A Novel Macroglossia Severity Index for Beckwith-Wiedemann Syndrome.

OBJECTIVE/ SUMMARY BACKGROUND DATA: We propose the first classification scheme for macroglossia in patients with Beckwith-Wiedemann Syndrome (BWS), the BWS Index of macroGlossia (BIG). METHODS: Patients with molecularly confirmed BWS seen from 2004-2023 were included to develop this system. Relationships among BIG scores, tongue reduction surgery, BWS clinical score, percent mosaicism, and polysomnography findings were examined. RESULTS: Patients were classified from BIG0 to BIG3. BIG0 includes those without macroglossia; BIG1 includes those with macroglossia not protruding beyond the teeth/alveolus; BIG2 includes those with tongue protrusion past the teeth/alveolus to the lips but that can be contained within the mouth; and BIG3 includes those with tongues that protrude beyond the teeth/alveolus and lips but that cannot be closed within the mouth. Of the 459 patients with molecularly confirmed BWS, 266 (58.0%) patients were scored. One hundred and eleven (41.7%) were BIG0, 44 (16.5%) were BIG1, 90 (33.8%) were BIG2, and 21 (7.9%) were BIG3. As scores increased, patients had an increased incidence of tongue reduction surgery (BIG0: 0% versus BIG1: 20.5% versus BIG2: 51.1% versus BIG3: 100%; r=0.66, P <0.01). Higher BIG scores were associated with elevated BWS clinical scores (r=0.68, P <0.01) and increased tissue mosaicism (r=0.50, P <0.01) as well as trends towards worse obstructive apnea-hypopnea indices (r=0.29, P =0.02) and lower SpO 2 nadirs (r=-0.29, P =0.02). CONCLUSION: In this large series of patients with Beckwith-Wiedemann Syndrome, increased BIG score correlates with undergoing tongue reduction surgery and increased phenotypic severity. Adoption of the BIG scoring system may facilitate communication and risk stratification across institutions.

Trends in Blood Mosaicism and Clinical Phenotype Score in Patients with Beckwith-Wiedemann Syndrome Evaluated for Tongue Reduction Surgery.

INTRODUCTION: Most patients with Beckwith-Wiedemann syndrome (BWS) have macroglossia with some requiring tongue reduction surgery (TRS). This study reports correlations between levels of affected cells (mosaicism) and BWS clinical score in patients evaluated for TRS. We also show correlations of clinical score and mosaicism with obstructive sleep apnea (OSA) severity. METHODS: Blood mosaicism levels and BWS clinical score were recorded in patients with macroglossia referred to plastic surgery for evaluation. Associations among blood mosaicism, BWS clinical score, TRS, and OSA were assessed with appropriate statistics. RESULTS: Of the 225 patients included, BWS blood testing was available in 128 (56.9%). Mosaicism levels were higher in those who underwent TRS compared to those who did not (85.9 85.9 (56.5-95.9)% vs. 29.7 (2.8-73.1)%, p<0.001). BWS clinical score was also higher in those requiring TRS (9.0 (8.0-11.0) versus 7.0 (6.0-9.0), p<0.001). There was a positive correlation between clinical score and obstructive apnea-hypopnea index (r=0.320, p=0.011). Receiver operating characteristic curve analysis showed a clinical score ≥11 had 100% specificity and 36.4% sensitivity for detecting patients requiring TRS. Blood mosaicism ≥80% had 63.6% sensitivity and 83.6% specificity for predicting surgery. A combined criteria of BWS clinical score ≥11 or mosaicism ≥80% had 72.7% sensitivity and 83.6% specificity for predicting TRS. CONCLUSION: Blood mosaicism levels and higher BWS clinical scores appear associated with a greater frequency of having surgery in patients with macroglossia referred for surgical evaluation. Elevations in BWS clinical scoring are associated with increased OSA severity while increased blood mosaicism is not.

Genetic variant classification by predicted protein structure: A case study on IRF6.

Next-generation genome sequencing has revolutionized genetic testing, identifying numerous rare disease-associated gene variants. However, to impute pathogenicity, computational approaches remain inadequate and functional testing of gene variant is required to provide the highest level of evidence. The emergence of AlphaFold2 has transformed the field of protein structure determination, and here we outline a strategy that leverages predicted protein structure to enhance genetic variant classification. We used the gene IRF6 as a case study due to its clinical relevance, its critical role in cleft lip/palate malformation, and the availability of experimental data on the pathogenicity of IRF6 gene variants through phenotype rescue experiments in irf6-/- zebrafish. We compared results from over 30 pathogenicity prediction tools on 37 IRF6 missense variants. IRF6 lacks an experimentally derived structure, so we used predicted structures to explore associations between mutational clustering and pathogenicity. We found that among these variants, 19 of 37 were unanimously predicted as deleterious by computational tools. Comparing in silico predictions with experimental findings, 12 variants predicted as pathogenic were experimentally determined as benign. Even with the recently published AlphaMissense model, 15/18 (83%) of the predicted pathogenic variants were experimentally determined as benign. In comparison, mapping variants to the protein revealed deleterious mutation clusters around the protein binding domain, whereas N-terminal variants tend to be benign, suggesting the importance of structural information in determining pathogenicity of mutations in this gene. In conclusion, incorporating gene-specific structural features of known pathogenic/benign mutations may provide meaningful insights into pathogenicity predictions in a gene-specific manner and facilitate the interpretation of variant pathogenicity.

A Decade of Nipple-Sparing Mastectomy: Lessons Learned in 3035 Immediate Implant-Based Breast Reconstructions.

BACKGROUND: Nipple-sparing mastectomy is commonly performed for breast cancer treatment or prevention. The authors present one of the largest breast reconstruction series in the literature. METHODS: A single-institution retrospective review was conducted from 2007 to 2019. RESULTS: The authors' query identified 3035 implant-based breast reconstructions after nipple-sparing mastectomy, including 2043 direct-to-implant and 992 tissue expander-to-implant reconstructions. The overall major complication rate was 9.15%, and the nipple necrosis rate was 1.20%. Therapeutic mastectomy was associated with higher overall complications and explantations compared with prophylactic mastectomy ( P < 0.01). In comparisons of unilateral and bilateral procedures, bilateral mastectomy had an increased risk for complications (OR, 1.46; 95% CI, 0.997 to 2.145; P = 0.05). Tissue-expander reconstructions had higher rates of nipple necrosis (1.9% versus 0.88%; P = 0.015), infection (4.2% versus 2.8%; P = 0.04), and explantation (5.1% versus 3.5%; P = 0.04) compared with direct-to-implant reconstruction. When assessing plane of reconstruction, the authors found similar rates of complications between subpectoral dual-plane and prepectoral reconstruction. There was no difference in complications between reconstruction with acellular dermal matrix or mesh compared with total or partial muscle coverage without acellular dermal matrix/mesh (OR, 0.749; 95% CI, 0.404 to 1.391; P = 0.361). Multivariable regression analysis revealed preoperative radiotherapy (OR, 2.465; 95% CI, 1.579 to 3.848; P < 0.001), smoking (OR, 2.53; 95% CI, 1.581 to 4.054; P < 0.001), and a periareolar incision (OR, 3.657; 95% CI, 2.276 to 5.875; P < 0.001) to be the strongest predictors of complications and nipple necrosis ( P < 0.05). CONCLUSIONS: Nipple-sparing mastectomy and immediate breast reconstruction has a low rate of complications. In this series, radiation therapy, smoking, and incision choice predicted overall complications and nipple necrosis, whereas direct-to-implant reconstruction and acellular dermal matrix or mesh did not increase risk. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

dact1/2 modifies noncanonical Wnt signaling and calpain 8 expression to regulate convergent extension and craniofacial development.

Wnt signaling plays a crucial role in the early embryonic patterning and development, to regulate convergent extension during gastrulation and the establishment of the dorsal axis. Further, Wnt signaling is a crucial regulator of craniofacial morphogenesis. The adapter proteins Dact1 and Dact2 modulate the Wnt signaling pathway through binding to Disheveled, however, the distinct relative functions of Dact1 and Dact2 during embryogenesis remain unclear. We found that dact1 and dact2 genes have dynamic spatiotemporal expression domains that are reciprocal to one another and to wnt11f2l, that suggest distinct functions during zebrafish embryogenesis. We found that both dact1 and dact2 contribute to axis extension, with compound mutants exhibiting a similar convergent extension defect and craniofacial phenotype to the wnt11f2 mutant. Utilizing single-cell RNAseq and gpc4 mutant that disrupts noncanonical Wnt signaling, we identified dact1/2 specific roles during early development. Comparative whole transcriptome analysis between wildtype, gpc4 and dact1/2 mutants revealed a novel role for dact1/2 in regulating the mRNA expression of the classical calpain capn8. Over-expression of capn8 phenocopies dact1/2 craniofacial dysmorphology. These results identify a previously unappreciated role of capn8 and calcium-dependent proteolysis during embryogenesis. Taken together, our findings highlight the distinct and overlapping roles of dact1 and dact2 in embryonic craniofacial development, providing new insights into the multifaceted regulation of Wnt signaling.

(Epi)genotype and Timing of Tongue Reduction Predict Safety and Long-Term Outcomes in Beckwith-Wiedemann Syndrome.

INTRODUCTION: Macroglossia is a cardinal feature of Beckwith-Wiedemann syndrome (BWS) with a clinical spectrum where the indication and timing for surgery remain to be validated. This study leverages a cohort of molecularly characterized patients with BWS to correlate epigenetic diagnosis with phenotype and treatment outcome. METHODS: Patients with BWS seen in consultation for macroglossia from 2009-2022 were reviewed for phenotype, molecular diagnosis, tongue reduction status, timing of surgery (early = under 12 months), and perioperative complications. RESULTS: Two hundred thirty-seven patients were included. Imprinting control region 2 loss of methylation (IC2 LOM) was the most common epigenotype (61%). Paternal uniparental isodisomy for chromosome 11 (pUPD11) comprised a larger proportion of patients undergoing tongue reduction (18%) than those not undergoing surgery (8%, p = 0.024) and was associated with need for repeat surgery (OR 4.49, 95% CI 1.06-18.98, p = 0.041). Complications including wound dehiscence, ventilator associated pneumonia, and unplanned extubation were more common in patients undergoing early surgery (20%) than late surgery (4%, OR 5.70, 95% CI 1.14-28.55, p = 0.034). CONCLUSIONS: This study presents one of the largest cohorts correlating molecular diagnosis with clinical course of macroglossia treatment in BWS. Macroglossia in patients with pUPD11 is associated with higher rates of reoperation. Relief of obstructive sleep apnea with early tongue reduction must be weighed against risk of perioperative complications, most of which are non-surgical. This study highlights how molecular diagnosis advances clinical care by risk stratifying clinical outcomes in a center providing integrated multidisciplinary care for the BWS population.

Associations between the timing of tongue reduction surgery, (Epi)genotype, and dentoskeletal development in patients with Beckwith-Wiedemann syndrome.

Tongue reduction surgery is often pursued to manage the adverse effects of macroglossia in patients with Beckwith-Wiedemann syndrome (BWS). This study characterized dental outcomes in patients with BWS based on surgical timing and molecular diagnosis. A retrospective study was designed to include patients with BWS over the age of two who had clinical or radiographic documentation of dental development. Patients were grouped by history of tongue reduction surgery and surgical timing (early: <12 months). One hundred three patients were included (55 no tongue reduction, 18 early, 30 late). Patients who underwent late surgery had lower odds of class I occlusion (OR 0.11, 95% CI 0.02-0.58, p = 0.009) and higher odds of anterior open bite (OR 7.5, 95% CI 1.14-49.4, p = 0.036). Patients with clinical diagnoses and negative molecular testing had anterior open bite less frequently than patients with imprinting center 2 loss of methylation and paternal uniparental isodisomy of 11p15.5 (p = 0.009). Compared to reference values, patients who had tongue reductions had an increased mandibular plane angle (32.0 ± 4.5° versus 36.9 ± 5.0°, p = 0.001), indicative of hyperdivergent growth. The results of this study help to understand the complex nature of dentoskeletal growth in BWS and shed insight on how surgical timing and molecular diagnosis influence prognosis.

Kaban-Pruzansky Grade Predicts Airway Severity in Hemifacial Microsomia.

BACKGROUND: Children born with hemifacial microsomia (HFM) can suffer from airway compromise. There is a paucity of data correlating degree of HFM severity with airway difficulty. This study aims to determine the relationship between degree of micrognathia and airway insufficiency in the HFM population. METHODS: Patient demographics, airway function, Kaban-Pruzansky (KP) grade, and Cormack Lehane (CL) grade were collected and compared with appropriate statistics for HFM patients treated between 2000 and 2022. RESULTS: Seventy patients underwent 365 operations with KP grading as follows: 34% I, 23% IIA, 11% IIB, and 33% grade III. Goldenhar syndrome was present in 40% of patients and 16% had bilateral disease. KP grade (p<0.001) predicted mean number of airway-affecting procedures undergone and difficult airway status (p<0.001), with 75% of difficult airways in KP III patients. There was no association of airway compromise with Goldenhar syndrome, laterality, or age (p>0.05). Most CL grades were I (61%) or IIA (13%), with fewer IIB, III, and IV (4-7%). KP grade predicted CL grade (p<0.001), with 71% of grade IV views and 64% of grade III views seen in KP III patients. CONCLUSIONS: Kaban-Pruzansky grade correlated with airway severity in HFM. Patients do not appear to outgrow their CL grade, as previously hypothesized, suggesting that KP III patients remain at increased risk for airway insufficiency into the teen years. Given the potential significant morbidity associated with airway compromise, proper identification and preparation for challenging airway is a critical part of caring for patients with HFM.

Nasal Construction in Congenital Arhinia Due to Novel SMCHD1 Gene Variant.

Arhinia, or congenital absence of the nose, is an exceedingly rare anomaly caused by pathogenic variants in the gene SMCHD1 . Arhinia exhibits unique reconstructive challenges, as the midface is deficient in skeletal and soft tissue structures. The authors present 2 related patients with arhinia who harbor a novel SMCHD1 gene variant and illustrate their surgical midface and nasal construction. Targeted sequencing was carried out on DNA samples from the 2 affected patients, 1 anosmic and 1 healthy parent, to identify variants in exons 3 to 13 of SMCHD1 . The affected patients and anosmic parent were found to have a novel SMCHD1 gene variant p.E473V. A staged surgical approach was applied. First, both patients underwent a LeFort II osteotomy and distraction osteogenesis to improve the projection of the midfacial segment, followed by tissue expansion of the forehead, and nasal construction with a forehead flap that was placed over a costochondral framework derived from rib cartilage. The novel gene variant could guide future investigations on genetic pathways and molecular processes that underly the physiological and pathologic development of the nose. Further investigations on the variable expressivity ranging from anosmia to arhinia could improve clinical genetic screens for risk stratification of individuals with anosmia on passing on arhinia to their children. Due to the exceptional rarity and complexity of congenital arhinia, most surgical approaches are developed on a single-case basis. This case series, albeit limited to 2 cases, is the largest pedigree of such cases in the literature. It highlights key principles of a staged approach to nasal construction in arhinia and discusses nuances and improvements learned between both patients. It subsequently offers an optimized guide to this surgical strategy.

The Timing of Acute and Late Complications Following Mastectomy and Implant-based Reconstruction.

BACKGROUND/OBJECTIVE: Implant-based breast reconstruction is a common plastic surgery procedure with well-documented clinical outcomes. Despite this, the natural history and timing of key complication endpoints are not well described. The goal of this study is to determine when patients are most likely to experience specific adverse events after implant-based reconstruction. METHODS: Retrospective consecutive series of patients who received mastectomy and implant-based reconstruction over a 6-year period were included. Complications and unfavorable outcomes including hematoma, seroma, wound infection, skin flap necrosis, capsular contracture, implant rippling, and implant loss were identified. A time-to-event analysis was performed and Cox regression models identified patient and treatment characteristics associated with each outcome. RESULTS: Of 1473 patients and 2434 total reconstructed breasts, 785 complications/unfavorable outcomes were identified. The 12-month cumulative incidence of hematoma was 1.4%, seroma: 4.3%, infection: 3.2%, skin flap necrosis: 3.9%, capsular contracture: 5.7%, implant rippling: 7.1%, and implant loss: 3.9%. In the analysis, 332/785 (42.3%) complications occurred within 60 days of surgery; 94% of hematomas, 85% of skin necrosis events, and 75% of seromas occurred during this period. Half of all infections and implant losses also occurred within 60 days. Of the remaining complications, 94% of capsular contractures and 93% of implant rippling occurred >60 days from surgery. CONCLUSIONS: Complications following mastectomy and implant-based reconstruction exhibit a discrete temporal distribution. These data represent the first comprehensive study of the timing of adverse events following implant-based reconstruction. These findings are immediately useful to guide postoperative care, follow-up, and clinical trial design.

Cost analysis of pre-pectoral implant-based breast reconstruction.

With improvement in mastectomy skin flap viability and increasing recognition of animation deformity following sub-pectoral implant placement, there has been a transition toward pre-pectoral breast reconstruction. While studies have explored the cost effectiveness of implant-based breast reconstruction, few investigations have evaluated cost with respect to pre-pectoral versus sub-pectoral breast reconstruction. A retrospective review of 548 patients who underwent mastectomy and implant-based breast reconstruction was performed from 2017 to 2020. The demographic and surgical characteristics of the pre-pectoral and sub-pectoral cohorts were well matched, except for reconstructive staging, as patients who underwent pre-pectoral reconstruction were more likely to undergo single-stage instead of two-stage reconstruction. Comparison of institutional cost ratios by reconstructive technique revealed that the sub-pectoral approach was more costly (1.70 ± 0.44 vs 1.58 ± 0.31, p < 0.01). However, further stratification by laterality and reconstructive staging failed to demonstrate difference in cost by reconstructive technique. These results were confirmed by multivariable linear regression, which did not reveal reconstructive technique to be an independent variable for cost. This study suggests that pre-pectoral breast reconstruction is a cost-effective alternative to sub-pectoral breast reconstruction and may confer cost benefit, as it is more strongly associated with direct-to-implant breast reconstruction.

One-Year Experience of Same-Day Mastectomy and Breast Reconstruction Protocol.

BACKGROUND: The prevalence of same-day mastectomy with reconstruction has continued to increase across the United States in recent years. Prior studies have shown that same-day mastectomy with reconstruction leads to increased patient satisfaction and allows hospitals to use resources better. This study sought to evaluate the implementation of same-day mastectomy with a reconstruction recovery protocol for patients undergoing mastectomy at our institution. METHODS: Under an institutional review board-approved protocol, a retrospective cohort analysis compared patients who underwent mastectomy April 2016 through April 2017 with those who had mastectomy March 2020 through March 2021. Length of stay, postoperative intravenous (IV) opioid administration, safety end points, and cost were the main variables examined. RESULTS: The study compared 457 patients in 2016-2017 with 428 patients in 2020-2021. The median hospital length of stay decreased from 24.6 h in 2016-2017 to 5.5 h in 2020-2021 (p < 0.001). The percentage of patients requiring postoperative IV opioids decreased from 69.1 % in 2016-2017 to 50 % in 2020-2021 (p < 0.001). The rates of unplanned readmissions within 30 days after mastectomy did not differ between the two groups, with a rate of 3.7 % in 2016-2017 and a rate of 5.1 % in 2020-2021 (p = 0.30). Reducing the rate of overnight admissions after mastectomy by 65.8 % resulted in a cost reduction of 65.8 %. CONCLUSIONS: Implementation of same-day mastectomy with a reconstruction protocol across a large academic center and two satellite sites was a safe alternative to conventional mastectomy recovery plans.

Zebrafish models of alx-linked frontonasal dysplasia reveal a role for Alx1 and Alx3 in the anterior segment and vasculature of the developing eye.

The cellular and genetic mechanisms that coordinate formation of facial sensory structures with surrounding skeletal and soft tissue elements remain poorly understood. Alx1, a homeobox transcription factor, is a key regulator of midfacial morphogenesis. ALX1 mutations in humans are linked to severe congenital anomalies of the facial skeleton (frontonasal dysplasia, FND) with malformation or absence of eyes and orbital contents (micro- and anophthalmia). Zebrafish with loss-of-function alx1 mutations develop with craniofacial and ocular defects of variable penetrance, likely due to compensatory upregulation in expression of a paralogous gene, alx3. Here we show that zebrafish alx1;alx3 mutants develop with highly penetrant cranial and ocular defects that resemble human ALX1-linked FND. alx1 and alx3 are expressed in anterior cranial neural crest (aCNC), which gives rise to the anterior neurocranium (ANC), anterior segment structures of the eye and vascular pericytes. Consistent with a functional requirement for alx genes in aCNC, alx1; alx3 mutants develop with nearly absent ANC and grossly aberrant hyaloid vasculature and ocular anterior segment, but normal retina. In vivo lineage labeling identified a requirement for alx1 and alx3 during aCNC migration, and transcriptomic analysis suggested oxidative stress response as a key target mechanism of this function. Oxidative stress is a hallmark of fetal alcohol toxicity, and we found increased penetrance of facial and ocular malformations in alx1 mutants exposed to ethanol, consistent with a protective role for alx1 against ethanol toxicity. Collectively, these data demonstrate a conserved role for zebrafish alx genes in controlling ocular and facial development, and a novel role in protecting these key midfacial structures from ethanol toxicity during embryogenesis. These data also reveal novel roles for alx genes in ocular anterior segment formation and vascular development and suggest that retinal deficits in alx mutants may be secondary to aberrant ocular vascularization and anterior segment defects. This study establishes robust zebrafish models for interrogating conserved genetic mechanisms that coordinate facial and ocular development, and for exploring gene--environment interactions relevant to fetal alcohol syndrome.

The safety of performing breast reconstruction during the COVID-19 pandemic.

PURPOSE: Elective operations including surgeries for breast cancer were significantly reduced during the height of the surge of COVID-19 cases in Massachusetts. The safety of performing breast reconstruction during the pandemic was unknown. This study aims to review the safety of performing mastectomy with immediate breast reconstruction during the first COVID-19 surge in Massachusetts. METHODS: A retrospective chart review of patients who underwent mastectomy with immediate breast reconstruction by Massachusetts General Hospital breast and plastic surgeons immediately preceding and during the COVID-19 pandemic was performed. RESULTS: Thirty patients (34 breasts) underwent mastectomies with immediate breast reconstruction during the COVID-19 restriction period in Massachusetts. Most reconstructions were unilateral. All reconstructions were performed with implants or expanders, and no autologous reconstructions were performed. Two patients (2 breasts) had operative complications. The complication rate during the pandemic was similar to the complication rate pre-pandemic. No patients or surgeons experienced symptoms or positive COVID-19 tests. Over 90% of patients were discharged the same day. CONCLUSION: Prosthetic breast reconstruction was able to be performed safely during the height of the COVID-19 pandemic surge in Massachusetts. Strict screening protocols, proper use of personal protective equipment, and same-day discharge when possible are essential for patient and surgeon safety during the pandemic.

Target coverage and cardiopulmonary sparing with the updated ESTRO-ACROP contouring guidelines for postmastectomy radiation therapy after breast reconstruction: a treatment planning study using VMAT and proton PBS techniques.

BACKGROUND: The European Society for Therapeutic Radiology and Oncology Advisory Committee in Radiation Oncology Practice (ESTRO-ACROP) recently released new contouring guidelines for postmastectomy radiation therapy (PMRT) after implant-based reconstruction (IBR). As compared to prior ESTRO guidelines, the new guidelines primarily redefined the chest wall (CW) target to exclude the breast prosthesis. In this study, we assessed the impact of these changes on treatment planning and dosimetric outcomes using volumetric-modulated arc therapy (VMAT) and proton pencil-beam scanning (PBS) therapy. METHODS: We performed a treatment planning study of 10 women with left-sided breast cancer who underwent PMRT after IBR. All target structures were delineated first using standard (ESTRO) breast contouring guidelines and then separately using the new (ESTRO-ACROP) guidelines. Standard organs-at-risk (OARs) and cardiac substructures were contoured. Four sets of plans were generated: (1) VMAT using standard ESTRO contours, (2) VMAT using new ESTRO-ACROP contours, (3) PBS using standard contours, and (4) PBS using new contours. RESULTS: VMAT plans using the new ESTRO-ACROP guidelines resulted in modest sparing of the left anterior descending coronary artery (LAD) (mean dose: 6.99 Gy standard ESTRO vs. 6.08 Gy new ESTRO-ACROP, p = 0.010) and ipsilateral lung (V20: 21.66% vs 19.45%, p = 0.017), but similar exposure to the heart (mean dose: 4.6 Gy vs. 4.3 Gy, p = 0.513), with a trend toward higher contralateral lung (V5: 31.0% vs 35.3%, p = 0.331) and CW doses (V5: 31.9% vs 35.4%, p = 0.599). PBS plans using the new guidelines resulted in further sparing of the heart (mean dose: 1.05 Gy(RBE) vs. 0.54 Gy(RBE), p < 0.001), nearly all cardiac substructures (LAD mean dose: 2.01 Gy(RBE) vs. 0.66 Gy(RBE), p < 0.001), and ipsilateral lung (V20: 16.22% vs 6.02%, p < 0.001). CONCLUSIONS: PMRT after IBR using the new ESTRO-ACROP contouring guidelines with both VMAT and PBS therapy is associated with significant changes in exposure to several cardiopulmonary structures.