The results showed that the MMN responses elicited to the duration deviant-stimuli are elicited and reliably detected over the course of several hours in healthy controls, at both group and single-subject levels. Preliminary findings in three comatose patients provide further evidence that the MMN is often present in coma, varying within a single patient from easily detectable to undetectable at different times. This highlights the fact that regular and repeated assessments are extremely important when using MMN as a neurophysiological predictor of coma emergence.The mismatch negativity (MMN) is considered the electrophysiological change-detection response of the brain, and therefore a valuable clinical tool for monitoring functional changes associated with return to consciousness after severe brain injury. Using an auditory multi-deviant oddball paradigm, we tracked auditory MMN responses in seventeen healthy controls over a 12-h period, and in three comatose patients assessed over 24 h at two time points. We investigated whether the MMN responses show fluctuations in detectability over time in full conscious awareness, or whether such fluctuations are rather a feature of coma. Three methods of analysis were utilized to determine whether the MMN and subsequent event-related potential (ERP) components could be identified: traditional visual analysis, permutation  Coma represents the most severe disruption in wakefulness and awareness that arises when cortical and brainstem pathways are damaged as a result of a catastrophic brain injury due to traumatic or non-traumatic causes . In compRecent guidelines provided by the American Academy of Neurology (AAN) and the European Academy of Neurology (EAN) recommend that patients in coma or other disorder of consciousness (DOC) should be diagnosed by using a multimodal approach including a comprehensive behavioral assessment along with advanced electroencephalography or functional neuroimaging, particularly in patients without command following abilities , 4. AlthIt is even more challenging to predict how one will progress while still in a coma state. In the acute stage post-injury, the decisions made in intensive care have a major impact on patient survival and outcome , 8. CritThe auditory MMN  is a neuA different neurophysiological interpretation has been proposed that raises the question of whether the MMN is an indicator of “partial awareness” in the absence of overt behavior , 21. UsiA pioneering study found that over 91% of comatose patients exhibiting the MMN returned to consciousness , and over 90% of those who did not show MMN were considered as non-awake patientsThis approach of repeated or extended testing must also apply when evaluating healthy control subjects for comparisons, since there is evidence -albeit to a lesser extent- that not all healthy individuals exhibit the MMN in a single first assessment . Single-In the present study, as part of an ongoing longitudinal study , we inveIn order to characterize typical ERP responses across a period of up to 12 h during full conscious awareness and to obtain a baseline for the experimental paradigm, 17 healthy control participants  were recruited. Participants were aged between 19 and 56 years old  and had no history of neuropsychiatric disorders, alcohol/drug abuse, head trauma, or known hearing impairment. Participants were paid $15/h up to a maximum of $180 at the end of the study period. The study was approved by the Hamilton Integrated Research Ethics Board .Continuous EEG/ERP data were collected over the course of 24 h from three female comatose patients. All were assessed over the course of 2 days in either the ICU or the neurological Step-Down Unit at the Hamilton General Hospital, and were classified as being in a comatose state with Glasgow Coma Scale (GCS) scores <8 at the first day of recording. Patients 1 and 2 had neurosurgical complications as their coma etiology, while Patient 3 had a traumatic brain injury following a road traffic accident see . PatientDiagnosis of coma and outcome were assessed by the GCS and the Glasgow Outcome Scale (GOS) , respectIn addition, we used the Full Outline of UnResponsiveness score (FOUR). The FOUR includes assessment of eye movements and brainstem reflexes, which are unavailable with the GCS. It reduces misdiagnosis of locked-in syndrome and MCS by including assessment of eye movement, and helps to distinguish between comatose and recovering patients .The MMN was recorded in an auditory three-deviant oddball paradigm , as partHealthy control subjects participated in several EEG/ERP tasks, that were repeated for a test day of up to 12 h. This schedule produced between three and five MMN recording blocks. Sufficient breaks were provided to the control subjects during the day to minimize movement artifacts and fatigue. Patients were tested in two recording sessions conducted 3 days apart, denoted as day 0 and day 3, respectively. Each recording session lasted up to 24 h with all testing done at the patient's bedside. Each test day comprised the same EEG/ERP protocol used in controls, including the MMN paradigm with resting state periods (10 min each) between each task. Behavioral scales were applied at the beginning of each testing day, before the EEG/ERP recordings. According to our protocol , if patiEEG was recorded online with a bandpass of 0.01–100 Hz and sampled at 512 Hz. For healthy controls and one comatose patient, the electrodes were placed on the scalp according to the extended 10/20 system using a 64-electrode cap. A reduced number of 11 electrodes  were used following the same 10/20 system in two patients (Patient 1 and 2) due to surgical incisions and external ventricular drains (EVD). For all controls and patients, vertical and horizontal electrooculogram (EOG) signals were monitored by electrodes placed above and over the outer canthus of the left eye, and reference electrodes were located bilaterally at the mastoids.Data pre-processing was conducted offline (Brain Products Inc.). All recordings were filtered with a bandpass of 0.1–30 Hz. Epochs containing non-ocular artifacts  were removed. Ocular artifacts were corrected using the Independent Component Analysis (ICA) transformation . EEG triIn addition to visual identification of the averaged ERP components, two main statistical methods were used to detect the presence of these components for each recorded MMN block at both the group level and the single-subject level in healthy controls.p-value as an indication of whether this hypothesis is probably true or false. The p-value could be derived from comparison to a Monte Carlo estimate of a permutation distribution, generated by randomly exchanging the trials from different conditions. In comparison to other conventional statistical tests, the permutation test seems to be preferred because of its greater statistical power, reliability for small samples and independence from any assumptions related to normal distribution of data and homogeneity of variances that are required when using parametric tests such as t-tests and analysis of variance (ANOVA)  .t-tests were performed over a mean of six frontocentral electrodes  at each time point to find the intervals where the deviant condition was significantly more negative  or positive  compared to the standard condition. For group-level analyses, dependent samples permutation-t testing was performed across individual-averaged ERPs for the entire epoch (−100 to 600 ms). Maximum effect sizes (Cohen's d) were calculated over 50 and 100 ms periods surrounding the peak latency, which was automatically detected as the most negative or positive peak within each component window of interest respectively (MMN: 80–230 ms and P3a: 250–350 ms). For single-subject analyses, independent samples permutation t-tests were conducted across trials/epochs from each subject. For both analyses, the number of permutations was set to 1,000, the p-values were corrected using the Tmax statistic for multiple comparisons.Here, one-tailed serial permutation p-values, which have been criticized extensively in the literature (H1 (difference between standard and deviants) over null hypothesis H0 (no difference), was quantified by Bayes factors (BF10). Maximum Bayes factors were calculated over the previous time periods surrounding the peak latency for each component of interest. Traditional interpretations of cut-offs  with deviant type  and block (1–5 blocks recorded over time) as within-subject factors at a cluster of six frontocentral electrodes (described above) with amplitude as the dependent variable. Mean amplitudes were exported in a ±50 ms window surrounding the group average peak: 180–230 ms for duration MMN and 80–130 ms for frequency and intensity MMN. When statistically significant differences were found, a Bonferroni ropriate . This ant-test, and Bayesian analysis) was performed at the single-subject level for every recorded MMN block.For the comatose patients, a similar procedure as outlined above  and Bayes factor analysis.t-tests were averaged across all five blocks, reaching values of 1.28 for the duration deviant, 0.79 for frequency, and 1.15 for intensity, indicating a very large, a medium and a large effect size, respectively, according to (d indicated a huge effect size for duration (2.25), and a very large effect size for both frequency (1.39) and intensity (1.51). Maximum Bayes factors computed at the time window of interest for each component mostly revealed very strong to extreme evidence for our hypothesis of significant difference between the deviant and standard stimuli in all blocks  = 7.13, p < 0.05, post-hoc test averaged over the levels of blocks revealed differences between duration and frequency deviants with a mean difference of −1.27 μV (p < 0.05), and between intensity and frequency with a mean difference of 1.33 μV (p < 0.01). No significant main effect was found for block [F = 0.71, p = 0.52, F = 0.84, p = 0.47, When differences between deviants and habituation effects were evaluated within the group, the repeated-measures ANOVA analysis showed a main effect for deviant type [t-test and Bayesian analysis. The serial permutation t-test showed that 3 out of 17 subjects did not exhibit significant MMNs to the frequency deviant in any of the recorded blocks, and one subject to the intensity deviant. Bayesian analysis showed evidence in favor of the presence of MMN responses to frequency and intensity deviants in all subjects in at least one block, confirming the visual inspection. Single-subject analysis showed that both MMN and P3a components elicited by the duration deviant were significantly detected across all blocks in all subjects by using both permutation t-test failed to capture a significant MMN in all blocks for the frequency deviant and in fourth blocks for the intensity deviant. The Bayesian analysis confirmed the visual inspection method by showing anecdotal or moderate evidence for the presence of a MMN in three blocks for frequency and intensity deviants.Patient 1 was a 41-year-old woman who was admitted to the step-down unit 20 days prior to our assessment. The patient had a history of multiple re-resections of a left frontotemporal oligodendroglioma. She was admitted to the neurosurgery operating room for surgical repair of cerebrospinal fluid (CSF) leak, which required reopening of left frontal subdural craniotomy for a lumbar drain and a subsequent right ventriculoperitoneal (VP) shunt. A right frontal EVD was inserted after a shunt infection and an intracranial abscess resection was performed at the previous surgical site. At the time of the first assessment (day 0), the patient had a GCS score of 5. A summary of the MMN results for this patient are given in After a few days of the EEG assessment, the patient's clinical condition worsened. Active care was withdrawn while maintaining comfort measures. The patient subsequently died.Patient 2 was a 53-year-old woman admitted to the ICU, deeply unconscious after a cystoperitoneal shunt malfunctioning that required neurosurgery. She had a history of meningioma resection from the right posterior cranial fossa, complicated by meningitis, CSF leak, and debridement surgeries.A summary of results for this patient are given in The second recording, denoted as day 3, included only two blocks of the MMN paradigm, since the patient exhibited behavioral signals of emerging from coma state as shown in GCS and FOUR scales in This patient was subsequently transferred to the neurosurgery inpatient unit where she was awake, oriented and talking. After a year, the patient had resumed her normal life with minor neurological deficits, which is congruent with a good recovery outcome.This was a 43-year-old patient included in the study 13 days post hospital admission for severe multisystem trauma after being involved in a road vehicle accident. On arrival to the ICU, she was intubated and sedated with a GCS of 3. Computed tomography scans revealed bilateral subarachnoid hemorrhage, with no herniation as well as diffuse axonal injury. Her GCS was 4 and 7 during the first and second EEG recordings, respectively see .On day 0, the patient showed a MMN confirmed by the three methods in block 8 for the duration deviant and in block 10 for the frequency deviant (block 10). A P3a component was reliably detected for the frequency deviant in block 8 and for the intensity deviant in the blocks 7 and 8 with all the methods. The presence of this component was confirmed in other blocks by two methods .On day 3, only a duration MMN was confirmed by visual and Bayesian analysis in 3 blocks see . A P3a rThis patient was transferred to another hospital. Based on her records, the patient remained dependent on the ventilator and the tracheotomy by the time of discharge. She was withdrawing and flexing to pain, and would occasionally open her left eye spontaneously, but not to voice or pain and would not track. She then was transferred to chronic care, after being diagnosed as a VS/UWS patient.All individual ERPs and statistical findings from all comatose patients are displayed in t-test and Bayesian analysis. We also provided preliminary evidence of the utility of monitoring auditory deviance detection in three comatose patients over a 24 h-period at two time points to predict coma outcome. We addressed the question of whether short-term fluctuations in MMN detectability may occur during full conscious awareness or is rather a feature of coma state  and standard stimuli in both MMN and P3a components in all recorded blocks. Bayesian analysis confirmed these findings, by showing “very strong to extreme” evidence. Consistent with the present results, several studies have shown that reliable MMNs can be recorded from session to session in a group of subjects  during the second recording see , suggestThe other two patients in the present study emerged from coma, but exhibited different functional outcomes. Patient 2 emerged 3 days following the first EEG assessment and after a year showed a positive functional outcome (good recovery). Patient 3, however, was transferred to a different hospital and then to a chronic care facility, with a diagnosis of VS/UWS. Regardless of the functional outcome, the MMN was present in at least a single recording occasion for each patient. Coupled with previous evidence of the link between MMN detection and coma emergence, we suspect that continuous electrophysiological monitoring of the MMN may be instrumental in achieving improvements in the sensitivity of coma emergence prediction.In general, the variability in the presence of the MMN component in these patients may be explained by their brain injuries and fluctuations in responsiveness inherent to DOC. Severe brain damage may alter ERP amplitude and topography, and cause temporal delays and inter-trial variability in comatose patients as result of white matter impairments and cortical dysfunction . PerhapsOur small sample-size limits the generalization of our findings and requires further replication in future work. Nevertheless, we consider these results relevant and very promising as they can serve as a foundation upon which to develop monitoring techniques for detecting transient periods associated with partial consciousness in patients with severe brain injury. Although it is challenging to run extended EEG studies without frequent interruptions in ICU environments, the recording of multiple blocks of data per day in a larger population would be ideal for tracking the trajectory of patients and identify those with potential for recovery.t-test was applied to the whole ERP time window in order to identify the significant latency windows of the MMN and P3a components, whereas the Bayesian analysis was applied to narrower time windows of interest. This approach of doing Bayesian test post-hoc after convincing results are obtained with permutations seems methodologically unnecessary. However, given that permutation t-tests are fairly conservative and showed more evidence in favor of null effects in comatose patients, the Bayesian evidence, even “weak or anecdotal” may still be valuable for this clinical population.Our different analysis methods used non-identical information about the waveforms, such as the selection of the time points. For instance, the permutation Importantly, the medical team responsible for patient care were blind to our results, which were never used to influence any clinical decision for treatment or the maintenance/withdrawal of life-sustaining therapies. The presence or absence of MMN alone did not impact such decisions. However, in the not too distant future it is apparent that the MMN, in combination with other potential biomarkers, could help critical care teams improve coma prognosis by relying on objective evidence rather than “perceptions of unfavorable prognosis for meaningful neurologic recovery” , p. 1 inThe results of the present study demonstrate that the MMN responses elicited by duration deviant stimuli are consistently detected over time in healthy controls, at both group and single-subject levels. This finding supports the use of the MMN elicited by duration deviants as a promising tool for monitoring brain functional changes in clinical settings. Preliminary findings in three acute coma patients, recorded over 24 h, provide further evidence that the MMN is present in coma, but can be transient  across hours. This highlights that regular and repeated assessments are extremely important for clinically-appropriate usage of the MMN as a neurophysiological predictor of coma emergence.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Hamilton Integrated Research Ethics Board . The patients/participants provided their written informed consent to participate in this study.JC, RB, JR, AF-R, CH, and AH-D contributed to the conception of the study. C-YL and PT contributed to the organization of the study and recruitment of controls. AH-D analyzed the data and wrote the first draft of the manuscript. AH-D, RK, NP, and EB conducted the experiments. All authors reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.


In medicine, the clinical decision-making process can be described using the dual-process theory consisting of the fast, intuitive “System 1,” commonly seen in seasoned physicians, and the slow, deliberative “System 2,” associated with medical students. System-1—type diagnostic reasoning is thought to be less cognitively burdensome, thereby reducing physician error. To date, limited literature exists on inducing System-1–type diagnosis in medical students through cognitive heuristics, particularly while using modern electronic health record (EHR) interfaces.In this experimental pilot study, we aimed to (1) attempt to induce System-1—type diagnostic reasoning in inexperienced medical students through the acquisition of cognitive user interface heuristics and (2) understand the impact of clinical patient data visualizations on students' cognitive load and medical education.The participants were third- and fourth-year medical students recruited from the University of Pittsburgh School of Medicine who had completed 1+ clinical rotations. The students were presented 8 patient cases on a novel EHR, featuring a prominent data visualization designed to foster at-a-glance rapid case assessment, and asked to diagnose the patient. Half of the participants were shown 4 of the 8 cases repeatedly, up to 4 times with 30 seconds per case (Group A), and the other half of the participants were shown cases twice with 2 minutes per case (Group B). All participants were then asked to provide full diagnoses of all 8 cases. Finally, the participants were asked to evaluate and elaborate on their experience with the system; content analysis was subsequently performed on these user experience interviews.P=.03, respectively). When comparing the novel EHR design to previously used EHRs, 73% (n=11) of participants rated the new version on par or higher (3+/5). Ease of use and intuitiveness of this new system rated similarly high . In qualitative thematic analysis of poststudy interviews, most participants  spoke to “pattern-recognition” cognitive heuristic strategies consistent with System 1 decision-making.A total of 15 students participated. The participants in Group A scored slightly higher on average than those in Group B, with a mean percentage correct of 76% (95% CI 0.68-0.84) versus 69% (95% CI 0.58-0.80), and spent on average 50% less time per question than Group B diagnosing patients (13.98 seconds vs 19.13 seconds, These results support the possibility of inducing type-1 diagnostics in learners and the potential for data visualization and user design heuristics to reduce cognitive burden in clinical settings. Clinical data presentation in the diagnostic reasoning process is ripe for innovation, and further research is needed to explore the benefit of using such visualizations in medical education. In medicine, the clinical decision-making process can be described using the dual-process theory, which postulates cognitive processes consist of the fast, intuitive System 1 and the slow, deliberative System 2 . ColloquSystem-1–type diagnostic reasoning in novices may be possible through the acquisition of cognitive heuristics. One example is Rosby et al , who accIn this experimental study, we aim to further explore the work done by Rosby et al  and the This study received approval from the institutional review board of the University of Pittsburgh Human Research Protection Office under STUDY19020169.t test and ANOVA of the demographic information collected  or metabolic syndrome. The correct diagnosis of each of the patients was one of the following: (1) has metabolic syndrome and NAFLD, (2) has metabolic syndrome and does not have NAFLD, (3) does not have metabolic syndrome and has NAFLD, or (4) does not have metabolic syndrome nor NAFLD. The correct diagnosis for each case was given to the participants, and case information was displayed on a novel EHR user interface featuring a prominent data visualization component .Next, students in each group were shown 4 cases and asked to provide a correct, full diagnosis  for all 4 cases in a row or 1 trial . Studentt test was performed on quantitative values using STATA/SE (StataCorp) and qualitative thematic analysis using the MAXQDA VERBI software was performed on this user interview portion of the study.After the study, the participants were asked to evaluate and elaborate on their experience with the novel EHR design. The questions asked included the following: (1) rating ease of system, (2) rating intuitiveness of system, (3) rating usefulness of system, (4) comparing the novel system with past EHRs used based on intuitiveness, (5) strategies used to compete the tasks, and (6) missing features that would have helped the completion of task and areas for improvement. Questions that asked the participants to give a rating or comparison were formatted on a scale of 1-5, where 1 was the low end of the spectrum  and 5 being the high end of the spectrum . The other questions were open-ended, and the study facilitators encouraged the participants to speak freely in this section. Unbiased follow-up questions eliciting clarification from the participants were occasionally asked. The Welch P=.40), the participants in Group A spent, on average, 50% less time per question than Group B diagnosing patients during the final, time-unlimited testing portion . A 2-sample equal variance (independent) 2-tailed t test was performed. The difference was found to be significant but inconclusive due to the small sample size  versus 69% (95% CI 0.58-0.80) during the final testing portion. While we fail to reject the null hypothesis , the consistency of the user interface layout and reducing number of clicks , and intuitive color coding  consistency of layout aiding in finding specific lab values, (2) trends between different lab values and subsequent diagnosis, and (3) visualization-specific features such as color coordination. One participant spoke of the “search pattern” they had developed through medical school and believed was represented in the layout of the user interface, stating the following:the way the page was set up, it felt very natural to look at the right areas. I would look at BMI first, then down at ALT and AST [common lab values for diagnosing metabolic syndrome and non-alcoholic fatty liver disease]…after a few patients, my eyes were moving where they needed to go.Our study had several limitations. First, it was only performed with 15 students at 1 academic institution, thereby making generalizability unlikely. Additionally, only 1 data visualization interface was shown to all participants. The specific design that was used may not adequately represent other potential iterations of clinical data visualizations on EHRs and again makes generalizability unlikely.We also did not compare the efficacy of the novel EHR with an existing EHR interface such as Epic or Cerner, as our participant criteria included previous EHR experience, and we were interested in the ability to induce System-1 thinking with a completely novel system. We chose to limit our study to participants who had previously used some sort of EHR as these participants were able to provide us design feedback informed by their past clinical experience, as opposed to purely aesthetic feedback on the novel EHR design.Finally, the incorporation of data visualization into EHRs is limited to the decision of the EHR companies; while there may be some benefit to teaching students clinical data through more illustrative methods, this benefit may be moot if visualizations are not adopted on the primary platform where students perform their clinical duties.Several of the qualitative themes hold promise in further investigation of amalgamating the current offerings of how medical education is delivered. Many of the issues students mentioned with current EHRs are solved usability problems in the consumer technology industry by companies such as Google and Apple, but the solutions are not widely adopted in health care today ,13. SimiThe heuristics participants alluded to mirror the widely accepted “10 Usability Heuristics” in consumer user experience web design by Nielsen , or founother than EHRs; introducing a new interface through an EHR that works differently from the consumer products users are accustomed to increases cognitive load by forcing them to learn something new [.” This serves as a good reminder that medical students, in addition to becoming physicians, are patients and technology consumers who have to context switch every time they use present-day EHRs.We begin first by talking about Heuristic #4, which states that “users should not have to wonder whether different words, situations or actions mean the same thing. Follow platform and industry conventions” . When tahing new . Data vihing new . The effHeuristic #8, Aesthetic and Minimalist Design, builds upon the basis set by Heuristic #4 and states, “interfaces should not contain information which is irrelevant or rarely needed. Every extra unit of information in an interface competes with the relevant units of information and diminishes their relative visibility” . The novHow clinical data are presented in the diagnostic reasoning process and medical education is ripe for innovation. In this study, students were able to diagnose patients more accurately after short, repeated exposure to the data visualization interface, implying the possibility of inducing type-1 diagnostics. Additionally, this study demonstrates how incorporating data visualizations and user design heuristics during care delivery can potentially reduce cognitive burden and allow even novices to diagnose quickly and correctly. Further experiments on different, visual displays of data and the benefits it may have on medical education should be conducted, especially in comparison to the existing commonly used EHRs. Studies using eye tracking to better understand what patterns students used, as well as which features were most or least used, should also be run to more precisely understand the search patterns mentioned by the students.


Pleuropulmonary blastoma (PPB) is a tumor occurring almost exclusively in infants and young children. This is the most common primary-lung malignancy in childhood. There is age-associated progression through a distinctive sequence of pathologic changes, from a purely multicystic lesion type I to a high-grade sarcoma type II and III. While complete resection is the cornerstone treatment for type I PPB, aggressive chemotherapy with a less favorable prognosis is associated with type II and III. DICER1 germline mutation is positive in 70% of children with PPB. Diagnosis is challenging, as it resembles congenital pulmonary airway malformation (CPAM) in imaging. Although PPB is an extremely rare malignancy, over the past five years we have encountered several children diagnosed with PPB in our medical center. Herein, we present some of these children and discuss diagnostic, ethical, and therapeutic challenges. Pleuropulmonary blastoma (PPB) the most common primary lung malignancy in childhood . First rPPB is unique among developmental malignancies of childhood in its age-associated progression through a distinctive sequence of pathologic changes from a purely multicystic lesion to a high-grade sarcoma. Type I PPB is composed of air-filled cysts with primitive mesenchymal cells beneath an intact, benign-appearing epithelium. These cysts can progress into type II PPB, in which the mesenchymal cells overgrow the septa, producing a cystic and solid neoplasm. Type III PPB is an exclusively solid sarcomatous neoplasm ,3.There is strong evidence for progression from type I to type II and type III PPB. Type Ir (regressed) PPB is a purely cystic lesion, microscopically devoid of subepithelial septal primitive cells, and it is considered to have a lower risk for neoplastic progression ,5. The pType I PPB may present with respiratory symptoms such as cough, dyspnea, chest pain or abdominal pain. Chest X-rays may show signs of pneumonia, and some cases may present with difficulty in breathing, from a pneumothorax or a large lung cyst, or a PPB can also present as an incidental radiologic finding of a lung cyst. The purely cystic type I PPB can be easily mistaken for other congenital lung malformations such as congenital pulmonary airway malformation (CPAM), as CPAM origins can be from the acinar structures of the lungs, thus creating a multiseptated cystic lesion similar to type I PPB. The diagnosis of type I PPB should be considered in the evaluation of any multicystic specimen of peripheral lung from young children. The final diagnosis requires meticulous pathological examination.Given the rarity and clinical heterogeneity, it is still unclear what is the optimal therapeutic approach. The treatment for type I and type Ir PPB evolved over time; most cases are treated with surgical resection alone, while in some cases adjuvant chemotherapy is added. Most type Ir PPBs are followed clinically after complete surgical resection, due to the low risk of tumor progression. Cases of type I PPB are treated with oncologic surgery alone. In cases of suspected incomplete resection or unresectable lesion, chemotherapy is added . A recenDICER1 variants as the first known genetic causes of PPB familial syndrome -fluoro-2-deoxy-d-glucose positron emission tomography-computed tomography showed no metastases : complex cystic lesion with aberrant vessels within the cyst septa located in the right upper lobe a. We susSix-year-old boy (older brother of patient no 3): two purely cystic lesions, one in the right middle lobe (diameter of 4 cm) and a smaller cyst in the left lower lobe b,c.Fifteen-month-old boy (younger brother of patient no 3): two purely cystic lesions, one in the right lower lobe (diameter of 0.6 cm) and a second cyst (diameter of 1 cm) in the left lower lobe d.We consulted the IPPBR team about the other three siblings as well; they considered the lesions to be a type I PPB, and resection was suggested.The parents were given the complete information about the findings and the consultations. They decided to proceed with a more conservative approach, with clinical and radiological follow up only. Two years later, the children are healthy, and the radiological findings are stable.DICER1-germline-positive patients. We summarize some of the challenges we dealt with while treating these patients.We presented six children with either proven PPB or DICER1-related cystic lung disease suspected to be PPB, all treated in our hospital within the last 5 years. This cluster of patients raised our awareness about this rare tumor and the diagnostic and management challenges it brings. Timely diagnosis and resection of type I PPB is crucial, but this entity is elusive, masquerading as a lung malformation, or growing silently in Can we differentiate CPAM from type 1 PPB, based on clinical aspects and imaging?Differentiating the entities may influence management. There are different approaches for the management of CPAM. Some centers advocate an aggressive approach by resection of all lesions, in fear of future progression to malignant PPB. Others choose to follow up, advocating that PPB is a rare entity and CPAM 1–3 are benign lesions that will not progress to PPB . The reap < 0.01) [Imaging alone cannot differentiate CPAM type 4 from type I PPB ,17,18. I < 0.01) .What are the differences between CPAM type 4 and type I PPB? Dehner et al. stated that CPAM type 4 and type I PPB are in fact synonymous, and, due to the concern of progression from type I PPB to the malignant type II and III PPB, it would be wiser to define these lesions as type I PPB rather than CPAM 4, and thus promote a more aggressive approach toward oncologic resection and genetic counselling .In Feinberg A. et al., the IPPBR team summarized their experience with the goal of answering this question. Overall, 112 cases of type I PPB gathered in the registry between 2002 and 2013 and 103 cases of CPAM that were resected in the same institution during the same period were reviewed. Features favoring CPAM were prenatal diagnosis, and CTA findings of a systemic feeding vessel and hyperinflated lung. Features that raised the suspicion of PPB were multi-segmental or bilateral lesions and the absence of prenatal ultrasonography findings .DICER1 germline mutation further confirmed our concern. We consulted the IPPBR, which supported our diagnosis of type I PPB. In the family with four children with DICER1 (patients 3–6), two of the three asymptomatic siblings have bilateral cystic lesions, and thus they are highly likely to having type I PPB.In our first two patients, the suspicion of type I PPB was high, due to the early symptomatic cystic lung lesion and normal prenatal follow up. In the recent IPPBR report, 85% of type I PPB cases were symptomatic at presentation, 32% with pneumothorax . The posDICER1 germline testing? Any congenital cystic lesion? Only in cases that are highly suspicious? Only in pathology-determined PPB?What are the indications for In 2016, the IPPBR convened an international DICER1 symposium and published a consensus paper on the indications for testing and the surveillance advised for DICER1-positive children [DICER1-germline-positive children are age based, with at least one chest CT performed in all cases [Recommendation for screening in ll cases . These iBased on the IPPBR recommendations, we tested and diagnosed the siblings of patient number 3, who presented with malignant PPB: all three siblings had CT findings suggestive of PPB. The family decided to continue with clinical and radiological follow up instead of resecting all lesions. This family evoked an ethical question regarding the indications for testing an asymptomatic sibling. The parents of patient no 3 stated during the follow up, post factum, that they preferred not to know the child’s DICER1 status. With increased awareness of the advantages of early detection of type I PPB, and the possible prevention of progression through early intervention, more families will eventually choose to know the DICER1 status. These four DICER1 siblings bring us to the next challenge.When can we safely say that a type I PPB lesion has regressed to Type Ir PPB?We know that pathology alone can provide the final discrimination between type I and Ir PPB, but in our DICER1 family, pathology was not available for the three siblings of patient no 3. The children differ in age and appearance of the lesions. The oldest sibling was 9 years old when diagnosed, and had a multiseptated single cyst, while the two younger brothers had multifocal simple cysts. Over 2 years of CT follow up, we saw no change in the appearance of the lesions in all three children (patients Nos. 4–6). Does it give us any reassurance? We know that the median age for diagnosis of type I PPB is 7 months, for type II PPB 35 months and for type Ir PPB 2.6 years , and thaThe IPPBR reported two cases of progression in type Ir PPB, both occurring within 2 years. They suggested 2 years of follow up for resected type Ir PPB. In type I PPB recurrence occurred more frequently and within 63 months, so they advised a longer follow up for type I PPB, of at least 6 years . We inteDICER1-germline-positive, asymptomatic child. Oncologic resection versus close radiologic and clinical follow-up: pros and cons.Multifocal cystic lesions in a Multifocal cysts are more difficult to manage. On the one hand, multifocal cysts have an increased risk of progression compared to a single cyst, while on the other hand multiple surgeries might increase surgical complications and decrease lung function. In the last IPPBR report , 25% of The role of chemotherapy in cases of suspected incomplete resection of type 1 PPB.PPB Ttpes II and III are aggressive malignant diseases and chemotherapy is mandatory. The primary treatment for type I and Ir PPB is surgery with complete resection. The reasoning for adjuvant chemotherapy in type IPPB and even type Ir PPB is to prevent recurrence or progression of any residual disease (microscopic or macroscopic) to the more aggressive tumor type II and type III PPB. In the recent report by the IPPBR , the groIs the prevalence of Type I PPB increasing in recent years, or have we misdiagnosed some of them as CPAM?Within five years we diagnosed six patients with DICER1 due to high level of suspicion, five of them were diagnosed with type I PPB. We consulted the IPPBR team in all our cases and learnt that there is a need for a high level of suspicion and experienced teamwork in order not to miss the type I PPB patients and to be able to treat them accordingly. It is possible that the prevalence of type I PPB is on the rise, due to the fact we might have misread some of our previous cases as CPAM. In fact, to emphasize the importance of a central pathology review for rare tumors such as PPB, it was reported that almost 20% of the pathology specimens submitted for review by IPPBR had another initial diagnosis. Thus, it may be challenging to identify a lesion as PPB, even for experienced pathologists .PPB is a rare tumor, with predicted progression from the benign type I PPB to malignant tumor. Timely diagnosis and complete resection of type I PPB correlates with the best prognosis. Symptomatic cystic lung lesion in infants, unidentified during pregnancy, especially when septated or multifocal, should raise the suspicion of type I PPB rather than CPAM, and induce testing for DICERI mutation and early complete resection. The management of multifocal cysts, the role of chemotherapy and management of older asymptomatic DICER1 children is complicated, and should sometimes be individualized. Consultation with the IPPBR team is recommended.