Clinical Outcomes of Percutaneous Biliary Endoscopy: A 7-Year Single-Institution Experience.

PURPOSE: To evaluate safety and effectiveness of percutaneous biliary endoscopy (PBE) performed on patients ineligible for surgery or endoscopic retrograde cholangiopancreatography. MATERIALS AND METHODS: Retrospective review was conducted for all patients who underwent PBE at a single academic institution between June 2013 and February 2020; 39 patients underwent 58 choledochoscopy sessions, and 21 patients underwent 48 cholecystoscopy sessions. Choledochoscopy indications included stone removal (23 of 39 patients) or biliary stenosis evaluation (19 of 39 patients). Cholecystoscopy indications included calculous cholecystitis (18 of 21 patients) and symptomatic cholelithiasis (3 of 21 patients). Technical success, procedural and fluoroscopy times, and tube-free survival were assessed. RESULTS: For all PBEs performed for stone clearance, using disposable endoscopes led to shorter mean ± SD procedural (128.7 minutes ± 56.2 vs 240.2 minutes ± 184.6; P < .01) and fluoroscopy times (10.7 minutes ± 7.9 vs 16.5 minutes ± 12.0; P = .01) than using reusable endoscopes. Increasing institutional experience was associated with reduced procedural time (ß = -56.73; P < .001). Choledochoscopy technical success was 94.8% with 1 adverse event of bile duct perforation with bile leak requiring drainage. For patients with choledocholithiasis, biliary drains were removed in 14 (60.9%) patients, with a mean tube-free survival of 22.1 months ± 23.8. For cholecystoscopy, technical success was 93.8% with no adverse events. Cholecystostomy tubes were removed in 15 (71.4%) patients, with a mean tube-free survival of 7.5 months ± 8.8. CONCLUSIONS: This study supports PBE as a safe and feasible option for nonsurgical patients or those with altered anatomy precluding endoscopic retrograde cholangiopancreatography. Moreover, PBE may result in tube-free survival.

Responsiveness of the Patient-Reported Outcome Measure for Vascular Malformation Questionnaire in Patients with Low-Flow Vascular Malformations.

PURPOSE: To assess the responsiveness, defined as the ability to detect change in a patient's health or function, of the Patient-Reported Outcome Measure for Vascular Malformation (PROVAM) questionnaire in a cohort of patients with low-flow vascular malformations (VMs). MATERIALS AND METHODS: PROVAM was previously developed to assess symptoms, functional limitations, and social/emotional effects experienced by patients with VMs. This is a prospective cohort study of 56 patients with venous and lymphatic VMs who completed at least 2 PROVAM questionnaires, of whom 43 had undergone treatment with sclerotherapy in the interim between questionnaires. External responsiveness was assessed using a receiver operating characteristic (ROC) curve to ascertain whether a change in the total PROVAM score predicts whether patients reported symptom improvement and by correlating the change in the total PROVAM score and change in symptoms reported during clinic visit. Internal responsiveness was evaluated using Wilcoxon signed rank test, Cohen d effect size (ESp), and standard response mean difference (SRM). RESULTS: The total PROVAM score demonstrated excellent discrimination for symptom improvement with an area under the ROC curve of 0.856. There was a statistically significant, moderate positive correlation between the change in the total PROVAM score and the change in patient symptoms as determined from clinical visits (Spearman correlation coefficient [rs] = 0.67, P < .001). The total PROVAM score and all subdomain scores improved significantly after treatment (all P < .05). ESp and SRM were 0.80 and 0.83, respectively. CONCLUSIONS: PROVAM is responsive to improvement after treatment and may be useful to assess health-related quality of life in patients treated for VMs.

Single-Use versus Reusable Endoscopes for Percutaneous Biliary Endoscopy with Lithotripsy: Technical Metrics, Clinical Outcomes, and Cost Comparison.

PURPOSE: To compare procedure and fluoroscopy time, technical and clinical success, and costs between single-use and reusable endoscopes in patients undergoing percutaneous biliary endoscopy (PBE) with lithotripsy. MATERIAL AND METHODS: Thirty-four patients (67 procedures) were retrospectively included in the study. The patients were treated with PBE for gallstone removal from October 24, 2014, to February 12, 2020, using reusable (28 procedures) or single-use (39 procedures) endoscopes. The procedure time, fluoroscopy time, technical success rate (accessing the biliary system and locating the gallstone), clinical success rate (at least partial gallstone removal), complication rate, and cost of use were compared between the procedures. RESULTS: The mean (± standard deviation) procedure time was not significantly different between single-use (136 minutes ± 45) and reusable endoscopes (136 minutes ± 51) (P = .47). The mean fluoroscopy time was significantly shorter for single-use endoscopes (11 minutes ± 8.4) than for reusable endoscopes (18 minutes ± 12) (P = .01). When comparing single-use versus reusable endoscopes, the technical success (95% [n = 37] vs 93% [n = 26]) and the clinical success (90% [n = 35] vs 75% [n = 21]) rates were not significantly different (both, P > .05). Only 1 complication was noted in the reusable endoscope group (P = .42). The cost per case was lower for single-use ($1,500) than for reusable ($3,987) endoscope procedures, primarily due to differences in capital costs and repair costs. CONCLUSIONS: Single-use endoscopes offer the potential for lower patient radiation exposure and lower cost per case, which may reduce the financial barriers to offering PBE in interventional radiology practices. The clinical and technical success rates did not differ by endoscope type.

Percutaneous Cholangioscopy for the Diagnosis and Management of Biliary Pathology in Pediatric Patients: A Single-Center Experience.

Transhepatic percutaneous cholangioscopy (PC) can be used for the diagnosis and treatment of biliary pathology. It allows for direct visualization of the biliary system to identify pathologic changes, perform biopsies, and treat biliary obstruction. The effectiveness and safety of PC in adults have been established. However, the data on the use of PC in pediatric patients are limited. In this case series, the outcomes in 4 pediatric patients (3 girls; mean age, 4 [range, 1-8] years) who underwent 6 PC procedures were examined. Three out of the 6 (50%) PC procedures were performed for diagnostic visualization of the biliary tree and/or small intestine, whereas the remaining 3 (50%) were performed for the treatment of biliary obstruction causing chronic cholestasis. The technical and procedural success rate was 100%, and no complications were encountered during or 30 days after the procedure. This study supports the feasibility and safety of PC in pediatric patients for the management of biliary pathology.

Development and Preliminary Validation of the Patient-Reported Outcome Measure for Vascular Malformation Questionnaire: A Prospective Cohort Study.

PURPOSE: To develop and validate the Patient-Reported Outcome Measure for Vascular Malformation (PROVAM) questionnaire to assess the health-related quality of life in patients with vascular malformations. MATERIALS AND METHODS: We developed and validated PROVAM using a mixed methods design during a prospective clinical trial at a vascular anomalies clinic. From July 2019 to February 2020, 108 consecutive patients completed 130 questionnaires. The 30-item instrument assessed the domains of pain, emotional/social well-being, functional impact, and treatment satisfaction. Two additional items assessed ease of understanding and relevance. The primary outcomes of instrument reliability and validity were evaluated across several indices. The secondary outcome of responsiveness evaluated total score changes for patients who completed questionnaires both before and after treatment. RESULTS: Instrument reliability, as measured by Cronbach alpha, was ≥0.79 for pain, emotional/social well-being, and functional impact domains. Primary domain structure was confirmed by factor analysis (P <. 001) and convergent construct validity for all but 1 Likert scale item. In the subgroup analysis of 13 participants who completed PROVAM before and after treatment, instrument responsiveness, as measured by the total score, showed a significant decrease (median, -10 points; interquartile range [IQR], -3 to -16; P = .04). Participants found the questions easy to understand (median, 5 points; IQR, 4-5 on a 5-point scale) and relevant (median score, 4; IQR, 3-5). CONCLUSIONS: Preliminary data support the reliability and validity of PROVAM in measuring the health-related quality of life in patients with vascular malformations.

Qualitative study of patients with venous malformations: symptom experiences and content validity of patient-reported outcome measures.

PURPOSE: To determine important symptoms and functional effects of venous malformations (VMs) to assess the content validity of commonly used patient-reported outcome (PRO) measures for use with VM patients. METHODS: This cross-sectional, qualitative study involved cognitive interviews with participants with VM aged ≥ 14 years. From February to June 2016, 11 participants (8 female) with a mean (± standard deviation) age of 31 ± 15 years were recruited from three clinical sites. The following subgroups were evaluated: 5 adults (aged ≥ 18) with trunk/extremity VMs; 3 adolescents (aged 14-17) with trunk/extremity VMs; and 3 adults with head/neck VMs. We evaluated the content validity of the Worst Pain Numeric Rating Scale (NRS), Patient-Reported Outcomes Measurement Information System (PROMIS®) Pain Interference 8-item short form, and PROMIS Physical Function 8-item short form. RESULTS: The most common participant-reported VM symptoms were swelling (n = 10), skin discoloration (n = 8), acute episodic pain (n = 8), chronic pain (n = 7), numbness (n = 7), and tingling/burning (n = 6). Participants reported that VMs affected their physical function (n = 10), appearance (n = 10), relationships/social activities (n = 7), and emotional health (n = 3). The Worst Pain NRS and PROMIS Pain Interference measures were relevant to all participants' VM experience. Only adults with head/neck VMs found the PROMIS Physical Function measure to be irrelevant. The assessed PRO measures did not address several symptoms commonly reported by VM patients (swelling, skin discoloration, numbness, and appearance). CONCLUSION: These results suggest that several VM symptoms are not assessed fully by commonly used PRO measures, and that the relevance of functional limitation questions may vary by VM location.

Evaluation of a three-session biliary dilation protocol following transplant-related biliary stricture in pediatric patients.

To evaluate whether a serial biliary dilation protocol improves outcomes and decreases total biliary drainage time for biliary strictures following pediatric liver transplantation. From 2006 to 2016, 213 orthotopic deceased and living related liver transplants were performed in 199 patients with a median patient age of 3.1 years at a single pediatric hospital. Patients with biliary strictures were managed by IR or surgically by the transplant team. Patients managed by IR were divided into two groups. The first group was managed with a standardized three-session protocol consisting of dilation every two weeks for three dilations. The second group was managed clinically with varying number and interval of dilations as determined by a multidisciplinary team. The location of biliary stricture, duration of drainage, number of balloon dilations, balloon diameter, time interval between dilations, and success of percutaneous treatment were recorded. Thirty-four patients developed biliary strictures. Thirty-one patients were managed with percutaneous intervention. Three strictures could not be crossed and were converted to operative management. Ten patients were managed in the three-session protocol, and 18 patients were managed in the clinically treated group. There was no significant difference in clinical success rates between groups, 80% and 61%, respectively. The three-session protocol group trended toward a lower total biliary drain indwell time (median 49 days) compared with the clinically treated group (median 89 days), P = .089. Our study suggests that a three-session dilation protocol following transplant-related biliary stricture may decrease total biliary drainage time for some patients.

Propranolol promotes accelerated and dysregulated adipogenesis in hemangioma stem cells.

BACKGROUND: Infantile hemangiomas (IHs) are the most common tumor of infancy, yet there are no Food and Drug Administration-approved therapeutics to date. Recently, the nonselective ß-adrenergic-blocker propranolol has been shown to be a safe and effective means of treating IHs, although its mechanism has yet to be elucidated. We have previously demonstrated that propranolol induces early and incomplete adipogenesis in stem cells derived from hemangiomas. We hypothesize that propranolol promotes dysregulated adipogenesis via the improper regulation of adipogenic genes. METHODS: Hemangioma stem cells (HemSCs) isolated from resected IH specimens were treated with adipogenic medium for 1 or 4 days in either propranolol or vehicle. Cell death was measured by the incorporation of annexin V and propidium iodide by flow cytometry. Adipogenesis was assessed by visualizing lipid droplet formation by Oil Red O staining. Proadipogenic genes C/EBPα, C/EBPß, C/EBPδ, PPARδ, PPARγ, RXRα, and RXRγ were analyzed by quantitative reverse transcription and polymerase chain reaction. RESULTS: Hemangioma stem cells treated with propranolol increased lipid droplet formation compared to vehicle-treated cells indicating increased adipogenesis. Cell death as measured by FACS analysis indicated that the propranolol-treated cells died due to necrosis and not apoptosis. During adipogenesis, transcript levels of PPARδ, PPARγ, C/EBPß, and C/EBPδ were significantly increased (P<0.01) in propranolol-treated cells relative to control cells. In contrast, RXRα and RXRγ levels were significantly decreased (P<0.05), and C/EBPα, a gene required for terminal adipocyte differentiation, was strongly suppressed by propranolol when compared to vehicle-treated cells (P<0.01). CONCLUSIONS: In HemSCs, propranolol accelerated dysregulated adipogenic differentiation characterized by improper adipogenic gene expression. Consistent with accelerated adipogenesis, propranolol significantly increased the expression of the proadipogenic genes, PPARγ, C/EBPß, and C/EBPγ compared to control. However, propranolol treatment also led to improper induction of PPARδ and suppression of C/EBPα, RXRα, and RXRγ. Taken together these data indicate that propranolol promoted dysregulated adipogenesis and inhibited the HemSCs from becoming functional adipocytes, ultimately resulting in cell death. Understanding this mechanism behind propranolol's effectiveness will be a vital factor in producing more effective therapies in the future.

Whole-lesion assessment of volume and signal changes after sclerotherapy of extremity venous malformations.

PURPOSE: To investigate quantitative changes in MRI signal intensity (SI) and lesion volume that indicate treatment response and correlate these changes with clinical outcomes after percutaneous sclerotherapy (PS) of extremity venous malformations (VMs). METHODS: VMs were segmented manually on pre- and post-treatment T2-weighted MRI using 3D Slicer to assess changes in lesion volume and SI. Clinical outcomes were scored on a 7-point Likert scale according to patient perception of symptom improvement; treatment response (success or failure) was determined accordingly. RESULTS: Eighty-one patients with VMs underwent 125 PS sessions. Treatment success occurred in 77 patients (95 %). Mean (±SD) changes were -7.9 ± 24 cm3 in lesion volume and -123 ± 162 in SI (both, P <.001). Mean reduction in lesion volume was greater in the success group (-9.4 ± 24 cm3) than in the failure group (21 ± 20 cm3) (P =.006). Overall, lesion volume correlated with treatment response (ρ = -0.3, P =.004). On subgroup analysis, volume change correlated with clinical outcomes in children (ρ = -0.3, P =.03), in sodium tetradecyl sulfate-treated lesions (ρ = -0.5, P =.02), and in foot lesions (ρ = -0.6, P =.04). SI change correlated with clinical outcomes in VMs treated in 1 PS session (ρ = -0.3, P =.01) and in bleomycin-treated lesions (ρ = -0.4, P =.04). CONCLUSIONS: Change in lesion volume is a reliable indicator of treatment response. Lesion volume and SI correlate with clinical outcomes in specific subgroups.

Clinical Outcomes and Safety Comparison of Vertebroplasty, Balloon Kyphoplasty, and Vertebral Implant for Treatment of Vertebral Compression Fractures.

BACKGROUND AND PURPOSE: Vertebral compression fracture represents a major health burden for the aging populations globally. However, limited studies exist on the relative efficacy and safety of surgical interventions for vertebral compression fracture. Here, we aim to compare clinical and patient-reported outcomes following vertebral augmentation using balloon kyphoplasty, vertebroplasty, and SpineJack vertebral implant. MATERIALS AND METHODS: An institutional review board-approved, retrospective, multi-institutional review of patients undergoing vertebral augmentation with kyphoplasty, vertebroplasty, and/or a SpineJack vertebral implant was performed between 2018 and 2021. Primary outcomes included pre- and postprocedural pain ratings and vertebral body height restoration. The secondary outcome was a change in the local kyphotic angle. The Kruskal-Wallis test was used to compare outcomes across 3 treatment options. Complications were reviewed during and 30-90 days after the procedure. RESULTS: Vertebral augmentation of 344 vertebral compression fracture levels was performed during the study period. Sixty-seven patients had 79 kyphoplasty procedures (55% women; mean age, 64.2 [SD, 12.3] years). Seventy-four patients underwent a mean of 84 vertebroplasty procedures (51% women; mean age, 63.5 [SD, 12.8] years), and 61 patients had a mean of 67 SpineJack vertebral implant procedures (57.4% women; mean age, 68.3 [SD, 10.6] years). Following kyphoplasty, vertebroplasty, and SpineJack vertebral implant, pain scores improved significantly (P < .001). Resting pain improvement was similar across the 3 procedures, whereas improvement of "worst pain" was significantly better following a SpineJack vertebral implant compared with kyphoplasty and vertebroplasty (P < .001). Patients with a SpineJack vertebral implant had greater improvement in vertebral body height restoration and local kyphotic angle compared with those undergoing kyphoplasty and vertebroplasty. Adjacent level fractures (6.7% incidence) occurred similarly in the 3 procedure types. There were no other peri- or postoperative complications. CONCLUSIONS: The SpineJack vertebral implant showed equivalent pain improvement compared with vertebroplasty and kyphoplasty, but it had superior vertebral body height restoration and local kyphotic angle improvement. This study supports the SpineJack vertebral implant as a safe and effective alternative (adjunct) for vertebral augmentation, especially in patients with moderate-to-severe vertebral compression fractures for greater improvement in vertebral body height restoration.

Assessing long-term locoregional control of spinal osseous metastases after microwave ablation.

Osseous metastases to the spine result in significant pain and decreased quality of life. The purpose of this study was to evaluate the long-term efficacy of microwave ablation (MWA) for the treatment of spinal metastases regarding pain reduction and local control of disease progression. In this single center retrospective study, patients with osseous metastases to the spine undergoing MWA with vertebroplasty from 2013 to 2020 were included. Locoregional control of metabolic activity at the treated level was assessed using PET/CT scan both pre- and post-procedure. Pain reduction was measured using change in visual analog scale (VAS) pain score. Forty-eight spinal levels were treated with MWA in 28 patients (57 % male, mean age 68 ± 9 years). Median ablation time, energy, and temperature were 4 min and 13 s, 3.6 kJ, and 80 °C, respectively. Median pre-procedure maximum standard uptake value (SUVmax) was significantly reduced following ablation, from 4.55 (IQR 3.65-6.1) to 0 (IQR 0-1.8; p < 0.001), over an average of 29 ± 14.1 month follow up period. Pre-procedure VAS pain score was reduced from median (IQR) of 8 (6.5-9) to 1(1-2), 2(1-3) and 1(0.5-3) at 24 h, four weeks, and six months post-procedure, respectively (all p < 0.001 with respect to pre-procedure scores). In conclusion, this study supports microwave ablation as an effective technique for pain palliation and long-term locoregional tumor control of oligometastatic spinal disease as assessed by metabolic response.

Estimating Catchment Populations of Global Health Radiology Outreach Using Geographic Information Systems Analysis.

PURPOSE: The purpose of this study was to design, develop, and test geographic information systems (GIS) analytic methods for quantifying and characterizing catchment populations across all sites served by a radiology global health organization. METHODS: The analysis included populations served by 78 low-resource medical facilities in 32 countries partnered with radiology nonprofit organization, RAD-AID International. Three constraints were used to approximate patient catchment areas: (1) 1-hour driving time, (2) 1-hour walking time, and (3) 10-mile circular radius. GIS calculated populations within each constraint using publicly available geospatial input databases, including a global digital elevation model, population and land cover data, and road locations from OpenStreetMap. Demographic and health data from the World Health Organization were incorporated to provide further characteristics of covered populations. RESULTS: The total populations served by all RAD-AID sites as measured by driving time, walking time, and 10-mile radius were 189,241,193 (47.8% female), 26,190,117 (48.7% female), and 110,884,095 (48.1% female), respectively. For individual locations, median population within 1-hour driving time was 1,795,977 (range: 8,742-30,630,800), with an average life expectancy of 68.4 ± 5.8 years. Median child mortality before age 5 was 3.8% (range: 0.9%-8.3%), and median prevalence of human immunodeficiency virus infection was 3.1% (range: 0.7%-10.9%). CONCLUSION: In this study, GIS provided a robust multisite analysis for estimating the potential global population reached by an international radiology outreach organization with targeted individual site measurements. Given heightened needs to accurately characterize global outreach populations, this GIS-based approach may be useful for analysis, outreach planning, and resource allocation among global health organizations.

Catheter-directed venography for evaluating internal jugular vein pseudo-occlusion.

The incidence and effects of stenosis of the cerebral venous system are poorly understood. When noninvasive computed tomography venography (CTV) of the head and neck suggests complete internal jugular vein (IJV) occlusion, invasive catheter-directed venography can discordantly show venous patency. We compared CTV vs digital subtraction venography (DSV) in the evaluation of patency/occlusion in the suspected IJV and contralateral IJV. We queried the venous intervention database of our U.S. academic tertiary-care hospital to identify patients with complete or near-complete IJV occlusion per CTV from March 1, 2019 to March 1, 2020. We included patients with both noninvasive and invasive imaging of the target segment and the contralateral IJV. Four patients had suspected occlusion of the IJV at the skull base. Invasive catheter-directed venography consisted of DSV to assess direction of flow and vessel caliber, as well as manometry proximal and distal to areas of suspected stenosis. DSV showed patency in all 4 IJVs for which CTV had shown suspected occlusions. CTV findings of the contralateral IJVs were patency (n = 2), moderate stenosis (n = 1), and severe/critical stenosis (n = 1). Contralateral IJV caliber, measured by DSV, was concordant with CTV findings. Median mean-pressure gradients across the apparent occlusion and contralateral segments were 1 (range, 1-4) mmHg and 0 (range, 0-5) mmHg, respectively. Although noninvasive CTV may suggest absence of or attenuated flow within the IJV, this technique may be insufficient to establish complete occlusion. Catheter-directed venography can be used to evaluate patency, vessel caliber, and mean-pressure gradient.

Thinking ahead: gallbladder intussusception following transperitoneal percutaneous cholecystostomy tube placement.

Percutaneous cholecystostomy (PC) is a common minimally invasive, image-guided procedure performed primarily on high-risk patients with acute cholecystitis for gallbladder decompression. Herein, we present a case of a patient undergoing PC placement using a transperitoneal approach. On subsequent upsizing attempts, the gallbladder fundus was found to invaginate during advancement of replacement drains, causing gallbladder intussusception. The use of a balloon and locked pigtail catheter were required to reposition the gallbladder to proper position. The patient's planned percutaneous cholecystoscopy was delayed by 4 weeks until intended upsizing could be performed. This case demonstrates the advantage of achieving transhepatic gallbladder access to support tract formation and limit procedural complications.

Strategic Radiology Outreach Planning for Underserved Populations Using Geographic Information Systems.

PURPOSE: Geographic information systems (GIS) are widely used in public health research but rarely used in radiology research. GIS can be an impactful tool in radiology global health to locate medically underserved populations and poor transportation infrastructure, characterize medical needs, and design outreach programs. Using the example of aircraft-based outreach in Alaska, we demonstrate the utility of GIS in radiological program planning for global health. METHODS: Multicriteria GIS evaluations were performed to create a health severity index, using life expectancy and percentage uninsured data, and an accessibility severity index, using distance from roads and health centers or hospitals. These indices were combined with population density to create a final health access severity index (HASI). A map presenting suitable hybrid airship operating areas was produced using land cover data. Alaskan health care facilities were georeferenced to create a coordinate data set. Infrastructure was obtained from OpenStreetMap. Health data were accessed from the 2017 American Community Survey and CDC US Small-area Life Expectancy Estimates Project. RESULTS: GIS analyzed 738,050 Alaskans. The health severity index identified decreased health outcomes (high or very high severity) in 285,446 (39%) Alaskans, and the accessibility severity index determined decreased access to care in 218,201 (30%). Combined, the HASI established 165,108 (22%) Alaskans as underserved with high or very high overall severity. Thirty-nine percent of Alaska land area is suitable for hybrid airship operations, including 27% of HASI high and very high severity areas. CONCLUSIONS: GIS identified underserved populations for mobile radiology outreach in Alaska and may be useful for global health outreach planning and resource allocation.

Propranolol Therapy in Infantile Hemangioma: It Is Not Just About the Beta.

BACKGROUND: Propranolol, a nonselective ß-adrenergic receptor antagonist, is approved by the U.S. Food and Drug Administration to treat problematic infantile hemangiomas, but a subset of patients experience treatment complications. Parents wary of long-term use and side effects consult plastic surgeons on surgical options or as a second opinion. Understanding the mechanism(s) of action of propranolol will allow plastic surgeons to better inform parents. METHODS: A systemic literature search was performed to query published translational and basic science studies on propranolol effects on infantile hemangiomas and cells derived from these lesions. RESULTS: In experimental studies, propranolol was antiproliferative and cytotoxic against hemangioma endothelial and stem cells and affected infantile hemangioma perivascular cell contractility. Propranolol inhibited migration, network formation, vascular endothelial growth factor A production, and vascular endothelial growth factor receptor 2 activation and down-regulated PI3K/AKT and mitogen-activated protein kinase signaling in hemangioma endothelial cells, but it increased ERK1/2 activity in hemangioma stem cells. At effective clinical doses, measured propranolol plasma concentration is 100 times higher than necessary for complete ß-adrenergic receptor blockade, yet was 10 to 100 times less than required to induce hemangioma stem cell death. CONCLUSIONS: Propranolol targets multiple cell types in infantile hemangiomas by means of ß-adrenergic receptor-dependent and -independent mechanisms. Plasma concentration played a significant role. At clinically relevant doses, incomplete infantile hemangioma suppression may explain the rebound phenomenon and worsening ulceration, and propranolol off target effects may lead to commonly reported adverse effects, such as sleep and gastrointestinal disturbances. Propranolol limitations and complications underscore the importance of surgical treatment options in cases of rebound and severe adverse effects. Surgical intervention remains an important treatment choice when parents are hesitant to use propranolol.