The management of cancer patients' symptoms in doctor consultations is a cornerstone in clinical care, this process being fundamental for the follow-up of the evolution of these. This article presents an application that allows collecting periodically and systematically the data of cancer patients and their visualization by the medical team. In this article, we made the analysis, design, implementation, and final evaluation by analyzing the correlation of this data collection with interaction patterns to determine how the user information can be enriched with information from the interaction patterns. We have followed an agile methodology based on the iterative and incremental development of successive prototypes with increased fidelity, where the requirements and solutions have evolved over time according to the need and assessments made. The comprehensive analysis of the patient's condition allowed us to perform a first analysis of the correlation of the states of patients concerning mood, sleeping quality, and pain with the interaction patterns. A future goal of this project is to optimize the process of data collection and the analysis of information. Another future goal is to reduce the time dedicated to reporting the evolution of symptoms in face-to-face consultations and to help professionals in analyzing the patient's evolution even in the period that has not been attended in person. The management of the symptomatology of patients consumes more than half the time spent by health professionals in monitoring the patient's evolution. It is considered a cornerstone of clinical care, particularly for patients with chronic diseases. However, symptoms and physical disabilities are not detected by health professionals until the patient has an appointment. As a result, the opportunity to intervene and alleviate suffering is lost. In addition, the incomplete information in the Electronic Health Records (EHRs) limits the ability of medical professionals to understand the results of patients. There are several mHealth applications that can remotely monitor patients to overcome this barrier in many medical fields, such as the app for monitoring patients with risk of suffering cerebral strokes by means of cloud services . There aThe number of people who suffer and overcome cancer is continuously increasing, so there is a great concern for their quality of life and quality of care. Most of these people adapt well psychologically and physically after completing their initial treatment. Thus, it is essential to identify the needs in progress to provide support as soon as possible. The need of monitoring oncological patients is considered a fundamental aspect in their follow-up , the maiThe articles , 7 agreeIn this work, the end users are cancer patients, being the evaluation of all the possible influential factors on their evolution  fundamental. For a better design and development of the application, we follow a patient-centered design, with patients and medical professionals in successive interviews with them.The objective of the present study is to perform an integral follow-up of cancer patients through the use of a mobile application that allows registering the levels of physical and psychological follow-up, as well as additional influential parameters in its evolution: treatments, medication, activities carried out, and quality of sleep among others. This monitoring allowed professionals to evaluate the effectiveness of the treatments, as well as to guide or personalize their selection, identifying additionally the population at risk and thus improving the quality of life of patients.Additionally, parameters are recorded to take interaction patterns into account, such as the choice changes made by the patient when replying to each question and the whole reply time. Through the study of the collected data, we made an analysis of the relationship between user variables  and the interaction patterns.The rest of the paper is structured as follows. The related work is studied in The Human-Computer Interaction (HCI) applied to the field of health is increasingly essential in the development of interactive systems for medical professionals and patients . The worThe analysis of emotions has begun to acquire scientific interest according to the possible applications, increasing the number of studies related to the emotional component and its form of evaluation in different areas .The role of emotional communication in the context of HCI is very relevant and challenging when considering the different areas of technological application , like inThe term mHealth is defined as the union of mobile computing, medical sensors, and communication technologies for health care . MHealthIn addition to the intervention of the doctors in the consultations with their patients, another relevant aspect is the optimization of their next consultations before doing them. In this way, they can improve the way in which the medical professionals dictate a new treatment. There is an application of medical treatment to optimize the consultations of medical patients according to the known preferences and other selection criteria . That woAndroid Mobile Informatics Application for Some Hereditary Diseases and Disorders (AMAHD) is a complementary framework for medical practitioners and patients. The mobile application will help to sensitize and complement the efforts of biomedical, medical, and bioinformatics researchers working in the areas of inheritance research and genetics. AMAHD has proven to be a valuable resource for the research company in the battle against hereditary diseases and disorders .There are some cancer-based applications. For instance, a smartphone-based pain management app for adolescents with cancer provides patients pain management support based on their individual pain . AnotherBesides implemented applications, some papers have studied the impact of emotions over the medical applications and how emotions can be related to the usability of the system that they are interacting with , 20. DefIn conclusion, monitoring and reminder applications have been helpful for users in assisting them in monitoring and keep track of the patient's health care records as well as their medication intake, and there are some studies that show how the emotions can affect the usability of mobile applications. This motivates the development of Close2U application with the intention to help the medical practitioners with the analysis that the app can bring them and help them in improving the treatment for the patient. In addition, a novelty of Close2U app is that it shows that the analysis of interaction patterns can enrich self-reported user information. This work analyzes the correlations among cancer-patient variables and interaction-pattern variables.The main material for this research is the mobile application Close2U. The application contemplates the integral monitoring of patients. Patients were able to see and manage both their medication and their appointments. For the part of the appointments that have both with the psychologist and with the doctor, a section was designed in which they can visualize the appointments in a calendar or in a detailed list, and they can be managed by them. The part of the patient's medication has also been designed, in this way they can keep track of his prescriptions, allowing them to visualize and manage them themselves; the medication can be viewed weekly or through a list with the details.The methodology used for the application Close2U was an agile methodology based on the iterative and incremental development of successive prototypes with increased functionality. The application has evolved in its phases of analysis, design, implementation, and evaluation. The successive refinements have allowed the evolution of the prototypes and the increase of their functionality and quality. The agile methodology may be the most appropriate for projects that suffer a high number of changes and need more control and communication with the client in real time and allows both adapting to problems that may arise and making the necessary changes at the beginning of each phase, without having to wait to finish all the actions.Nowadays, it is crucial to incorporate the user into the design and implementation cycle of a mobile application. In addition, in the medical-scientific research community, there is a growing thought that states that the control and prevention of cancer must incorporate a communication with the patient . In thisTo design and develop the application, a conceptual framework was first made; then the necessary algorithms for data capture were designed and the software tools necessary to design it were selected. The developed application allows one to treat and use all the information collected about physical condition, activities, treatments, and so on. Each element of the follow-up was fundamental to know the overall situation of the patient, maintaining their privacy. Information was collected and, in order of priority, actions to be carried out were defined.This section presents the user interface showing the most relevant screens of the final implementation of Close2U app. The changes that occurred in the successive evaluations will be explained, since changes were made throughout the implementation, with the help of the evaluation we made together with the psychologists and the cancer patients.In the screen of Another valued aspect was the parts where the patient felt pain or discomfort, and a screen was made with which the patient could visualize a body in which a pain could be indicated by buttons to make it more visual. This is intended to be more intuitive for the patient as seen in The purpose of the design phase was to ensure that the developed application meets the requirements of the end user before the prototype is translated into the production application. We used the Unified Modeling Language (UML) for defining the design diagrams.To carry out the plan of user activities, the psychologists of the AECC Teruel were taken into consideration. In this way, the interactions that the user must perform with the application were identified. For the selection of the questions to be shown in the survey, a previous analysis was carried out and they were refined through successive evaluations. Next, the interface associated with each of them was designed, as described in In the next stage of the design, once the activities were defined, a sequence diagram was defined, and At the sequence diagram, the objects are shown as lifelines along the survey and with their interactions over time represented as arrows from the origin lifeline to the destination lifeline. Sequence diagrams are appropriate for showing which objects communicate with each other and the messages that trigger those communications.For the implementation, the IDE (Integrated Development Environment) Android Studio was used, together with its emulator to perform the patient part. The implementation and validation were carried out over twelve months.The validation of the application has been made from the requirements analysis phases until the final implementation with the medical professionals of the AECC Teruel. The first tests with patients allowed us to correct the existing conceptual and design errors.Once the first functional prototype of the application was ready, tests were carried out with the users. Based on them, we got back to the design phase and improved the design. Through the evaluation carried out, the interfaces were modified to improve aspects of the usability and functional application, for example, so that this would be intuitive for the patient. In addition, being able to assess the mood of the users during the use of the live system had a practical meaning for the design and improvement of our application.There were 23 users that voluntarily participated in this study, without any economical compensation. They were 50.21 years old in average with a standard deviation (SD) of 10.09. They were 6 males and 17 females. The sample included 7 cancer patients and 16 healthy people.Category 1: overwhelmed, agitated, ashamed, depressed, angry, exhausted, hurt, scared, alone, apprehensive, defeated, desperate, despondent, exhausted, helpless, angry, frustrated, impatient, pessimistic, self-critical, irritated, defensive, despised, and resentfulCategory 2: guilty, stressed, angry, bad, grumpy, dizzy, nervous, sad, discouraged, apathetic, worried, anxious, agitated, hurt, disappointed, distressed, nostalgic, offended, hungry, lacking confidence, impotent, repentant, insecure, and rejectedCategory 3: bored, confused, asleep, busy, pensive, tired, neutral, unequal, confused, hesitant, lazy, disconnected, reserved, indifferent, apprehensive, conflicted, disconnected, reserved, indifferent, scattered, restless, sensitive, and vulnerableCategory 4: well, happy, awake, relieved, cared, empathetic, not critical, confident, calm, and sincereCategory 5: super, proud, satisfied, confident, alive, enthusiastic, strong, encouraged, excited, grateful, hopeful, and open-mindedWe evaluated sleep quality with the self-reported question “How did you sleep?” replied in a 0–10 range . We determined the existence of pain with the question “Have you noticed any pain or discomfort in the last 12 hours?” with an answer from “yes,” “no,” and “discomfort” options. If the user replied affirmatively, then the app asked, “What level of pain/discomfort do you have now?” which was answered in a 1–10 range . The app recorded zero level if the user had previously answered to feel neither pain nor discomfort. We evaluated the mood by asking the user “How are you feeling?” with a multiple response among 97 moods classified in five mood categories , categorized by the medical professionals with who we worked in every step of the design and development of the app. These moods were the following ones:We labeled the responses with more than one mood as undecided. We assessed the indecision for each question with the number of times that the user changes their reply before submitting it. We applied this measure to (a) sleep quality, (b) whether the user felt pain, (c) the level of this pain, and (d) the mood.We used System Usability Scale (SUS)  to measuFirstly, we followed a user-centered design. Three psychologists familiar with cancer tested the Close2U app during the whole development process and provided feedback. The developer improved the app following their recommendations until they were satisfied, to achieve a high level of usability. In this way, the functionalities of the app were enriched according to the common specific needs of cancer patients and their doctors.The app was uploaded to Google Play, which is the main store of apps for Android. We encouraged cancer patients to use the app in a noncontrolled environment, advising them to use the app regularly.We measured the collected information about users  and the information from interaction patterns . We analyzed the correlations among all these variables.We measured the usability of the app at the end of the study with SUS scale.In In a first approximation, it can be estimated that the indecision corresponds to positive moods, since the average completion time of the undecided survey was similar to the times of positive states.What we can observe in the graph of In the graph of What we can observe in the graph of In order to determine if there were statistically significant correlations, we conducted the Pearson correlation test between user variables  and the number of changes when selecting these variables. Regarding the user variables and interaction patterns concerning the numbers of changes, the test found significant correlations in the pairs (a) mood and number of changes when selecting mood, (b) sleep and number of changes when selecting sleep, (c) pain and number of changes when selecting pain, (d) pain and number of changes when selecting pain level, (e) pain level and number of changes when selecting mood, (f) pain level and number of changes when selecting sleep, (g) pain level and number of changes when selecting pain, and (h) pain level and number of changes when selecting pain level. Concerning the user variables among each other, the test found significant correlations in all the possible pairs among the user variables (1) mood, (2) sleep, (3) pain, and (4) pain level. All the significant correlations between mood-related variables and other variables had a negative correlation coefficient. However, all the significant correlations among non-mood-related variables had a positive correlation coefficient.In order to determine if the correlations between survey time and user variables were significant, we conducted Pearson's correlation test, and Regarding usability, the average result of SUS test was 69.2 in the standard range of 0–100, and the standard deviation (SD) was 20.0. We detected a correlation between mood and the number of changes when selecting the answers. This reveals that the number of changes when selecting mood is relevant as it is correlated with useful information. This implies that cancer apps can collect enriched information from users by counting the number of changes when selecting a response in questions. Therefore, interaction patterns provided relevant information concerning moods.The results revealed that users were doubtful  when selecting (a) negative moods, (b) high-quality levels of sleep, and (c) high levels of pain. Notice that we distinguished between low and high values for each user variable, and this was concluded from the sign of correlation coefficients. For example, in the case of moods, this may reveal that users perceived negative emotions as a combination of some basic emotions, in accordance to the theory of Ekman  about baAnother relevant finding was that pain level was significantly correlated with all the other studied variables including the user variables and the numbers of changes when selecting any user variable. Hence, pain level was the variable with most relevant information due to its correlations with all the other variables.In the significant correlations, the sign of correlation coefficients showed that mood-related variables were inversely correlated with sleep-related variables and pain-related variables. The inverse correlation between mood and sleep variables makes sense because the pain negatively influenced on the mood of users, as the pain probably did not let them sleep well.The correlation between the survey time and the pain (including the existence and its level) revealed that the interaction patterns also provided useful information about pain. The survey of the app dedicated a large part to the pain, since the user was asked about the specific locations of the pain in a silhouette-based interface. Users spent more time depending on when they had a higher level of pain. Thus, future applications for cancer patients with silhouette-based interfaces could indirectly help in estimating the pain level.One of the limitations of this research is the small sample size of participants. This sample size only allowed us to detect correlations with large effect sizes. Thus, we may have not detected correlations with small or medium effect sizes.A mobile application has been developed that performs a complete follow-up of the patient. This article has focused on the self-reported moods, sleeping quality, and pain when the patient is using our application, to provide a tool for psychologists to (a) improve their treatment, (b) improve appointments with them, (c) carry out a daily monitoring of patients, and (c) be able to communicate with them outside face-to-face consultations. This increased the patients' sense of being taken care of daily, since they did not feel alone.This article shows (1) how a mobile health application can assist patients in being more active in managing their care, (2) how the emotions affect when completing the survey, and (3) taking more time or making more changes usually depend on their mood, pain, or sleep quality at that time. Our research revealed that interaction-patterns variables provided useful information from some user variables, proved with the statistically significant correlations detected in this study.This work motivates future research concerning the extraction of implicit information from interaction patterns in cancer monitoring apps. The correlation between user variables and interaction patterns triggers a promising research line about getting patients' information from their patterns when interacting with apps, being able to enrich the collected information with this non-self-reported information. This research could also lead to take implicit-extracted mood to adapt the interface to the needs of patients.According to medical professionals, the app helped them to collect relevant data about the disease more easily than if they had had to collect these manually. In the future, we plan to analyze how treatment improves and how waiting times are reduced before face-to-face consultations.In the future, it is intended to perform the noninvasive recording and measurement of the evolution of patients, by means of devices or sensors, to improve both their treatment and their quality of life. For this purpose, we will search available devices or sensors that will support the capture of evaluable parameters that affect patients, at the same time that our application will collect data. Initially, smart sensors and wristbands will be used to record the heart rate and the Electrocardiograms (ECG), blood pressure, and Heart Rate Variability (HRV). We will also explore the registry of other parameters such as oxygen level in the blood, skin and body temperature, and breathing patterns among others.


Perioperative care after appendectomy may be the first exposure to opioids for many children. A quality improvement project was implemented to assess current practice of prescribing pain medications after a laparoscopic appendectomy to decrease unnecessary opioid use via simple, targeted steps.Three measures were implemented in patients undergoing laparoscopic appendectomy for acute appendicitis: (1) ice packs to incision in postanesthesia care unit, (2) standard pain scores within 30 minutes of admission to ward postoperatively, and (3) standardized postoperative order set minimizing opioid utilization and limited number of opioids prescribed at discharge. Pre- and postimplementation data were compared with the primary outcome variable: opioid utilization during the postoperative period.There were no statistically significant differences in age or gender between the 814 preimplementation and 263 postimplementation patients. Postimplementation compliance is 66.9% for icepacks, 88% for pain scores, and 94.7% for postoperative order set. There were statistically significant decreases in intravenous and enteral opioids administered, number of opioid doses prescribed at discharge, and patients discharged with an opioid prescription.By using a multidisciplinary assessment of current state, culture, and management of parental, patient, and nursing expectations, our institution was able to reduce overall opioid consumption. There is a current opioid crisis in the United States. Kane et al noted that there is an increase in hospitalizations and critical care admissions for ingestions in the pediatric population, and the death rate from opioid medications doubled since 2000 . PrescriGuidelines established by the American Pain Society recommend the concomitant use of acetaminophen and nonsteroidal inflammatory drug (NSAID) pain medications in the postoperative pain management of pediatric patients . In a meBy studying past and current practice and defining a process for prescribing pain medications after laparoscopic appendectomy, we can provide appropriate pain control and decrease unnecessary opioid use. The aim of this study was to determine whether a systematic protocol for postoperative pain reduction would reduce opioid utilization. We also wanted to monitor the incidence of postdischarge returns for pain and opioid-related problems such as constipation in this patient population.Children's Hospital of Wisconsin (CHW) is a 298-bed tertiary American College of Surgeons–verified Level I Children's Surgical Center affiliated with the Medical College of Wisconsin. Approximately 350 appendectomies are performed at CHW annually with 250 for acute appendicitis. A single group of pediatric surgeons and providers cared for these patients. Once developed, the entire group was engaged in the implementation of the quality improvement (QI) project. The number of acute appendectomies performed annually did not vary significantly before and after implementation of the interventions.Data were obtained from the Appendectomy Pediatric Prospective Index, a database maintained by the Division of Pediatric Surgery that uses a REDCap  platformInstitutional review board approval was obtained for collection and analysis of retrospective data used to inform the practice initiatives. The QI process and associated prospective data were deemed “Not Human Subjects Research” by the institutional review board.The selection and implementation of quality interventions were based on a hands-on, project-based quality improvement training course developed at CHW based on Plan–Do–Study–Act (PDSA) methodology . The surThe QI team defined the problem by looking at institutional and national data . Locally, there was a high incidence of unplanned returns to the medical system for pain and constipation. Based on these findings, the team defined its aims: (1) to reduce opioid use after appendectomy for acute appendicitis and (2) decrease unplanned returns to the system .Data on patients from 2013 to 2016 were obtained. Hospital readmissions, emergency room, and clinic visits were plotted on run charts (P Chart) to assess the number of patients successfully discharged before a return to system occurred for pain or constipation. Prescriptions were evaluated for total doses prescribed at discharge and were validated in the Wisconsin Enhanced Prescription Drug Monitoring Program to determine if the prescription was filled. All prescriptions filled in the state of Wisconsin that are submitted by pharmacies and other dispensers are captured in this registry. The baseline data were used to inform the global aim: create an efficient and effective care process to reduce the incidence of postdischarge returns for pain and constipation, while decreasing opioid use in pediatric appendectomy patients, and the presence of opioids in the community.A). Once these were defined, the potential interventions were added. The aim and primary drivers were concrete: reduce opioid use during admission and at discharge, use primarily nonopioid analgesia medication, and obtain a 50% reduction in returns to the system for pain and constipation.Once the team was assembled, meetings were held every 2 weeks. Each meeting had ground rules established, assessment tools used, and homework assigned. The first project was for the team leaders to create a driver diagram of the aim, as well as primary and secondary drivers , A. OnceB) which occurred over 3 sessions of 1.5 hours each. Complex in-depth discussions led to multiple underlying causes for returns. Once the current state was defined, an impact/effort assessment tool [Analysis of current state included the use of a fish bone diagram , B whichent tool  for rankA retrospective review of 608 patients with acute appendicitis in our institution evaluating nonpharmacologic measures versus pharmacologic ones demonstrated a significant decrease in narcotic use when nonpharmacologic agents were used with nonopioids. Based on that review, the team selected the following interventions: (1) application of ice packs applied to incisions in the postanesthesia care unit, (2) pain assessment within 30 minutes upon arrival to the ward, and (3) utilization of a specific postoperative appendectomy order set using alternating acetaminophen and ibuprofen with oxycodone available for rescue therapy. To validate that pain was controlled on return to the general unit, pain scores were documented within 30 minutes of arrival. The nurses documented the pain score using Verbal  ; the FacOf note, intraoperative analgesia included injection of local anesthesia around incisions as well as administration of IV ketorolac prior to awakening the patient. These intraoperative processes were continued and not part of the QI process.All of the outcomes were evaluated and discussed at project meetings and the department surgical educational series, ensuring appropriate use and monitoring of pain with weekly feedback to all end users for appendectomy patients.All acute appendicitis patients undergoing laparoscopic appendectomy were included in the PDSAs. PDSA worksheets were completed for each change. End-user education was undertaken by a member of the project team. The changes were implemented from September 2017 to December 2017, and variables from each patient during this period were entered in the database. Weekly graphical feedback was presented on project boards with directed feedback to each end user. After the first week, adjustments were made to improve the workflow and ensure end-user buy in. Frequent sponsor engagement was used to keep all members of the team engaged with the process to monitor and communicate feedback to all end users. Sponsors were members of the executive team with authority who acted as liaisons with leadership to meet strategic aims, provide resources, help overcome any barriers, and hold the QI team accountable.n = 3), complex social situation (n = 1), and patients with complex clinical comorbidities (n = 3) who required customized pain management.Outcome variables for the study included pain scores, inpatient postoperative IV and enteral narcotics use, and number of opioid doses prescribed at discharge. Other variables included length of stay, returns to system for pain or constipation, and total doses of opioids prescribed at discharge. Trends were followed using run charts to assess for special cause variation and sustainment of changes. Excluded patients included transfers from another facility postoperatively, incidental appendectomies, and chronic abdominal pain. Outliers that were not included were nonoperative management failure with subsequent appendectomy , ice pack placement in the postanesthesia unit, use of appendectomy order set, and opioid administration postoperatively and to assess for sustainment or special cause variation. The pre- and postimplementation groups were compared using the Wilcoxon rank sum test for continuous characteristics and the The timeline and implementation of the quality improvement initiative are outlined in Postimplementation, 66.9% had local ice packs in recovery unit, 87.5% had appropriately documented pain scores on return to the unit, and the order set was used in 94.7%.W) (A). Enteral opioids were administered in 92.4% of the preimplementation group, whereas only 41.8% of the postimplementation group had administration of enteral opioids (< .001W) (B).Parenteral opioids were administered in 22.5% of patients during the preimplementation period, whereas only 1.9% of the postimplementation group received parenteral opioids (<.001W) , A. Ente< .001W) , B.Fig 3W) (C). There was a statistically significant change in the number of opioid doses prescribed at discharge from the preimplementation period to the postimplementation period (< .001W). The number of prescriptions filled at discharge is not statistically significant.Prior to implementation of the QI project, 97.4% (59.8% filled) of appendectomy patients received opioid prescriptions, whereas only 66.9% (62.5% filled) were prescribed opioids postimplementation (< .001W) , C. TherD).Both the preimplementation group and postimplementation group were placed on a bowel regimen postoperatively, which was continued after discharge if clinically indicated. Prior to implementing the QI process, returns to the system for pain were 10.7% and constipation was 31.3%. After implementation, returns to the system decreased for pain (0.76%) and constipation (1.9%). These changes are not statistically significant , D.Appendicitis is the most common surgical emergency in children . TherefoCharacterizing historical perioperative pain management was essential in creating the aims for our study. It became quickly apparent that there was wide variation among our providers in the management of postoperative pain and in opioid prescribing and administration practices in response to perceived characterization of pain. By targeting these specific areas, we were able to show a statistically significant improvement in both enteral and parenteral opioid administration and enteral opioid prescriptions provided at discharge. These changes were made possible through targeted standardization of the postprocedural workflow that included a reliable way to measure pain scores, placement of ice packs immediately after appendectomy, and use of standardized postoperative order set. An essential factor in sustaining our program was providing directed feedback to surgeons to improve compliance with the postoperative order set, as well as education of both the patients and parents using the stepping stone document to appropriately adjust expectations. Compliance with our new bundle was ensured by reviewing adherence to the protocol through a structured review process and providing real-time feedback—both positive and negative—to the responsible parties with compliance or deviation from the protocol. One factor that diminished compliance, especially with ice pack placement, was the variation in nursing staff coverage on holidays and weekends. Knowledge of the process was decreased when there was staff only working in a casual position . This study illustrated that the use of standardization decreases variation in both provider and nursing practice.Utilization of quality tools can allow for consistency in the improvement process. As an academic training center, an essential part of maintaining these changes includes ongoing education of the guideline and order set to new trainees every 6 weeks. Furthermore, creating and implementing change require a shift in culture and buy-in from all members of the team. The way that we did this was to include nurses, providers, resident trainees, and staff at all levels in the process to provide perspective and feedback on how to structure these changes in a thoughtful and meaningful way. We also scheduled frequent meetings with established expectations and “homework”  to encourage team member participation and hold all team members accountable. To create sustainable changes, we had to target specific objectives and limit the scope of our interventions so that we were not working beyond the capabilities of the system. However, one of the greatest benefits is we can now not only implement this process to further streamline our care for appendicitis patients but use this infrastructure to create other similar quality initiatives.Limitations of this study include those inherent with a single-institution study. Although patients were not compared in a randomized manner, we did use a comparative control group with similar baseline demographics. The data collection and sharing may have triggered a Hawthorne (or observer) effect, whereby the desired outcome was a temporary change that would disappear once the end users were no longer being observed. Additionally, opioid prescription practices are different in each state based on their legislature, so our results may not be applicable to other centers. Also, other centers may have different opioids on formulary or different first-line pain medications due to insurance coverage; hence, they may use a different regimen. However, regardless of the agent, the overall utilization was decreased. Also, we had a very specific regimen, but we did not account for patients that received regional analgesia nerve blocks in lieu of infiltration into the incision.In conclusion, targeted multidisciplinary groups can be used to evaluate a problem and to recommend and implement change. This initiative was successful in decreasing perioperative opioid utilization and returns to the system by providing an infrastructure that allows for decreased variability, improved compliance, and better outcomes in patients undergoing surgery for pediatric acute appendicitis.QI team members and Daniel Eastwood, MCW Biostatistician.There are no known conflicts of interest associated with this work. All authors made substantial contributions to the design, analysis, and interpretation of data for the work. All authors worked on drafting or revising the manuscript, and gave final approval of the version to be published. All authors are accountable for the work with regard to its accuracy and integrity.There are no conflicts of interest by any of the authors.This research was not supported by grants or funding agencies in the public, commercial, or not-for-profit sectors.


Post-traumatic headache (PTH) is one of the most common and long-lasting symptoms following mild traumatic brain injury (TBI). However, the pathological mechanisms underlying the development of persistent PTH remain poorly understood. The primary purpose of this prospective pilot study was to evaluate whether early pain modulatory profiles (sensitization and endogenous pain inhibitory capacity) and psychological factors after mild TBI predict the development of persistent PTH in mild TBI patients.Adult mild TBI patients recruited from Level I Emergency Department Trauma Centers completed study sessions at 1–2 weeks, 1-month, and 4-months post mild TBI. Participants completed the following outcome measures during each session: conditioned pain modulation to measure endogenous pain inhibitory capacity, temporal summation of pain and pressure pain thresholds of the head to measure sensitization of the head, Pain Catastrophizing Scale, Center for Epidemiological Studies – Depression Scale, and a standardized headache survey. Participants were classified into persistent PTH (PPTH) and no-PPTH groups based on the 4-month data.The results revealed that mild TBI patients developing persistent PTH exhibited significantly diminished pain inhibitory capacity, and greater depression and pain catastrophizing following injury compared to those who do not develop persistent PTH. Furthermore, logistic regression indicated that headache pain intensity at 1–2 weeks and pain inhibitory capacity on the conditioned pain modulation test at 1–2 weeks predicted persistent PTH classification at 4 months post injury.Overall, the results suggested that persistent PTH is characterized by dysfunctional alterations in endogenous pain modulatory function and psychological processes in the early stages following mild TBI, which likely exacerbate risk for the maintenance of PTH. Approximately 1.7 million traumatic brain injuries (TBIs) occur in adults each year in the United States, with mild TBI accounting for the majority (~ 79%) of these injuries . The IntPain is modulated by complex endogenous systems that both facilitate and inhibit pain. Many chronic pain conditions are characterized by abnormal and unbalanced endogenous pain modulatory function  –11. ImpoThe purpose of this prospective pilot study was twofold. First, we sought to determine differences in pain sensitization and pain inhibitory capacity on quantitative sensory tests in mild TBI patients who develop persistent PTH compared to mild TBI patients who do not develop persistent PTH across 4 months post injury. Additionally, we evaluated differences in psychological factors across time, with a focus on depression and pain catastrophizing. Both depression and pain catastrophizing are elevated following mild TBI , 16 and Fifty-five participants with mild TBI were enrolled in this study. Eleven participants dropped out of this study before completing the last study visit at 4 months. These 11 participants were no-shows for the last follow-up visit and/or did not return calls and emails of research staff to schedule the follow-up visit. Thus, 44 participants completed the study and will be the focus herein. Mild TBI participants had to have a mild TBI diagnosis according to the criteria recommended by the World Health Organization Task Force : 1) a GlThe mild TBI participants were recruited from Level 1 trauma centers within hospitals located in the Indianapolis area. Potentially eligible patients had their electronic medical records screened by study recruiters to identify patients that met the inclusion/exclusion criteria. A mild TBI diagnosis was also confirmed by the attending Emergency Department (ED) Physician. Potentially eligible patients were then approached in the Emergency Room and handed a study information sheet describing important details of the study. If the patient expressed interest in the research, his/her identification was put into a secure database. At this point, the research staff would contact the potential participant within 48 h by phone or email to review the inclusion and exclusion criteria again with the participant as well as give particular details of the study to the potential participant. For those still interested, the laboratory session was scheduled within 2 weeks of the injury. Approximately, 33% of patients that were entered into the database by the recruitment staff were enrolled in this study. Patients in the database that were not enrolled 1) did not meet inclusion/exclusion criteria and therefore were not scheduled for first study session, 2) were scheduled for first study session and did not show up, or 3) did not respond to phone calls or emails of research staff.The Indiana University and St. Vincent Indianapolis Hospital Human Subject Review Boards approved this study. In this prospective, observational study, participants completed three laboratory visits. The first visit occurred within 2 weeks post injury while visits 2 and 3 occurred approximately 1-month and 4-months post injury, respectively. During visit 1, participants reviewed and signed a written informed consent form approved by the IRB. To verify participants met inclusion/exclusion criteria, participants completed a health history questionnaire supplemented by interview. During each visit, participants completed the same questionnaires and quantitative sensory tests (QST). These assessments are described below. All participants were asked to refrain from pain-relief medication and consuming caffeine on the day of testing before their session.Prior to each QST test, subjects were made familiar with each sensory test to be performed and were taught the 0–100 pain rating system. The tests of central sensitization  were performed first followed by the CPM test. A minimum of 10 min separated each central sensitization and CPM test.Several quantitative sensory tests in human experimental studies have been used to identify the presence of central sensitization including temporal summation of pain and generalized pressure hyperalgesia .2 probe was placed against the skin of one of the five sites and pressure was gradually increased at a slow constant rate of pressure (30kPA/s). The participant was instructed to verbally signal when (s) he first experienced pain caused by the pressure device at which time the algometer was removed. Two trials were performed at each site with twenty-second intervals between each trial. The PPTs at all sites were averaged for a single PPT score (PPT-Head) to be used in the data analysis *100. A positive percent change score indicated an increase in PPTs following the conditioning stimulus and thus pain inhibition.The most frequently used test of endogenous pain inhibition in humans is condition pain modulation (CPM). CPM refers to the reduction of pain produced by a test stimulus by a second noxious conditioning stimulus in a remote body site  , 22. ForThe CES-D is a 20-item measure of symptoms of depression that has been shown to be reliable and valid in both general and clinical populations . The scoThe PCS assesses negative mental responses to anticipated or actual pain . The PCSParticipants were classified into a persistent PTH (PPTH) group and no persistent PTH (no-PPTH) group after all assessments were collected. This classification was made based on a standardized headache survey (described below) and in consultation with a neurologist.A Headache Survey that has been used successfully in previous studies of post-traumatic headache was administered to all patients , 18. Thepersistent headache attributed to mild traumatic injury to the head. Diagnostic criteria of PPTH attributed to mild head injury according to the ICHD-3 includes [(A)Headache fulfilling criteria C and D;(B)associated with none of the following: a) loss of consciousness for > 30 min, b) Glasgow Coma Scale (GCS) score < 13, c) post-traumatic amnesia lasting > 24 h, d) altered level of awareness for > 24 h, e) imaging evidence of a traumatic head injury such as skull fracture, intracranial hemorrhage and/or brain contusion;associated with one or more of the following symptoms and/or signs: a) transient confusion, disorientation or impaired consciousness, b) loss of memory for events immediately before or after the head injury, c) two or more of the following symptoms suggestive of mild traumatic brain injury: i. nausea, ii. Vomiting, iii. Visual disturbances, iv. dizziness and/or vertigo, v. gait and/or postural imbalance, vi. impaired memory and/or concentration.Head injury fulfilling both of the following:(C)Headache is reported to have developed within 7 days after one of the following: 1) the injury to the head, 2) regaining of consciousness following the injury to the head, 3) discontinuation of medication(s) impairing ability to sense or report headache following the injury to the head;(D)Headache persists for > 3 months after its onset.(E)Not better accounted for by another ICHD-3 diagnosis.Mild TBI participants were classified as having PPTH based on the International Classification of Headache Criteria 3rd edition (ICHD-3) for Participants who did not report headaches at 4 months post injury were classified into the no-PPTH group.p-value for significance was set at p < 0.05.Descriptive statistics were calculated for all the outcome variables. The Chi-square test was conducted to determine whether differences in sex existed between the PPTH and no-PPTH groups. Independent-t tests examined group differences between BMI and age. First, we sought to determine differences in the primary outcome measures in mild TBI patients who developed PPTH’s compared to mild TBI patients who did not develop PPTH’s at 1-week, 1-month, and 4 months post injury. Shapiro-Wilk’s test of normality indicated that the TS variables were not normally distributed. Thus, Mann-Whitney U tests were conducted to determine if TS at the hand and forehead differed between the PPTH and No-PPTH groups at each time point. We conducted 2(Group) × 3(Time) mixed model ANOVAs with repeated measures on time on CPM score, PPT-Head, PCS score, CES-D score, and HA-intensity score. Due to difficulties with the algometer for one participant visit, the no-PPTH group had data for one participant missing in the analysis for PPT-Head. Because the Chi-square test indicated that sex differed between groups, sex was considered as a covariate in each analysis. Tukey’s post hoc tests were used for significant main effects or interactions. The p < 0.10 were retained in the final model. The goodness of fit of the final multivariate model was evaluated by Hosmer–Lemeshow (H–L) test, with p > 0.05 representing the acceptable result. The p-value for significance was set at p < 0.05.Secondly, we used multiple logistic regression to identify baseline (1–2 week) predictors of the presence of PPTH at 4 months post injury . Due to the large number of potential predictors, the initial choice of the independent variables for the model was based on the results of the Chi-square tests and ANOVAs discussed above. Because sex was a potential confounding variable, sex was added into the model first. Other primary outcome variables with n = 42, with an alpha = .05 and power of .80 would allow detection of a moderate effect size (f = 0.27) for the within-between interaction of the mixed model ANOVA.Forty-four participants completed the entire study. Two participants were removed from the data analysis for the following reasons: 1) one participant reported conflicting data on headaches at 4 months and 2) another participant reported headaches at 4 months, but the headaches were not worse than their headaches prior to the injury. Thus, 42 participants were included in the data analysis. Twenty-one participants met the criteria for PPTH and 21 participants were in the no-PPTH group. A power analysis using G-Power indicated that a total sample size of p-values for participant characteristics are presented in Table Means ± standard deviations and Table p < .001) and group (p < .001), which was superseded by a significant time by group interaction (p < .001). The follow-up tests indicated that headache pain intensity significantly decreased from 1 to 2 weeks to 1 month to 4 months post injury in the no-PPTH group. No changes across time were found for the PPTH group. Also, the PPTH group had significantly greater headache pain at all time points compared to the no-PPTH group.The mixed model ANOVA on headache pain intensity revealed a significant effect of time . For CPM score, the ANOVA revealed a significant main effect of group (p = .001), with the no-PPTH group (M = 29.5 ± 3.6) exhibiting greater pain inhibition on the CPM test compared to the PPTH group (M = 11.9 ± 3.6). The main effect of time (p = .824) and interaction were not significant (p = .232).The non-parametric tests showed that TS of the hand and forehead did not significantly change across time or differ between groups at any time point (p’s > .43). The ANOVA conducted on PPT-head also did not demonstrate any significant effects (main effect of time p = .001). The PPTH group (M = 20.8 ± 1.9) exhibited higher pain catastrophizing compared to the no-PPTH group (10.7 ± 1.9), regardless of time point. The main effect of time (p < .001) was also significant, with pain catastrophizing significantly greater at 1-week post injury (19.9 ± 1.6) compared to 1-month (14.9 ± 1.7) and 4 months post injury (12.3 ± 1.6). The interaction was not significant (p = .900). The ANOVA conducted on CES-Depression scores revealed a main effect of group (p = .016). The PPTH group (M = 20.7 ± 2.1) reported higher depression scores compared to the no-PPTH group (M = 13.4 ± 2.1). The main effect of time (p < .001) was also significant, with depression scores significantly greater at 1-week post injury (21.6 ± 1.9) compared to 1-month (15.3 ± 1.4) and 4 months post injury (14.4 ± 1.7). The interaction was not significant (p = .271).For pain catastrophizing, the mixed model ANOVA showed a significant effect of group , indicating that the model fit the data well. The results for the individual predictors are provided in Table The final model for the multiple logistic regression included sex, headache pain intensity at 1-week, and CPM score at 1-week as independent variables. The overall model was statistically significant, ult p = .40, indicThe current pilot study is the first to prospectively evaluate whether endogenous pain modulatory function in the early stages following mild TBI predicts the development of persistent PTH’s. Several key findings emerged from this study. First, we found that persistent PTH is characterized by dysfunctional alterations in endogenous pain modulatory function in the early stages following mild TBI. Second, deficient endogenous pain inhibitory capacity at 1-week post injury predicted the presence of persistent PTH’s at 4 months post injury. Third, mild TBI patients with persistent PTH showed elevated psychological distress across the 4-months post injury compared to mild TBI patients not developing persistent PTH.Preclinical and human studies suggest that mild TBI is characterized by diminished pain inhibitory capacity in the early stages following injury –14. For We also hypothesized that sensitization of the head/neck area, as measured by quantitative sensory tests, at 1–2 weeks post injury would play a role in persistent PTH’s. Prior research indicates that central sensitization is characteristic of many chronic pain conditions , 33, 34 Mild TBI is often accompanied by psychological distress , includiWhile not the primary focus of the current study, we also evaluated other potential variables as predictors of persistent PTH. Notably, headache pain intensity at 1–2 weeks post injury increased the risk for persistent PTH, such that every 1-point increase in headache pain nearly doubled the risk for being in the PPTH group. Additionally, the PPTH group reported significantly greater headache pain in the early phase following injury compared to the no-PPTH group. However, the no-PPTH group averaged over a 4 on a 0–10 NRS scale at 1–2 weeks, indicating moderate headache pain still existed in the early phase post injury in those not developing chronic headaches. Other research has also shown the importance of acute pain in the development of chronic pain. For example, a large prospective observational study of PTH following mild and moderate TBI found that having a headache during the emergency department visit for the head injury  was a risk factor for persistent PTH . ResearcWe also found a greater percentage of females in the PPTH group compared to the no-PPTH group. However, sex was not a significant predictor in the regression model. Research examining sex as a risk factor for persistent PTH has shown mixed results. A recent preclinical study found that traumatic head injury leads to an enhanced and prolonged cephalic hyperalgesic response in female compared to male rats . Along tA few limitations of this study should be noted. First, all participants were recruited from the Emergency Department and we excluded patients with fracture or polytrauma. Thus, we do not know whether the current study’s results would generalize to mild TBI patients not seen at the ED or those with multiple injuries at the time of head injury. Secondly, we only followed participants for 4 months. Predictors of PTH’s at a longer duration post injury  could be different from those found in this study. Third, at the four-month assessment, headaches were assessed retrospectively with an interview versus using a headache diary. Additionally, while we consulted with a neurologist on PTH classification, the neurologist did not personally conduct the headache interviews. Finally, no single defining, clinical characteristic exists for post-traumatic headache . ProspecThe transition from acute to persistent PTH following mild TBI likely involves a complex interaction of neurobiological processes. Consequently, the medical management of the condition is unsatisfactory with current treatments often ineffective . Indeed,


Concerns exist regarding the analgesia effect and safety of epidural steroid injection (ESI) after discectomy. There is an urgent need of studies that efficiently control for confounding, conduct comprehensive and consecutive observation of potential risks of ESI, and investigate its clinical applicability. We thus further designed a randomized controlled study to assess the efficacy of ESI on postoperative pain and complications in patients undergoing unilateral lumbar microdiscectomy.This prospective, blinded randomized controlled trial was conducted at our single hospital. This study was approved by the Committee at the No.2 People's Hospital of Yibin. All procedures were performed by a single surgeon and informed consent was obtained from each patient. Ninty eligible patients diagnosed at our institution with herniated lumbar disc during a period from June 2020 to July 2021 will be assessed. Group 1 was a mixture of 1 mL of 0.5% bupivacaine and 10 mg of triamcinolone acetonide in 1 mL. Group 2 was a mixture of 1 mL of 0.5% bupivacaine and 1 mL of normal saline. The primary outcome measure was the amount of morphine consumption from a patient-controlled analgesia pump at 12, 24, and 48 hours after surgery. The following secondary outcomes were also assessed: postoperative pain score, back pain score, functional disability, and adverse effect.We hypothesized that the ESI was associated with lower pain score, morphine consumption, and hospital stay, with no significant difference in complications for ESI application after lumbar discectomy in lumbar disc herniation when compared with placebo.This study protocol was registered in Research Registry (researchregistry5683). However, many patients with lumbar discectomy experience moderate to severe back pain and radicular leg pain. Lumbar discectomy will remove the mechanical cause of pain, but the painful inflammatory process might persist for a few more days. In addition, the inflammation together with the surgical intervention might negatively influence the long-term results by initiating fibrosis which is considered one of the reasons for late reappearance of pain.–4Lumbar disc herniation is considered to be one of the main causes of sciatica, and lumbar discectomy is the most popular surgical procedure performed in patients with sciatica in China.–8 Many surgeons routinely use ESI during lumbar discectomy to reduce traumatic nerve root inflammation and edema. However, glucocorticoids have multiple adverse effects. Administration of exogenous glucocorticoids dramatically reduces bone mineral density and increases the risk of fracture.–13Reduction of inflammation and edema of the affected nerve root should, theoretically, reduce the postoperative pain intensity. Epidural steroid injection (ESI) is widely used to treat pain originating from the spine, such as pain accompanying spinal stenosis, intervertebral disc herniation, and other degenerative spinal pathologies.–16 Other studies on perioperative steroid vary within administration, diagnostic criteria, surgical technique, and postoperative care. Furthermore, the number of patients in most studies has been low and 2 randomized controlled studies (RCTs) showed no significant effect. However, the other studies reported a positive effect of steroids on pain. Four previous meta-analyses were published–21; 2 meta-analyses reported that intraoperative ESI when compared to placebo was effective in reducing pain in the early stage and reducing consumption of analgesia with no statistically significant differences in terms of overall complications and infection in lumbar discectomy.,19 One meta-analysis reported that intraoperative ESI application offers some benefits in pain control with a significant reduction in the length of hospital stay. The most recent meta-analysis indicated a lower back and leg pain score, decreased morphine consumption, and shorter hospital stay without difference in complications for ESI application compared to placebo after lumbar discectomy in lumbar disc herniation that was not detected in previous meta-analyses. However, these meta-analyses still have many limitations.Previous studies on the effect of ESI following discectomy for herniated lumbar disc disease has been inconclusive and without long-term follow-up.Despite the evidence above, concerns exist regarding the analgesia effect and safety of ESI after discectomy. There is an urgent need of studies that efficiently control for confounding, conduct comprehensive and consecutive observation of potential risks of ESI, and investigate its clinical applicability. Considering different conclusion and limitation of previous studies, we thus further designed a RCT to assess the efficacy of ESI on postoperative pain and complications in patients undergoing unilateral lumbar microdiscectomy. We hypothesized that the ESI was associated with lower pain score, morphine consumption, and hospital stay, with no significant difference in complications for ESI application after lumbar discectomy in lumbar disc herniation when compared with placebo.22.1This prospective, blinded randomized controlled trial was conducted at our single hospital. This study was approved by the Committee at the No.2 People's Hospital of Yibin (YBH22470), and the protocol of the study was registered in Research Registry (researchregistry5683). All procedures were performed by a single surgeon and informed consent was obtained from each patient. Ninty eligible patients diagnosed at our institution with herniated lumbar disc during a period from June 2020 to July 2021 will be assessed.Eligible patients were those undergoing primary single-level unilateral lumbar discectomy. All patients involved in the study had been diagnosed with a prolapsed intervertebral lumbar disc with nerve compression demonstrated on magnetic resonance imaging, with clinically correlated clinical findings and had failed conservative treatment before enrolment. Excluded were patients with central or lateral spinal stenosis due to spondylosis or disc degeneration who needed bilateral decompression, laminectomy, or fusion, and patients with cauda equina syndrome who needed acute operative treatment.2.2The patients were randomly allocated by stratified block randomization using a computer-generated random number into the treatment group or the placebo group. The allocation was made by opening sequentially numbered opaque sealed envelopes. Concealment of allocation was maintained until the time of the study drugs or saline was injected. All other clinical personnel, participants, and outcome assessors were blinded to the intervention. After discharge, the participant's personal information was eliminated from the study number and was therefore not traceable back to the patients Fig. .2.3Group 1 was a mixture of 1 mL of 0.5% bupivacaine and 10 mg of triamcinolone acetonide in 1 mL. Group 2 was a mixture of 1 mL of 0.5% bupivacaine and 1 mL of normal saline. The trained assessor and the patient were blinded to treatment assignment for the duration of the study. Study and data monitor was not blind.In both groups, prophylactic cephalosporin 1500 mg intravenous was given 15 minutes before surgery. General anesthesia was standardized with remifentanil, propofol, rocuronium, glycopyron, and at the end of operation fentanyl 100 μg and toradol 30 mg. For treatment of postoperative nausea and vomiting dihydrobenzperidol 0.625 to 125 mg intravenous was given at induction of anesthesia and ondansetron 4 mg intravenous at the end of anesthesia. Both groups received postoperative pain treatment with acetaminophen 1 g 6 hourly and celecoxib 200 mg daily. When necessary oxycontin 20 mg twice daily, oxynorm 5 mg at demand, or morphine 50 to 100 μg/kg intravenous was given. Nutrition with protein supplements >1.3 g/kg, iron, and vitamins were given from the day before operation including the day of operation and until discharge.2.4The primary outcome measure was the amount of morphine consumption from a patient-controlled analgesia pump at 12, 24, and 48 hours after surgery. The following secondary outcomes were also assessed: postoperative pain score, back pain score, functional disability, and adverse effect.Postoperative pain intensity at rest and pain on cough were assessed at 12, 24, and 48 hours after surgery on a verbal numerical rating scale ranging from 0 (no pain) to 10 (worst pain possible). Back pain intensity was assessed before surgery and at 1 week, 1 month, and 3 months after surgery on a verbal numerical rating scale. Functional disability was assessed before surgery and at 1 and 3 months after surgery using the Oswestry Disability Index, a disease-specific questionnaire designed for use in patients with low back pain that evaluates the patient's overall level of functional disability in terms of percentage score, with higher values representing higher levels of disability. General health status was assessed before surgery and at 1 and 3 months after surgery using the Short Form SF-36 Health Survey Questionnaire, a validated general health questionnaire that document functional status, well-being, and patients’ overall evaluation of their health as a percentage score, with 100% representing the best possible function and 0% the worst possible function. Adverse effect such as sedation and nausea/vomiting was assessed during patients using a patient-controlled analgesia pump.2.5The sample size was calculated to detect a mean difference in 24-hour postoperative morphine consumption between ESI and placebo after unilateral lumbar microdiscectomy. For the previous meta-analysis, the mean and standard deviation of 24-hour postoperative morphine consumption in ESI group were 31.3 and 3.62, respectively. From this, it was determined that 50 subjects would be required to reach an α value of 0.05 and a power of 85%. It was estimated that the attrition rate due to canceled surgery or reasons of late patient ineligibility could be up to 20% and, therefore, to account for this, the final sample size selected was n = 140 (70 per group).2.6U variance analysis was used for discrete numerical variables that did not show normal distribution. Relationships between the categorical variables were determined by preparing crosstabs and using the χ2 test. P < .05 was accepted as statistically significant.The statistical analyses in this study were performed using the Statistical Package for the Social Sciences 20.0 software . Continuous variables were presented in the form of mean ± standard deviation or error. The Kolmogorov-Smirnov normality test was used to assess continuous variables. Group comparisons on the variables that showed normal distribution were performed using 1-way analysis of variance. Mann-Whitney 3,23 Recently, a shorter onset time for steroid effect has been found. The mechanism of this action is probably transmitted by cell membrane receptors decreasing release of glutamate and γ-amino butyric acid. Based on these action mechanisms, the effects of ESI administration after a lumbar discectomy have been studied extensively. However, the results have previously been inconclusive. Therefore, we further conducted a double-blinded RCT to assess the efficacy of ESI on postoperative pain and complications in patients undergoing unilateral lumbar microdiscectomy. The strength of this study was its prospective and randomized design.Steroids suppress the production of prostaglandins by inhibiting Cyclooxygenase-2 mRNA expression centrally and peripherally. Furthermore, steroids inhibit mediators of inflammatory hyperalgesia, such as tumor necrosis factor-α, interleukin-1β, and interleukin-6. These effects require protein synthesis and have a latency of onset. Another late effect of steroids is suppression of proliferation of intercellular proteoglycans and collagen, thereby reducing adhesion and formation of fibrosis.Conceptualization: Jianping Cai.Data curation: Jianping Cai.Formal analysis: Jianping Cai, Wei Jiang.Funding acquisition: Yuguang Song.Investigation: Jianping Cai, Wei Jiang.Methodology: Jianping Cai, Wei Jiang.Resources: Yuguang Song.Software: Jianping Cai, Wei Jiang.Supervision: Yuguang Song.Validation: Beiming Qiu.Visualization: Beiming Qiu.Writing – original draft: Jianping Cai.Writing – review & editing: Yuguang Song, Beiming Qiu.


To provide an overview on the available treatments to prevent and reduce gynecomastia and/or breast pain caused by antiandrogen therapy for prostate cancer.The German Society of Radiation Oncology (DEGRO) expert panel summarized available evidence published and assessed the validity of the information on efficacy and treatment-related toxicity.Eight randomized controlled trials and one meta-analysis were identified. Two randomized trials demonstrated that prophylactic radiation therapy (RT) using 1 × 10 Gy or 2 × 6 Gy significantly reduced the rate of gynecomastia but not breast pain, as compared to observation. A randomized dose-finding trial identified the daily dose of 20 mg tamoxifen (TMX) as the most effective prophylactic dose and another randomized trial described that daily TMX use was superior to weekly use. Another randomized trial showed that prophylactic daily TMX is more effective than TMX given at the onset of gynecomastia. Two other randomized trials described that TMX was clearly superior to anastrozole in reducing the risk for gynecomastia and/or breast pain. One comparative randomized trial between prophylactic RT using 1 × 12 Gy and TMX concluded that prophylactic TMX is more effective compared to prophylactic RT and furthermore that TMX appears to be more effective to treat gynecomastia and/or breast pain when symptoms are already present. A meta-analysis confirmed that both prophylactic RT and TMX can reduce the risk of gynecomastia and/or breast pain with TMX being more effective; however, the rate of side effects after TMX including dizziness and hot flushes might be higher than after RT and must be taken into account. Less is known regarding the comparative effectiveness of different radiation fractionation schedules and more modern RT techniques.Prophylactic RT as well as daily TMX can significantly reduce the incidence of gynecomastia and/or breast pain. TMX appears to be an effective alternative to RT also as a therapeutic treatment in the presence of gynecomastia but its side effects and off-label use must be considered. Androgen deprivation therapy (ADT) is commonly used in metastatic prostate cancer (PCA) or combined with primary radiation therapy (RT) for patients with localized PCA with intermediate- to high-risk features, locally advanced PCA or biochemically recurrent prostate cancer –3.A common side effect of ADT, due to the disturbed balance between estrogens and androgens throughout the body, can be swelling of the male breast called gynecomastia and/or breast pain (mastodynia). Generally, stimulation of estrogen receptors in the breast tissue stimulate growth, while stimulation of androgen receptors inhibits growth. Nonsteroidal antiandrogens like bicalutamide or flutamide block androgen receptors, which through a feedback loop increase the secretion of luteinizing hormone (LH). Increased LH stimulates testosterone secretion, which, however, is then converted to estrogen by peripheral aromatization . As andrGynecomastia and/or breast pain can be observed in up to 85% of patients after therapy with high-dose nonsteroidal antiandrogens, negatively impacting patients’ quality of live (QoL) and treatment compliance .The use of enzalutamide, an androgen receptor signaling inhibitor, besides binding to the androgen receptor inhibiting also DNA binding and coactivator recruitment, has likewise been shown to be associated with a 49% rate of gynecomastia and 21% rate of nipple pain within 2 years . A lowerFor apalutamide, a new selective androgen signal inhibitor, gynecomastia is not described as a drug-related side effect.ADT-related gynecomastia and/or breast pain can be treated by antiproliferative low-dose RT to the breasts. Alternatively, gynecomastia and/or breast pain can be treated by drug intervention using either tamoxifen (TMX) which blocks the estrogen receptor, or theoretically by anastrozole which inhibits the peripheral aromatization of androgens into estrogens. Surgery might also be a treatment option but due to its invasiveness is commonly preserved for those patients were aforementioned treatments have failed , 4. The Complete reports of randomized controlled trials or meta-analysis of RCTs of RT and/or drug interventions to prevent gynecomastia and/or breast pain (prophylactic treatment) or to treat existing gynecomastia and/or breast pain (therapeutic treatment) in patients receiving ADT for prostate cancer were searched in May 2019 using MEDLINE, Current Contents, PubMed, and references from relevant articles. The search strategy included the terms “prostate cancer”, “androgen deprivation therapy”, “hormonal therapy”, “antiandrogen therapy”, “gynecomastia”, “breast pain”, “mastodynia”, “treatment”, alone or in combination.The primary objective was efficacy to treat gynecomastia and/or breast pain as well as treatment-related toxicities.Original articles written in English language and published in peer-reviewed journals after the year 2000 were included. Two authors (P.G. and T.W.) selected studies for inclusion.A total of 8 randomized controlled trials  and one meta-analysis was identified testing the effect of radiation therapy for ADT-related gynecomastia and/or breast pain. Two randomized controlled trials compared prophylactic RT with no RT or sham RT , 7. Two A meta-analysis included five randomized controlled trials analyzing RT vs. observation or RT vs. TMX, or TMX vs. observation .No randomized trials were found using surgery as treatment modality for gynecomastia and/or breast pain.The two identified randomized controlled trials are summarized in Table p < 0.001) after one year. Breast pain was similar in both arms  but developing pain appeared to be less severe after RT (p = 0.043) [One randomized trial was conducted in a double blind, sham-controlled fashion. One hundred-six prostate cancer patients who underwent bicalutamide treatment were randomized to prophylactic single dose electron beam RT with 10 Gy vs. sham RT . The dos= 0.043) .p < 0.001) after one year, while the incidence of breast pain was not significantly lower . RT was directed toward a 5 cm diameter circle of tissue centered on each nipple. The dose was prescribed to the 90% isodose line covering the superficial 3–4 mm of the pectoral muscle using 6 to 12 MeV [In another randomized controlled trial in 125 prostate cancer patients who underwent bicalutamide treatment the use of prophylactic electron beam RT using 2 × 6 Gy vs. observation significantly reduced the rate of gynecomastia from 50.8% to 15.8%  or placebo given for 12 months during bicalutamide therapy, followed by 12 months where bicalutamide was given alone. Primary endpoint was breast-related events (gynecomastia and/or breast pain) at 6 months. Increasing doses of TMX were associated with a decreased incidence of breast events in a dose-dependent manner at the 3‑, 6‑ and 12-month assessments. At 6 and 12 months breast events were presented in 96.7% or 98.3% of patients after placebo and in 8.8% or 20.6% of patients after 20 mg TMX. At 24 months , a high incidence of breast events (>90%) was seen in all groups. There was no evidence of a negative effect of TMX on PSA inhibition at any assessment compared to placebo. An increased incidence of dizziness and hot flushes was observed with prophylactic TMX [In another trial in which prostate cancer patients underwent bicalutamide treatment patients were randomized into either 20 mg daily TMX continuously or 20 mg daily TMX for the first 8 weeks, then at a single weekly dose of 20 mg thereafter for a total of 36 months (or for 24 months in selected patients) in both arms. The trial was stopped early after inclusion of 80 evaluable patients after a planned interims analysis showed the inferiority of the weekly TMX schedule. Breast ultrasonography was used as an objective technique to monitor gynecomastia. There was no difference in treatment-related toxicity between the trial arms. Again, no negative effect on PSA inhibition was observed .p < 0.0001). Interpretation of the results at 6, 9, and 12 months after randomization was confounded by the retreatment of some patients with TMX or anastrozole for gynecomastia/breast pain developing before these timepoints, and therefore not presented. The number of patients actively retreated for gynecomastia/breast pain in the TMX, anastrozole, and placebo groups was 26 (76.5%), 32 (88.8%), and 32 (88.8%), respectively. Resolution of gynecomastia and breast pain occurred in 65.4% of patients in the TMX group, 71.8% of patients in the placebo group (who received TMX) and 18.8% of patients in the anastrozole group [Saltzstein et al. included 107 patients with prostate cancer who received bicalutamide therapy in a randomized placebo-controlled trial comparing 3 months of prophylactic daily 20 mg TMX with daily 1 mg anastrozole or placebo with the primary endpoint being gynecomastia and/or breast pain after 3 months. After the 3‑month prophylactic treatment patients continued for another 9 months with the bicalutamide treatment [p = 0.001); breast pain developed in 39%, 6%, and 27% of patients, respectively (p = 0.006). Treatment was well tolerated and the incidence of toxicity was higher in the anastrozole arm (69.5% of patients) as compared to placebo (37.5%) or TMX (35.1%). There was no major difference among groups regarding PSA response [In a placebo-controlled randomized trial on prostate cancer patients who received bicalutamide therapy, 114 patients were randomized into 48 weeks of prophylactic daily 20 mg TMX, or daily 1 mg anastrozole or placebo. Gynecomastia developed in 73% of patients in the bicalutamide group, 10% of patients in the bicalutamide–TMX group, and 51% of patients in the bicalutamide–anastrozole group (p = 0.0001). The differences in prevalence of gynecomastia and breast pain between the two arms both favored TMX prophylaxis . There was no difference in toxicity observed between the trial arms and there was no difference in PSA control between the trial arms [Serretta et al. conducted a randomized controlled trial on 176 patients with prostate cancer undergoing bicalutamide therapy. Patients were randomized to either 1 year daily 20 mg TMX within 1 month from the onset of gynecomastia and/or breast pain  or 1 year prophylactic daily 10 mg TMX (Arm B). In Arm A gynecomastia and/or breast pain increased with time with a rate of 39.8%, 57.8%, 69.9%, and 78.3% at 3, 6, 9, and 12 months after initiation of bicalutamide. After therapy with TMX gynecomastia and/or breast pain persisted in 27.7% of cases. In arm B, the prevalence of gynecomastia and/or breast pain was 35% after 12 months of therapy. Although TMX was quite effective in the majority of patients of arm B, the action of the drug was slow, with only 18.5% of patients having a clinical response after 3 months of therapy. After 6 months of TMX therapy, the response rate was 43.8%, and many other patients required up to 12 months of administration. The difference in gynecomastia and/or breast pain between the two arms was statistically significant . In patients of the control group who had gynecomastia and/or breast pain a significant decrease in symptoms was achieved in those receiving TMX (p = 0.05). There was no difference of treatment-related toxicity or PSA control between the two arms [Of the control group 67% of patients developed gynecomastia compared with 8% after prophylactic TMX and 34% after prophylactic RT. Regarding the power of the study, prophylactic TMX and prophylactic RT both reduced expected frequency by 50% or more and were therefore effective. However, breast pain was more frequent in the control group than after TMX or RT . Differences were significant (two arms .n = 17) or RT (n = 18). In this subgroup, TMX significantly reduced the frequency of gynecomastia (p = 0.02). After 6 months and 9 months, gynecomastia was recorded in 2 of 17 patients allocated TMX compared with 10 of 18 allocated RT. Of these 35 patients, 29 developed concomitant gynecomastia and breast pain, and a higher reduction in pain was recorded in the TMX group than in the RT group (p = 0.045). After 6 months and 9 months, breast pain was reported in 4 of 14 patients assigned TMX compared with 12 of 15 assigned RT.Data from the latter trial were published again but with more included patients and with similar main results . The 35 p < 0.0001, and OR, 0.34; 95% CI 0.20–0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction of 29.4 and 19.9%, with a number needed to treat of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. In comparison, pooled results from trials comparing TMX vs. observation likewise showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms . TMX resulted in a larger absolute risk reduction of 64.1% and 47.6%, with a number needed to treat to avoid one case of gynecomastia and breast pain of 1.56 and 2.1, respectively.A recent meta-analysis included five randomized trials , 11, 14 Considering adverse effects, these were reported in three included trials with a total population of 330 patients within the meta-analysis. The incidence of adverse effects  were highest in the RT arms 45/155; 29%) compared with observation arms , resulting in an absolute risk increase to harm of 1.6% and number needed to harm of 62.5. On the other hand, the incidence of adverse effects in TMX arms was higher (mostly dizziness and hot flushes) compared to the observation arms  with an absolute risk increase to harm of 9.8% and a number needed to harm of 10 . The aut5; 29% coThe incidence of gynecomastia and/or breast pain after treatment with nonsteroidal antiandrogens or more recently also with enzalutamide is high and effective prophylactic and therapeutic treatments are important. Prophylactic RT (1 × 10–12 Gy or 2 × 6 Gy) is generally well tolerated and can significantly reduce gynecomastia and to a lesser extent breast pain. Secondary cancers are generally a risk after every RT; however, the risk after usage of lower-doses, usually used for treatment of benign diseases, renders the development of second cancers, to the best of our knowledge, very unlikely . LikewisDaily 20 mg TMX is also a well-established approach and appears to be more effective than RT for prophylaxis and therapeutic treatment for gynecomastia and/or breast pain –15. TMX,The resolution rate for gynecomastia is strictly related to the duration of therapy with bicalutamide . ResolutAs expected, based on the pharmacologic mechanisms involved, the benefits of prophylactic TMX 20 mg do not persist once therapy was discontinued . TherefoAlthough low-dose breast RT is usually well tolerated and allows patients to avoid year-long exposition to TMX, late cardiac effects and secondary malignant disease might be of some concern following the delivery of this treatment, especially in the individuals with longer life expectancies, like those who are candidates to receive bicalutamide as an adjuvant treatment . This caA comparative histologic examination of breast tissue one year after RT with 12.5 Gy (3 fractions) and normal tissue without previous RT found a significantly improved but not completely inhibited diethylstilboestrol-induced gynecomastia . GynecomFor clinical practice, besides the comparative effectiveness of TMX and RT also side effects have to be considered. Although RT appears to be less effective than TMX as prophylactic treatment, side effects of RT are only modest and of short duration, whereas the side effects of TMX are usually lasting throughout the whole course of therapy. Patients need to be counseled well regarding this and it might also be an option to start prophylactic RT and switch to TMX, when RT should turn out to be not effective enough.Due to the associated high incidence of gynecomastia and/or breast pain, prophylactic treatment should only be offered to patients undergoing treatment with nonsteroidal antiandrogens or enzalutamide but not to patients undergoing treatment with other forms of ADT. Currently, gynecomastia is not an issue with the new antiandrogen apalutamide.Unfortunately, there is no evidence from randomized trials available regarding different fractionation schedules of RT neither as a prophylactic or therapeutic treatment. Today, besides the established 1 × 10–12 Gy single shot treatment, or the 2 × 6 Gy schedule, commonly hypofractionated schedules with 3–5 fractions of 3 Gy are applied, as recently reviewed by the guideline for radiotherapy of benign diseases published by the German Society for Radiation Oncology (DEGRO) and others , 24.For therapeutic treatment of existing gynecomastia and/or breast pain again, TMX is more effective than RT; however, treatment-associated side effects and their duration also have to be considered in decision making and discussed with patients.For therapeutic RT of existing gynecomastia and/or breast pain even higher doses of around 30–40 Gy total dose are used and recommended , but theAnastrozole has been shown to be ineffective for the prophylactic treatment of gynecomastia and/or breast pain and should therefore not be used , 11.Long-standing gynecomastia resulting from the fibrotic changes in the adipose tissue appears to be best managed by surgery . HoweverProphylactic RT as well as daily TMX can significantly reduce the incidence of gynecomastia and/or breast pain. TMX appears to be an effective alternative to RT also as a therapeutic treatment in the presence of gynecomastia but its side effects and off-label use must be considered.