate atopic dermatitis. AN2690 (tavaborole) is a benzoxaborole in Phase 3 clinical trials for the topical treatment of onychomycosis, a fungal infection of the toenails and fingernails. Another benzoxaborole derivative, AN2728, a phosphodiesterase-4 (PDE4) inhibitor, is in Phase 2 clinical trials for the treatment of atopic dermatitis. AN2898, also a PDE4 inhibitor, has been studied in clinical trials for atopic dermatitis and psoriasis. AN3365 is a leucyl-tRNA synthetase inhibitor that has been in clinical development for the treatment of various Gram-negative bacterial infections. These five representative compounds were negative in the three genotoxicity assays. Furthermore, AN2690 has been studied in mouse and rat 2-year bioassays and was not found to have any carcinogenic potential. These results demonstrate that it is possible to design boron-based therapeutic agents with no genetic toxicology liabilities., (Copyright © 2013 Wiley Periodicals, Inc.)

There is an increasing interest in in vivo metabolite identification in early drug discovery in order to (i) give a more complete picture of metabolic profile in investigational animal models, (ii) propose phase I and phase II metabolites using the same pharmacokinetic/toxicokinetic study samples, (iii) expose metabolically labile groups where chemical modifications could improve stability, and (iv) enable early safety assessment of metabolites. In the early discovery stage of our anti-inflammatory program, one novel benzoxaborole, AN6414, exhibiting both PDE4 enzyme and TNFα inhibition activities, became our primary candidate for further investigation. The traditional metabolite identifications usually require high dosed samples with long data scans and analysis. In this study, we conducted quick and more selective core-structure related precursor scans followed by daughter ion scans and identified a total of 10 major phase I and phase II metabolites using rat plasma samples from a toxicokinetic study at an oral dosing of 30 mg/kg. Plasma samples were treated with solid phase extraction (SPE) prior to LC/MS/MS. An AB SCIEX API 4000 QTRAP mass spectrometer coupled with a Shimadzu LC system was used for LC/MS/MS analysis. We found the major metabolites of AN6414 to be oxidative deboronation, protodeboronation, oxidation products and their sulfate-conjugated species. This analysis drove analoging efforts which improved the pharmacokinetic profile, namely, lowering clearance and increasing exposure relative to AN6414. Toxicity predictions by the software program DEREK suggest the identified potential metabolites to be safe., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: A system has been developed to inactivate a wide spectrum of blood-borne pathogens in red blood cells (RBCs) before transfusion. The system utilizes S-303 to target nucleic acids of pathogens and white blood cells. The safety of pathogen inactivated RBC was assessed using S-303-treated RBCs (S-303 RBCs) and S-300, the primary degradation product of S-303., Study Design and Methods: As part of a preclinical safety evaluation program, intravenous toxicity, safety pharmacology, toxicokinetic, and pharmacokinetic studies were conducted in rats and dogs with S-303 RBCs and S-300., Results: Single and repeated transfusions of S-303 RBCs were well tolerated in rats and dogs at S-303 concentrations up to five times higher than that used to prepare RBCs for clinical use. For S-300, the doses ranged from the lowest level representative of a clinical exposure from transfusion of 1 unit (0.052 mg/kg/day) to up to the amount of S-300 that would result from exposure to more than 1900 units of RBCs (100 mg/kg/day). There were no related effects of S-303 RBCs or S-300 on mortality, clinical status, body weight, or clinical laboratory assessments and no evidence of organ toxicity. S-300 did not accumulate in the plasma of rats and dogs after repeated transfusions. For all the studies, plasma S-303 was consistently below the limit of quantitation., Conclusion: The level of residual S-303 and S-300 in the treated blood component is well below that at which no adverse effects were observed. These results support further clinical development of S-303 RBCs for prevention of transfusion-transmitted infections., (© 2011 American Association of Blood Banks.)

Background: It is estimated that approximately 300,000 neonates undergo transfusions annually. The neonatal immune system is immature, making such patients more susceptible to the effects associated with transfusion-transmitted bacteria, viruses, protozoa, and white blood cells (WBCs). The INTERCEPT Blood System is a photochemical process (PCT) utilizing amotosalen and long-wavelength ultraviolet to inactivate pathogens and WBCs in both platelet (PLT) and plasma components for transfusion. A series of clinical studies has shown PCT PLTs and PCT plasma to be safe and effective for transfusion in adults and pediatric patients. Because clinical studies in neonates are technically difficult and ethically challenging, preclinical toxicologic studies were conducted in neonatal rats to evaluate the safety of PCT blood components for neonates., Study Design and Methods: This study examined daily intravenous administration to neonatal rats of amotosalen in 35 percent:65 percent plasma:InterSol from 1 microg per kg per day (representing 1-unit transfusion) to 457 microg per kg per day (representing multiple transfusions) from Postnatal Day 4 (PND4) to PND31. Rats were observed for viability, clinical signs, and body weights until PND31 and then subjected to pathology evaluation. Hematology, clinical chemistry, and urinalysis data were also collected on PND31. Toxicokinetic parameters were evaluated on PND4 and PND31., Results: There were no amotosalen-related effects on clinical signs, body weight, hematology, clinical chemistry, urinalysis, gross pathology, or histopathology, despite the exposure of neonatal rats to amotosalen concentrations as high as approximately 48 times the standard exposure in adult patients., Conclusion: This study demonstrates the safety of PCT for transfusion in neonatal rats and augments data from other studies and clinical use supporting the use of PCT in neonatal patients.

Helinx technology (Cerus Corp, Concord, CA) uses amotosalen HCl (S-59) and ultraviolet A (UVA) light in an ex vivo photochemical treatment (PCT) to inactivate viruses, bacteria, and leukocytes in platelet concentrates while preserving therapeutic function. A comprehensive preclinical safety program was conducted, which included carcinogenicity, single-dose and multiple-dose (up to 13 weeks' duration) toxicity, safety pharmacology (central nervous system [CNS], renal, and cardiovascular), reproductive toxicity, genotoxicity, vein irritation, phototoxicity, and toxicokinetic testing. The results of the toxicokinetic analyses indicated that the test articles provided large multiples of the clinical exposure to S-59, whether the comparison was based on dose, maximum plasma concentration, or area under the concentration-time curve. No specific target organ toxicity, reproductive toxicity, or carcinogenicity was observed. S-59 and/or PCT formulations demonstrated CNS toxicity, electrocardiographic (ECG) effects, and phototoxicity at supraclinical doses. On the basis of the extremely large safety margins, the CNS and ECG observations (at >30,000-fold the expected clinical exposure) as well as the results of genotoxicity and phototoxicity studies are not considered to be of toxicological relevance. The results of an extensive series of studies have thus demonstrated no toxicologically relevant effects of platelets treated with Helinx technology., (Copyright 2001 by W.B. Saunders Company.)

While HMG-CoA reductase inhibitors such as fluvastatin, lovastatin, pravastatin and simvastatin demonstrate lack of in vitro and in vivo mutagenicity and clastogenicity in bacterial and mammalian cells, long term rodent carcinogenicity studies resulted in an increased incidence in neoplasms at high doses. These effects may be attributable to an exaggeration of the desired biochemical effect of the drug and/or a tumor promoting effect. The genotoxicity of atorvastatin, a newly developed HMG-CoA reductase inhibitor, was evaluated in a variety of test systems. In bacterial mutagenicity tests, the E. coli tester strain WP2(uvrA) and S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed to concentrations of atorvastatin as high as 5000 micrograms/plate both in the absence (S9-) and presence (S9+) of metabolic activation. Atorvastatin was not mutagenic in either E. coli or S. typhimurium. Chinese hamster lung V79 cell cultures were exposed to atorvastatin at concentrations of 50-300 micrograms/ml (S9-) and 100-300 micrograms/ml (S9+) and structural chromosome aberrations were assessed. Mutation at the hgprt locus was assessed at concentrations of 100-300 micrograms/ml (S9-) and 150-275 micrograms/ml (S9+). Atorvastatin was neither mutagenic nor clastogenic in the absence or presence of S9. The lack of in vitro genotoxicity was corroborated in vivo in a mouse micronucleus study in which single oral doses of atorvastatin were administered to male and female CD-1 mice at 1, 2500, or 5000 mg/kg. No biologically significant increases in the frequency of micronucleated polychromatic erythrocytes in bone marrow at 24, 48, or 72 h postdosing were observed. Thus, atorvastatin, as with the other tested HMG-CoA reductase inhibitors, is not genotoxic.

This animal study was designed to investigate HBO as a treatment or prophylaxis for radiation myelitis. All animals received identical spinal cord radiation doses of 69 Gy in 10 daily fractions. Group I received no HBO; group II began HBO at the onset of signs of myelitis; group III received HBO with prophylactic intent beginning 6 wk after irradiation; and group IV received both modalities on the same day, but radiation always preceded HBO by at least 4 h. HBO consisted of 90 min oxygen at 2.4 atm abs for 20 daily treatments. Animals were objectively assessed for the loss of certain neurologic reflexes indicative of four levels of myelitis. Although all animals progressed to severe myelitis, group III animals had group-averaged levels of myelitis consistently less than control. The differences were statistically significant for several weeks. Group IV animals progressed to severe myelitis much more rapidly than any other group. Additional study is justified by this trial. Key questions to be answered include the optimal timing of HBO to produce a beneficial rather than detrimental effect.

In our laboratories we are conducting investigations of potential interactions between radio-frequency electromagnetic radiation (RFR) and chemicals that are toxic by different mechanisms to mammalian cells. The RFR is being tested at frequencies in the microwave range and at different power levels. We report here on the 1) ability of simultaneous RFR exposures to alter the distribution of cells in first and second mitoses from that after treatment by adriamycin alone, and 2) on the ability of simultaneous RFR exposure to alter the extent of sister chromatid exchanges (SCEs) induced by adriamycin alone. This chemical was selected because of its reported mechanism of action and because it is of interest in the treatment of cancer. In our studies, Chinese hamster ovary (CHO) cells were exposed for 2 h simultaneously to adriamycin and pulsed RFR at a frequency of 2,450 MHz and a specific absorption rate of 33.8 W/Kg. The maximal temperature (in the tissue-culture medium) was 39.7 +/- 0.2 degrees C. The experiments were controlled for chemical and RFR exposures, as well as for temperature. Verified statistically, the data indicate that the RFR did not affect changes in cell progression caused by adriamycin, and the RFR did not change the number of SCEs that were induced by the adriamycin, which adriamycin is known to affect cells by damaging their membranes and DNA.

A fibroblast cell line (Balb/c 3T3) was sham/exposed to ultrasound (2.2 MHz resonant frequency, 35.4 W/cm2 SPTP, 3 microseconds pulse duration, 200 Hz prf) for 30 min and subsequently scored for cell motility and alterations in cell morphology. Cell motility was assessed by computerized tracking of cells. Cell morphology ("normal" or "abnormal") was determined blindly by three independent scorers. A positive control (1-4 Gy) yielded statistically significant alterations in cell motility and morphology; no such differences were observed for the ultrasound regimen. The results thus fail to confirm an earlier report by Liebeskind et al. (Brit. J. Cancer 45(Suppl. V):176-186; 1982) of ultrasound-induced alterations in cell motility and morphology.

In this study, the influence of fetal exposure to ultrasound on the development of immunocompetence is addressed. Pregnant BALB/c mice were exposed to various intensities of ultrasound ranging from 0.1-3.0 W/cm2. B cells from 19 day old fetal livers or 5 and 10 day old neonatal spleens were assessed for the following: (a) differentiation into plasma cells after mitogenic stimulation with lipopolysaccharide (LPS); (b) development and frequency of 2,4-dinitrophenyl (DNP)-specific B cells, and (c) the ability to produce antibody in response to DNP. Comparison between ultrasound-exposed and sham-treated groups did not reveal any evident differences in the above tests. The results suggest that ultrasound neither hinders nor augments the development of immunocompetent B cells.

Fertilised chicken eggs were incubated for 48 hours while exposed to pulsed trains of magnetic fields having a duration of 0-5 ms, a rise time of 42 microsecond, and a pulse repetition rate of 100 at a magnetic field flux density of 1 microT. Some eggs were exposed to 1,552 rad X-rays as a positive control. After exposure the embryos were scored blind for a variety of morphological features. X-irradiated eggs displayed highly significant and repeatable anatomical alterations. There were no differences between magnetic field-exposed, sham-exposed and control eggs.

The purpose of this study was to determine if ultrasound radiation would affect the ability of antigen-stimulated B cells and their clonal progeny to undergo the isotype switch and produce diverse antibody classes. Pregnant BALB/c mice were exposed to various intensities of ultrasound (0.1-3.0 W/cm2) at different ages of gestation. Spleens from the resulting offspring were removed five or ten days after birth. The splenocytes were analyzed for the frequency of B cells capable of responding to the hapten 2,4 dinitrophenyl (DNP) using the splenic fragment assay, a B cell cloning assay. The DNP-responsive B cell clones were then classified on the basis of isotype expression. It was found that ultrasonic radiation during gestation did not alter the frequency of B cells responding to DNP. Furthermore, ultrasound had no apparent effect on the B lymphocyte's capacity to switch to different isotypes after antigenic stimulation. Thus, the results indicate that prenatal exposure to ultrasound does not appreciably affect the genetic and cellular processes necessary for the isotype switch and antibody class production.

Chinese hamster ovary (CHO) cells were exposed for 2 hr with and without mitomycin C (MMC) (1 X 10(-8)M) to pulsed wave radiofrequency radiation (RFR) at 2450 MHz. The repetition rate of 25,000 pulses per sec (pps), pulse width of 10 microseconds, and exposure geometry used, resulted in a specific absorption rate (SAR) of 33.8 W/kg. The following exposure regimens were used: a 37 degrees C water bath control; a water bath temperature control (TC) in which the continuously monitored medium temperature closely followed the temperature rise in the RFR-exposed flasks; and the RFR-exposed cells in a water bath set at 37 degrees C prior to exposure. RFR exposure resulted in a maximum cell culture medium temperature of 39.2 degrees C. In the absence of MMC, there was no significant increase in sister chromatid exchange (SCE) in the RFR-exposed or TC groups over that of the 37 degrees C control. When a simultaneous treatment of RFR and MMC occurred there was no statistical difference in SCE frequency from that caused by chemical treatment alone.

Human lymphocytes were exposed in vitro to therapeutic levels of ultrasound (1 W/cm2, CW, 0.87 MHz, durations of 80 and 160 sec). There were no significant differences in sister-chromatid exchange frequencies between controls and ultrasound-exposed cells. Exposure of lymphocytes to the positive control (mitomycin C) resulted in a significant increase in sister-chromatid exchanges. The data do not verify a report by Stella et al. (Mutation Res., 138 (1984) 75-85) that such exposures result in increased frequencies of SCEs.