Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2023;13(3):e2023177 1 Development of a Patient-Reported Outcome Measure (PROM) for Dysgeusia During Treatment With Smoothened (SMO) Inhibitors for Basal Cell Carcinomas: The SMO-iD Questionnaire Elisa Camela1, Alessia Villani1, Sonia Sofia Ocampo Garza2, Claudia Costa1, Gabriella Fabbrocini1, Matteo Megna1, Luca Potestio1, Angelo Ruggiero1, Massimiliano Scalvenzi1 1 Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy 2 Universidad Autónoma de Nuevo León, University Hospital ̈ Dr. José Eleuterio González ̈, Dermatology Department, Monterrey, Nuevo León, México Key words: patient-reported outcome measure, dysgeusia, sonic hedgehog inhibitors, PROM, basal cell carcinoma Citation: Camela E, Villani A, Ocampo Garza SS, et al. Development of a Patient-Reported Outcome Measure (PROM) for Dysgeusia During Treatment With Smoothened (SMO) Inhibitors for Basal Cell Carcinomas: The SMO-iD Questionnaire. Dermatol Pract Concept. 2023;13(3):e2023177. DOI: https://doi.org/10.5826/dpc.1303a177 Accepted: February 16, 2023; Published: July 2023 Copyright: ©2023 Camela et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Elisa Camela, Dermatology Unit, Department of Clinical Medicine and Surgery, University of Naples, Federico II, Naples, Italy. Tel: +39 - 081 -7462457 Fax: +39 - 081 – 7462442 ORCID: 0000-0001-7201-9163 Email: elisacamela@gmail.com Acknowledgement: The patients in this manuscript have given written informed consent to publication of their case details Introduction: Dysgeusia may occur during conventional or target-therapies and affect patients adherence-to-treatment. Therefore, it should be monitored to improve clinical outcome. To date, available questionnaires on dysgeusia relate to traditional antineoplastics and do not apply to target-therapies as the pathogenetic mechanism and clinical expression differ. Objectives: To develop a patient-reported outcome measure (PROM) to screen for and monitor the occurrence and severity of dysgeusia in patients under Smoothened (SMO) inhibitors: the SMO-iD questionnaire. Methods: Patients with locally advanced basal cell carcinomas referring dysgeusia under SMO inhib- itors at the University Hospital of Naples Federico II, were enrolled between January-December 2020. The PROM was elaborated based on chemotherapy-induced dysgeusia (CiTas) scale (development phase) and then validated by measuring internal consistency and reliability (validation phase). ABSTRACT 2 Original Article | Dermatol Pract Concept. 2023;13(3):e2023177 Introduction Dysgeusia is a prominently subjective gustatory disturb that may occur during chemotherapies and affect patients ad- herence to treatment and quality of life with severe implica- tions on clinical outcome [1,2]. Therefore, physicians should thoroughly monitor the occurrence of any taste alteration in order to undertake strategies to address it and at the same time not compromise the therapeutic goal. To date, there are several questionnaires that investigate dysgeusia and related symptoms following traditional chemotherapies and radio- therapy [2,3]; however, the advent of new target therapies has led to the occurrence of selective side effects, including taste impairment, that are different under both the qualita- tive and quantitative aspects and brought out the need of new reporting tools. Objectives In detail, dysgeusia occurring during treatment with Smoothened (SMO) inhibitors results from the blockade of the Sonic Hedgehog (SHH) pathway, that has been proven to be a fundamental regulator of the gustatory functioning without impacting the olfactory one [4,5]. For this reason, we developed a new and specific patient-reported outcome mea- sure (PROM) to characterize it: the SMO inhibitors-induced Dysgeusia (SMO-iD) questionnaire. Methods The COSMIN (COnsensus-based Standards for the selec- tion of health Measurement Instruments) ‘study design for PROMs’ checklist was followed during the process of ques- tionnaire creation [6]. A prospective study was conducted on patients affected by locally advanced basal cell carcinomas (laBCCs) treated with Smoothened inhibitors (Sonidegib and Vismodegib) referring dysgeusia, that were admitted to the University Hospital Federico II of Naples, Italy, between January 2020 and December 2020. Informed consent was required before participation. Inclusion criteria were laB- CCs treated with SMO inhibitors and age ≥ 18 years old. By contrast, exclusion criteria included any pre-existing gusta- tory and/or olfactory disturbs, gastrointestinal and/or men- tal diseases that could interfere with the analysis. The study was drawn according to the ethical standards laid down in the World Medical Association Declaration of Helsinki (June 1964) and its later amendments and was approved by the lo- cal Ethical Committee. The questionnaire creation was struc- tured in two phases: development and validation. The Development Phase (January 2020- June 2020) An extensive literature research concerning question- naires on dysgeusia was performed. Above all, the Chemotherapy-induced Taste alterations (CiTas) scale devel- oped by Kano and Kanda in 2013 was selected and employed as theorical model from which developing the questionnaire in issue, given its high consistency in literature [3,7,8]. Such questionnaire consists of 18 items exploring taste alterations, nausea/discomfort, food temperature intolerability and ol- factory disturbs [7]. The Citas scale was administered by 5 investigators (EC, AV, MS, SS OG, MM) to enrolled pa- tients together with broader and open questions to better define the quality and severity of dysgeusia and any po- tential impact on eating habits. Interviews were conducted in-person every 8 weeks from study start and patients an- swers were recorded and transcribed verbatim. The Validation Phase (July 2020-December 2020) All enrolled patients took part in the second phase of PROM development. They were administered the SMO-iD question- naire by the same investigators with the same schedule and procedure of the previous one (the CiTas), ie, every 8 weeks, and answers recorded. The validation process of PROM went through qualitative and quantitative analysis as follows. Results Preliminary Results of the Development Phase Thirty-nine patients meeting the inclusion and exclusion criteria were enrolled in the study. Overall, 160 interviews were made and recorded. From the answers analysis, some Results: Thirty-nine patients were enrolled and interviewed every 8 weeks. In the first phase, 160 CiTas questionnaires were collected, and the SMO-iD questionnaire was developed. In the second phase, 195 SMO-iD questionnaires were recorded, and reliability and validity assessed. Cronbach alpha was 0.89. Conclusions: The SMO-iD questionnaire is a validated questionnaire that shows high face and con- tent validity as well as high internal consistency and reliability. Hence, it may be introduced in daily clinical setting to monitor dysgeusia in patients under SMO-inhibitors. Original Article | Dermatol Pract Concept. 2023;13(3):e2023177 3 questions of the Citas scale resulted redundant and inap- propriate: indeed, they explored aspects not reported by the study population nor in literature concerning SMO inhibitors side effects, such as olfactory impairment and food tempera- ture intolerance [9,10]. Moreover, from the open questions, patients referred variable impact of dysgeusia on social life and eating habits (appetite, nausea and weight) and better detailed the quality and severity of their taste alteration. On this basis, a new and specific questionnaire consisting of 4 domains and 14 items was developed as illustrated in Table  1: the SMO-iD questionnaire. The herein provided version was translated from Italian into English according to the COSMIN-principles. No scoring was provided since the questionnaire is intended to give physicians a toll to screen for and monitor the occurrence of dysgeusia and related symptoms in patients under SMO inhibitors. Moreover, as displayed in the last domain, patients’ self-assessment of dys- geusia severity may guide physicians in changing drug posol- ogy or eating behaviors during treatment to improve their quality of life and increase compliance. Preliminary Results of the Validation Phase The qualitative validation of the PROM in issue derived from investigators interviews recording participants’ opin- ion about accuracy of questions and standardized answers as well as overall approval of the questionnaire. A total of 195 SMO-iD questionnaires were collected and analyzed. In general, the questionnaire was appreciated by patients and defined as more focused to describe their taste alterations compared to the previous one. Moreover, it was depicted as easily understandable, repeatable, and fast. Also, the quan- titative validation was performed employing the Cronbach alpha (CA), a test that measures the internal consistency of a survey, since it makes inferences about the health sta- tus of individuals (ie, dysgeusia), which is an unobservable variable for the practitioner, using available evidence (ques- tions), which instead is observable. The test gave an alpha coefficient of 0.89 which indicates high internal consistency (note that a reliability coefficient of .70 or higher is consid- ered “acceptable” in most social science research situations). Also, the 95% confidence intervals were computed based on 1000 bootstrapped samples which resulted in [0.83, 0.950]. The narrow bands, small standard errors, also supported the accuracy of the survey. In addition to computing the alpha coefficient of reliability, the dimensionality of the scale was investigated, since the unobservable variable was assumed unidimensional. Factor analysis is one method of checking dimensionality (Table 2). Looking at the table labeled “To- tal Variance Explained”, the eigenvalue for the first factor is significantly larger than the eigenvalue for the next factor Assessing taste perception Do you perceive the salty taste? Do you perceive the sweet taste? Do you perceive the bitter taste? Do you perceive the sour taste? Do you perceive the umami taste? □ no □ little □ tolerably □a lot □ no □ little □ tolerably □a lot □ no □ little □ tolerably □a lot □ no □ little □ tolerably □a lot □ no □ little □ tolerably □a lot Assessing taste distortion Do you have a metallic taste in your mouth? Do you have a bitter taste in your mouth? Do you have a foul taste in your mouth? Do you have a salty taste in your mouth? Do you have a sickly-sweet taste in your mouth? □ yes □no □ yes □no □ yes □no □ yes □no □ yes □no Assessing impact on food habits Do you have nausea? Have you lost appetite? Have you lost weight? □ yes □no □ yes □no □ yes □no Assessing severity of dysgeusia How would you grade your dysgeusia? □ mild □moderate □severe Table 1. Smoothened inhibitors-induced dysgeusia (SMO-iD) questionnaire: it is composed by 4 domains that investigate the quality of taste perception and distortion, the impact on food habits and an overall patient self-assessment of dysgeusia severity. 4 Original Article | Dermatol Pract Concept. 2023;13(3):e2023177 and frame [3,7,8]. On the basis of the answers given by in- terviewed patients, the CiTas questionnaire was restructured and modified, reducing the number and topic of items as to make it more focused and specific. Moreover, such new version, the SMO-iD, gives the possibility to have a direct es- teem of patients self-assessment of dysgeusia, that may guide the development of tailored treatment strategies. Hence, the SMO-iD questionnaire was developed and subsequently val- idated, showing high face and content validity as well as high internal consistency and reliability. Such results suggest its potential important applicability in daily clinical practice to collect, monitor and screen for such side effect with a specific tool. Hence, further and real-life studies are needed to sup- port our findings. The SMO-iD questionnaire has been proven to be char- acterized by high face and content validity as well as high internal consistency e reliability. Hence, it may be promis- ingly introduced in daily clinical settings to help physicians screen for and monitor the occurrence and the social impact of dysgeusia in patients under SMO-inhibitors. References 1. Jafari A, Alaee A, Ghods K. The etiologies and considerations of dysgeusia: A review of literature. J Oral Biosci. 2021;63(4):319- 326. DOI: 10.1016/j.job.2021.08.006. PMID: 34487857. 2. Malta CEN, de Lima Martins JO, Carlos ACAM, et al. Risk factors for dysgeusia during chemotherapy for solid tumors: a retrospective cross-sectional study. Support Care Cancer. 2022; 30(1):313-325. DOI: 10.1007/s00520-021-06219-4. PMID: 34283319. 3. Sözeri E, Kutlutürkan S. Taste Alteration in Patients Receiving Chemotherapy. Breast Health. 2015;11(2):81-87.DOI: 10.5152 /tjbh.2015.2489. PMID: 28331697. PMCID: PMC5351492. 4. Kumari A, Ermilov AN, Allen BL, et al. Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation. J Neurophysiol. 2015;113(3):1034-1040. DOI: 10.1152/jn.00822.2014. PMID: 25392175. PMCID: PMC4312875. 5. Hall JMH, Bell ML, Finger TE. Disruption of Sonic hedgehog signaling alters growth and patterning of lingual taste papil- lae. Dev Biol. 2003;255(2):263-277. DOI: 10.1016/s0012 -1606(02)00048-9. PMID: 12648489. (3.10 versus 0.52). Additionally, the first factor accounts for 76.23% of the overall variance. This suggests that the scale domains are unidimensional, that is, the questions in the sur- vey are inherent to one single common factor, ie, the presence of dysgeusia. Conclusions The rationale of creating a new questionnaire to investigate chemotherapy-induced dysgeusia derives from development of the so called “target therapies”- ie, agents that selectively target a specific pathogenetic mechanism that sustains an oncological disease [11]. Hence, the concept of chemother- apy -induced side effects has changed dramatically as they are not the result of a generalized antimitotic effect common to the category of traditional antineoplastics but appears to be class-specific [11]. Moreover, the development of target therapy implies a complete knowledge of the role of certain molecules in the pathogenesis of the disease and in some way may foresee its side effects [11]. Concerning the SMO in- hibitors, the SHH pathway has been proven to be crucial for taste functioning maintenance, and its tackle predictably leads to gustatory impairment [5,12]. In fact, an alteration of the morphology of fungiform papilla, a reduction in the number of taste buds and an impairment in the chorda tym- pani response to all taste quality has been described in pa- tients with laBCCs treated with such agents [4]. By contrast, SHH pathway is not involved in olfactory functioning, that is not affected [4,5]. In those patients, taste alterations have been proven to affect quality of life as well as therapeutic compliance and efficacy [13,14]. In literature, no PROMs or questionnaire on target-chemotherapy induced dysgeusia exist, as the available questionnaires relate to conventional chemotherapies or radiotherapy, and do not perfectly apply to the condition in issue, with the risk of not completely understanding patients’ discomfort. For this reason, we de- cided to create a target-therapy specific questionnaire to in- vestigate the peculiarity of dysgeusia under SMO inhibitors, that manifests with different characteristics compared to conventional antineoplastic agents. A validated and certified questionnaire, the CiTas, has been used as theoretical model Table 2. Principal component analysis: the table shows the results of principal component analysis applied to domains survey. Components Eigenvalues Percentage variance % Cumulative percentage% 1 3.10 76.23 76.23 2 0.52 11.22 87.45 3 0.20 9.40 96.85 4 0.18 3.15 100.00 Original Article | Dermatol Pract Concept. 2023;13(3):e2023177 5 6. Mokkink LB, Patrick DL, Alonso J, et al. COSMIN Study De- sign checklist for Patient-reported outcome measurement instru- ments. 2019. Available at: https://www.cosmin.nl/wp-content /uploads/COSMIN-study-designing-checklist_final.pdf. Accessed January 2022). 7. Kano T, Kanda K. 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